Patent application title: USE OF MARKERS IN THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER
Inventors:
Niven Rajin Narain (Cambridge, MA, US)
Niven Rajin Narain (Cambridge, MA, US)
Rangaprasad Sarangarajan (Boylston, MA, US)
Rangaprasad Sarangarajan (Boylston, MA, US)
Vivek K. Vishnudas (Newton, MA, US)
IPC8 Class: AG01N3368FI
USPC Class:
506 9
Class name: Combinatorial chemistry technology: method, library, apparatus method of screening a library by measuring the ability to specifically bind a target molecule (e.g., antibody-antigen binding, receptor-ligand binding, etc.)
Publication date: 2014-02-06
Patent application number: 20140038838
Abstract:
The invention provides method for diagnosis, monitoring, and prognosis of
prostate cancer using one or more of keratin 4, keratin 7, keratin 8,
keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, and LY9,
and PSA. The invention provides kits for practicing the methods of the
invention.Claims:
1. A method for diagnosing an abnormal prostate state in a subject
comprising: (1) determining a level of one or more prostate cancer
related markers selected from the group consisting of filamin B, LY9,
keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and
tubulin-beta 3 in a biological sample from the subject; and (2) comparing
the level of the one or more prostate cancer related markers in the
biological sample with the level of the one or more prostate cancer
related markers in a normal control sample, wherein an altered level of
the one or more prostate cancer related markers in the biological sample
relative to the normal control sample is indicative of an abnormal
prostate state in the subject.
2. The method of claim 1, wherein the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19.
3. The method of claim 1, wherein an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of an abnormal prostate state in the subject.
4. The method of claim 1, wherein no increase in the detected level of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of a normal prostate state in the subject.
5. The method of claim 1, further comprising detecting the level of prostate specific antigen (PSA) in the biological sample.
6. The method of claim 5, further comprising comparing the level of PSA in the biological sample to the level of PSA in a normal control sample.
7. The method of claim 6, wherein an increase in the level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample relative to the level of PSA in the normal control sample is indicative of an abnormal prostate state in the subject.
8. The method of claim 7, wherein no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of a normal prostate state in the subject.
9. The method of claim 2, wherein the one or more prostate cancer markers selected from the group consisting of filamin B, LY9 and keratin 19 is: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
10. The method of claim 1, wherein the abnormal prostate state is prostate cancer.
11-15. (canceled)
16. A method for identifying a subject as being at increased risk for developing prostate cancer, the method comprising: (1) determining a level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a biological sample from the subject; and (2) comparing the level of the one or more prostate cancer related markers in the biological sample with the level of the one or more prostate cancer related markers in a normal control sample, wherein an altered level of the one or more prostate cancer related markers in the biological sample relative to the normal control sample is indicative of an increased risk for developing prostate cancer in the subject.
17. The method of claim 16, wherein the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19.
18-37. (canceled)
38. A method for monitoring prostate cancer in a subject, the method comprising (1) determining a level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a first biological sample obtained at a first time from a subject having prostate cancer; (2) determining a level of expression of the one or more prostate cancer related markers in a second biological sample obtained from the subject at a second time, wherein the second time is later than the first time; and (3) comparing the level of the one or more prostate cancer related markers in the second sample with the level of the one or more prostate cancer related markers in the first sample, wherein a change in the level of the one or more prostate cancer related markers in the second sample as compared to the first sample is indicative of a change in prostate cancer status in the subject.
39. The method of claim 38, wherein the subject is actively treated for prostate cancer prior to obtaining the second sample.
40. The method of claim 38, wherein the subject is not actively treated for prostate cancer prior to obtaining the second sample.
41. The method of claim 38, wherein the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19.
42. The method of claim 38, wherein an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of progression of the prostate cancer in the subject.
43. The method of claim 38, wherein no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of non-progression of the prostate cancer in the subject.
44. The method of claim 38, further comprising determining the level of prostate specific antigen (PSA) in the first biological sample and the second biological sample.
45. The method of claim 44, further comprising comparing the level of PSA in the second biological sample to the level of PSA in the first biological sample.
46-61. (canceled)
62. A method for detecting a set of prostate cancer related markers, the method comprising: (1) analyzing a biological sample from a subject for a level of two or more prostate cancer related markers of a set of prostate cancer related markers, wherein the set of prostate cancer related markers comprises filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3; (2) detecting each of the two or more prostate specific makers in the biological sample, thereby detecting the set of prostate cancer related biomarkers.
63. The method of claim 62, wherein the set of prostate cancer related markers comprises filamin B, LY9, and keratin 19.
64. The method of claim 63, wherein the two or more prostate cancer related markers of the set of prostate cancer related markers is: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
65. The method of claim 62, wherein the set of prostate cancer related markers comprises keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3.
66. The method of claim 62, wherein the set of prostate cancer related markers comprises keratin 7, keratin 8, and keratin 15.
67. The method of claim 62, wherein the set of prostate cancer related markers comprises keratin 7 and keratin 15.
68-75. (canceled)
76. A panel of reagents for use in a detection method, the panel comprising at least two detection reagents, wherein each detection reagent is specific for the detection of at least one prostate cancer related marker of a set of prostate cancer related markers, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3 and PSA.
77. The panel of claim 76, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19.
78. The panel of claim 77, wherein the two or more prostate cancer related markers is: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
79. The panel of claim 76, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3.
80. The panel of claim 76, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 7, keratin 8, and keratin 15.
81. The panel of claim 76, wherein the set of prostate cancer specific markers comprises keratin 7 and keratin 15.
82. The panel of claim 76, wherein the set of prostate cancer specific markers further comprises PSA.
83. The panel of claim 82, wherein the panel of reagents comprises a detection reagent specific for the detection of PSA.
84. (canceled)
85. A kit for the diagnosis, monitoring, or characterization of an abnormal prostate state, comprising: at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9.
86. The kit of claim 85, wherein the kit further comprises instructions for the diagnosis, monitoring, or characterization of an abnormal prostate state based on the level of the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 detected.
87. The kit of claim 85, wherein the kit further comprises instructions to detect the level of PSA in a sample in which the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected.
88. The kit of claim 85, further comprising at least one reagent specific for the detection of a level of PSA.
89. A kit comprising at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, and LY9 and at least one reagent specific for the detection of a level of PSA.
Description:
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Ser. No. 61/665,201, filed Jun. 27, 2012; U.S. Provisional Application Ser. No. 61/672,090, filed Jul. 16, 2012; U.S. Provisional Application Ser. No. 61/673,094, filed Jul. 18, 2012; U.S. Provisional Application Ser. No. 61/702,523, filed Sep. 18, 2012, and U.S. Provisional Application Ser. Nos. 61/718,064, 61/718,080, and 61/718,081 all filed on Oct. 24, 2012. Each of the applications is incorporated herein by reference in its entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 25, 2013, is named 119992-06604_SL.txt and is 461,537 bytes in size.
FIELD OF THE INVENTION
[0003] The invention relates to treatment, prevention, reduction, diagnosis, monitoring, and prognosis of abnormal prostate states, including benign prostate hyperplasia and oncological disorders, especially prostate cancer, in humans using filamin B, lymphocyte antigen 9 (LY9), keratins and tubulin, specifically using keratins 4, 7, 8, 15, 18, and 19, and tubulin-beta 3, particularly keratins 7, 15, or 19. The filamin B, lymphocyte antigen 9 (LY9), keratins and tubulin can further be used in conjunction with prostate specific antigen (PSA) for the treatment, prevention, reduction, diagnosis, monitoring, and prognosis of abnormal prostate states, including benign prostate hyperplasia and oncological disorders, especially prostate cancer. The invention also relates to panels and kits for use in practicing the methods of the invention.
BACKGROUND OF THE INVENTION
[0004] Oncological disorders, such as cancer, are presently one of the leading causes of death in developed nations and is a serious threat to modern society. Cancer can develop in any tissue of any organ at any age. Worldwide, more than 10 million people are diagnosed with cancer every year and it is estimated that this number will grow to 15 million new cases every year by 2020. It is believed that cancer causes six million deaths every year or 12% of the deaths worldwide.
[0005] Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing. However, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly to the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.
[0006] Rates of detection of prostate cancers vary widely across the world, with detection rates in south and east Asia being lower than those in Europe, and especially in the United States. Prostate cancer tends to develop in men over the age of fifty and, although it is one of the most prevalent types of cancer in men, many never have symptoms or undergo therapy for prostate cancer, and eventually die of other causes. Further, treatment of prostate cancer may do more harm to the subject than the prostate cancer itself. Prostate specific antigen (PSA) screening has lead to a significant rise in the number of men diagnosed with prostate cancer with an associated increase in potentially unnecessary biopsies preformed. Despite its limitations, including a positive predictive value of only 25-40%, PSA remains the only generally accepted biomarker for prostate cancer.
[0007] Prostate cancer is, in most cases, slow-growing and symptom-free. Moreover, since men with the condition are typically older, they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unrelated cancers, or old age. On the other hand, the more aggressive prostate cancers account for more cancer-related deaths among men in the United States than any other cancer except lung cancer.
[0008] About two-thirds of prostate cancer cases are slow growing, whereas the other third are more aggressive and fast developing. It is important to be able to distinguish between aggressive and non-aggressive forms of the disease, and further, to distinguish prostate cancer from benign prostate hyperplasia (BPH). Commonly used screening tests, e.g., for prostate specific antigen (PSA) cannot distinguish between prostate cancer and BPH.
SUMMARY OF THE INVENTION
[0009] The present invention is based, at least in part, on Applicants' discovery that keratins 4, 7, 8, 15, 18, and 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) are differentially regulated in prostate cancer cells.
[0010] Accordingly, the invention provides methods for diagnosing, monitoring (e.g., of disease progression or treatment), prognosing, treating, alleviating symptoms of, inhibiting progression of, or preventing, an oncological disease state, e.g., prostate cancer, in a mammal. The invention further provides panels and kits for practicing the methods of the invention.
[0011] In one aspect, the invention provides methods for diagnosing an abnormal prostate state in a subject comprising:
[0012] (1) determining a level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a biological sample from the subject; and
[0013] (2) comparing the level of the one or more prostate cancer related markers in the biological sample with the level of the one or more prostate cancer related markers in a normal control sample, wherein an altered level of the one or more prostate cancer related markers in the biological sample relative to the normal control sample is indicative of an abnormal prostate state in the subject.
[0014] In certain embodiments, the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19. In certain embodiments, an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject.
[0015] In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject. In such embodiments, levels of one, two, or all three of filamin B, LY9, and keratin 19 can be detected. For the marker levels detected, none of the markers have increased levels.
[0016] In certain embodiments, the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample and preferably further comprising comparing the level of PSA in the biological sample to the level of PSA in a normal control sample. In certain embodiments, an increase in the level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample has greater predictive value of the subject having an abnormal prostate state than the predictive value of a single marker alone. In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample has a greater predictive value of the subject having a normal prostate state than any single marker alone.
[0017] Throughout the methods, kits, and panels of the invention, one or more of filamin B, LY9 and keratin 19 is understood as any of filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
[0018] In certain embodiments of the invention, the abnormal prostate state is prostate cancer.
[0019] In certain embodiments of the invention, the prostate cancer is androgen-dependent prostate cancer. In certain embodiments of the invention, the prostate cancer is androgen-independent prostate cancer. In certain embodiments of the invention, the prostate cancer is aggressive prostate cancer. In certain embodiments of the invention, the prostate cancer is non-aggressive prostate cancer.
[0020] In certain embodiments of the invention, the abnormal prostate state is benign prostate hyperplasia.
[0021] In another aspect, the invention provides a method for identifying a subject as being at increased risk for developing prostate cancer, the method comprising:
[0022] (1) determining a level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a biological sample from the subject; and
[0023] (2) comparing the level of the one or more prostate cancer related markers in the biological sample with the level of the one or more prostate cancer related markers in a normal control sample, wherein an altered level of the one or more prostate cancer related markers in the biological sample relative to the control sample is indicative of an increased risk for developing prostate cancer in the subject.
[0024] In certain embodiments, the one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19. In certain embodiments, an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of an increased risk for developing prostate cancer in the subject. In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample is indicative of no increased risk for developing prostate cancer in the subject.
[0025] In certain embodiments, the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample. In certain embodiments, an increase in the level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample has greater predictive value of an increased risk for developing prostate cancer in the subject than an increase in any of the individual markers alone. In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, has greater predictive value of no increased risk for developing prostate cancer in the subject than any single marker alone.
[0026] In the embodiments of the invention, one or more prostate cancer markers selected from the group consisting of filamin B, LY9 and keratin 19 is: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
[0027] In certain embodiments of the diagnostic or prognostic methods of the invention, one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments, one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments, one or more prostate cancer related markers is selected from the group consisting of keratin 7 and keratin 15. In certain embodiments, one or more prostate cancer markers is selected from the group consisting of keratin 7, 15, and 19. In certain embodiments, the diagnostic and prognostic methods of the invention further comprise detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprise comparing the level of PSA in the biological sample to a level of PSA in a control sample.
[0028] In certain embodiments, the control sample for PSA is the same control sample as for the other prostate cancer related markers of the invention. In certain embodiments, the control sample for PSA is different from the control sample for the other prostate cancer related markers of the invention
[0029] In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an abnormal prostate state in the subject. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of a normal prostate state in the subject.
[0030] In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an increased risk of developing prostate cancer in the subject. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of an increased risk of developing prostate cancer in the subject. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of no increased risk of developing prostate cancer in the subject. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to a normal control sample is indicative of no increased risk of developing prostate cancer in the subject.
[0031] In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increase in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an abnormal prostate state in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an decrease in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an abnormal prostate state in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of a normal prostate state in the subject. In certain embodiments of the diagnostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of a normal prostate state in the subject.
[0032] In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, the method further comprises detecting the level of prostate specific antigen (PSA) in the biological sample, and preferably further comprises comparing the level of PSA in the biological sample to the level of PSA in a normal control sample. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increase in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an increased risk for the subject of developing prostate cancer wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an decrease in the level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with an increase in the level of PSA in the biological sample as compared to the level of PSA in the normal control sample is indicative of an increased risk for the subject of developing prostate cancer wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of an decreased risk or normal risk of developing prostate cancer in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the prognostic methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased or normal level of one or more of the prostate cancer related markers in the biological sample relative to the normal control sample, in combination with a decreased or normal level of PSA in the biological sample as compared to the level of PSA in the normal control sample, is indicative of a decreased risk or normal risk of developing prostate cancer in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
[0033] In various embodiments of any of the diagnostic or prognostic methods of the invention, the method may further comprise comparing the level of the one or more prostate cancer related markers in the biological sample with the level of the one or more prostate cancer related markers in a control sample selected from the group consisting of: a sample obtained from the same subject at an earlier time point than the biological sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and a sample from a subject with non-aggressive prostate cancer. In such embodiments, comparison with one or more additional control sample can facilitate differentiating between two prostate cancer states selected from the group consisting of: normal prostate and prostate cancer, benign prostate hyperplasia and prostate cancer, benign prostate hyperplasia and normal prostate, androgen dependent and androgen independent prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, and metastatic prostate cancer and non-metastatic prostate cancer; or differentiating between any two or more of normal prostate, prostate cancer, benign prostate hyperplasia, androgen dependent prostate cancer, androgen independent prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
[0034] In certain embodiments of the invention, when a tumor is present, the method further comprises detecting the size of the prostate tumor in the subject.
[0035] In certain embodiments of the diagnostic and prognostic methods the invention, the method further comprises obtaining a sample from a subject.
[0036] In certain embodiments of the diagnostic and prognostic methods the invention, the method further comprises selecting a subject who has or is suspected of having prostate cancer.
[0037] In certain embodiments of the invention, the method further comprises selecting a treatment regimen for the subject based on the level of the one or more prostate cancer markers. In certain embodiments of the invention, the method further comprises treating the subject with a a treatment regimen based on the level of the one or more prostate cancer markers. In certain embodiments, a treatment regimen comprises one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
[0038] In yet another aspect, the invention provides methods for monitoring prostate cancer in a subject, the method comprising
[0039] (1) determining a level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a first biological sample obtained at a first time from a subject having prostate cancer;
[0040] (2) determining a level of expression of the one or more prostate cancer related markers in a second biological sample obtained from the subject at a second time, wherein the second time is after or later than, the first time; and
[0041] (3) comparing the level of the one or more prostate cancer related markers in the second sample with the level of the one or more prostate cancer related markers in the first sample, wherein a change in the level of the one or more prostate cancer related markers in the second sample as compared to the first sample is indicative of a change in prostate cancer status in the subject.
[0042] In certain embodiments, the subject is actively treated for prostate cancer prior to obtaining the second sample. That is, the subject is undergoing active treatment for prostate cancer.
[0043] In certain embodiments, the subject is not actively treated for prostate cancer prior to obtaining the second sample. That is, the subject is being monitored using watchful waiting.
[0044] In certain embodiments, one or more prostate cancer related markers is selected from the group consisting of filamin B, LY9, and keratin 19. In certain embodiments, an increased level of one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of progression of the prostate cancer in the subject. In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample as compared to the first biological sample is indicative of non-progression of the prostate cancer in the subject.
[0045] In certain embodiments, the methods further comprise determining the level of prostate specific antigen (PSA) in the first biological sample and the second biological sample and preferably, further comprising comparing the level of PSA in the second biological sample to the level of PSA in the first biological sample. In certain embodiments, an increased level of the one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample relative to the level of the one or more prostate cancer related markers in the first biological sample, in combination with an increase in the level of PSA in the second biological sample relative to the level of PSA in the first biological sample has greater predictive value of progression of the prostate cancer in the subject than any single marker alone. In certain embodiments, no increase in the detected level of expression of each of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second biological sample relative to the level of the one or more prostate cancer related markers in the first biological sample, in combination with a decreased or same level of PSA in the second biological sample relative to the level of PSA in the first biological sample has greater predictive value of non-progression of the prostate cancer in the subject than any single marker alone.
[0046] In embodiments of the invention, the one or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 is: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
[0047] In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7, keratin 15, and keratin 19. In certain embodiments of the monitoring methods of the invention, the one or more prostate cancer related markers is selected from the group consisting of keratin 7 and keratin 15.
[0048] In certain embodiments of the monitoring methods of the invention, wherein the one or more prostate cancer markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, the methods further comprise determining the level of prostate specific antigen (PSA) in the first biological sample and the second biological sample, and preferably further comprise comparing the level of PSA in the second biological sample to the level of PSA in the first biological sample.
[0049] In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of prostate tumor progression in the subject. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of prostate tumor progression in the subject. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of no prostate tumor progression in the subject. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to a first sample is indicative of no prostate tumor progression in the subject.
[0050] In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, the method further comprises detecting the level of prostate specific antigen (PSA) in the second sample, and preferably further comprises comparing the level of PSA in the second sample to the level of PSA in a first sample. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increase in the level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with an increase in the level of PSA in the second sample as compared to the level of PSA in the first sample is indicative of prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an decrease in the level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with an increase in the level of PSA in the second sample as compared to the level of PSA in the first sample is indicative of prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, a decreased or normal level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with a decreased or normal level of PSA in the second sample as compared to the level of PSA in the first sample, is indicative of no prostate tumor progression in the subject. In certain embodiments of the monitoring methods of the invention, wherein one or more prostate cancer related markers is selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3, an increased or normal level of one or more of the prostate cancer related markers in the second sample relative to the first sample, in combination with a decreased or normal level of PSA in the second sample as compared to the level of PSA in the first sample, is indicative of no prostate tumor progression in the subject wherein the method has greater diagnostic or predictive value than the value of any of the individual markers alone.
[0051] In certain embodiments of the monitoring methods of the invention, the methods further comprise comparing the level of the one or more prostate cancer related markers in the first biological sample or the second biological sample with the level of the one or more prostate cancer related markers in a control sample selected from the group consisting of: a normal control sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and a sample from a subject with non-aggressive prostate cancer.
[0052] In certain embodiments of the monitoring methods of the invention, the methods further comprise detecting the size of the prostate tumor in the subject.
[0053] In certain embodiments of the monitoring methods of the invention, the methods further comprise obtaining a first sample and a second sample from the subject.
[0054] In certain embodiments of the monitoring methods of the invention, the methods further comprise selecting and/or administering a different treatment regimen for the subject based on progression of the prostate cancer in the subject.
[0055] In certain embodiments of the monitoring methods of the invention, the methods further comprise comprises maintaining a treatment regimen for the subject based on non-progression of the prostate cancer in the subject.
[0056] In certain embodiments, the treatment regimens comprise one or more treatments selected from the group consisting of: surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
[0057] In certain embodiments of the monitoring methods of the invention, the methods further comprise withholding an active treatment of the prostate cancer in the subject based on non-progression of the prostate cancer in the subject. In certain embodiments, the active treatment is one or more treatments selected from the group consisting of: surgery, radiation, hormone therapy, antibody therapy, growth factor therapy, cytokine therapy, and chemotherapy.
[0058] In still another aspect, the invention provides methods for detecting a set of prostate cancer related markers, the method comprising:
[0059] (1) analyzing a biological sample from a subject for a level of two or more prostate cancer related markers of a set of prostate cancer related markers, wherein the set of prostate cancer related markers comprises filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0060] (2) detecting each of the two or more prostate specific makers in the biological sample, thereby detecting the set of prostate cancer related biomarkers.
[0061] In certain embodiments, the set of prostate cancer related markers comprises filamin B, LY9, and keratin 19. In certain embodiments, the two or more prostate cancer related markers are: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19. In certain embodiments, the set of prostate cancer related markers comprises keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments, the set of prostate cancer related markers comprises keratin 7, keratin 8, and keratin 15. In certain embodiments, the set of prostate cancer related markers comprises keratin 7, keratin 15, and keratin 19. In certain embodiments, the set of prostate cancer related markers comprises keratin 7 and keratin 15.
[0062] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises isolating a component of the biological sample.
[0063] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises labeling a component of the biological sample.
[0064] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises processing the biological sample.
[0065] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises contacting a prostate cancer related marker to be detected with a prostate cancer related marker binding agent.
[0066] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises forming a complex between a prostate cancer related marker to be detected and a prostate cancer related marker binding agent.
[0067] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises contacting each of the one or more prostate cancer related markers with a prostate cancer related marker binding agent.
[0068] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises forming a complex between each of the one or more prostate cancer related markers and a prostate cancer related marker binding agent.
[0069] In various embodiments of any of the methods of the invention, the step of detecting or determining a level of one or more prostate cancer related markers in a biological sample comprises attaching a prostate cancer related marker to be detected to a solid surface.
[0070] In yet another aspect, the invention provides a panel of reagents for use in a detection method, the panel comprising at least two detection reagents, wherein each detection reagent is specific for the detection of at least one prostate cancer related marker of a set of prostate cancer related markers, wherein the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3 and PSA.
[0071] In certain embodiments, the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19. In certain embodiments, the two or more prostate cancer related markers is: filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19.
[0072] In certain embodiments, the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments, the set of prostate cancer specific markers comprises two or more prostate cancer related markers selected from the group consisting of keratin 7, keratin 8, and keratin 15. In certain embodiments, the set of prostate cancer specific markers comprises keratin 7 and keratin 15.
[0073] In certain embodiments, the set of prostate cancer specific markers further comprises PSA. In certain embodiments, the panel of reagents comprises a detection reagent specific for the detection of PSA.
[0074] In yet another aspect, the invention provides for the use of any of the foregoing panels of the invention in any of the methods provided by the invention.
[0075] In still another aspect, the invention provides a kit for the diagnosis, monitoring, or characterization of an abnormal prostate state, comprising: at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9.
[0076] In certain embodiments, the kit further comprises instructions for the diagnosis, monitoring, or characterization of an abnormal prostate state based on the level of the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 detected.
[0077] In certain embodiments, the kit further comprises instructions to detect the level of PSA in a sample in which the at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected.
[0078] In certain embodiments, the kit further comprises at least one reagent specific for the detection of a level of PSA.
[0079] In one embodiment, the invention provides a kit comprising at least one reagent specific for the detection of a level of at least one prostate cancer related marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, and LY9 and at least one reagent specific for the detection of a level of PSA.
[0080] Further, the invention provides methods for diagnosing prostate cancer comprising determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a biological sample obtained from a subject; and comparing the level of expression of the one or more markers in the biological sample obtained from the subject with the level of expression of the corresponding one or more markers in a control sample, wherein a modulation in the level of expression of the one or more markers in the biological sample is an indication that the subject is afflicted with prostate cancer. In certain embodiments, an increase in the level of expression of filamin B (FLNB), lymphocyte antigen 9 (LY9), or keratin 19 in the biological sample as compared to a normal control sample is an indication that the subject is afflicted with prostate cancer.
[0081] The invention further provides methods prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a biological sample obtained from the subject; and comparing the level of expression of the one or more markers present in the biological sample obtained from the subject with the level of expression of the corresponding markers in a control sample, wherein a modulation in the level of expression of the one or more markers in the biological sample obtained from the subject with the level of expression of the corresponding marker in a control sample is an indication that the subject is predisposed to developing prostate cancer. In certain embodiments, an increase in the level of expression of filamin B (FLNB), lymphocyte antigen 9 (LY9), or keratin 19 in the biological sample as compared to a normal control sample is an indication that the subject is predisposed to prostate cancer.
[0082] The invention further provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of a corresponding one or more markers in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of the one or more markers in the first sample with the expression level of the corresponding one or more markers in the second sample, wherein a modulation in the level of expression of the one or more in the second sample as compared to the one or more markers in the first sample is an indication of a modulation in prostate cancer status in the subject. In certain embodiments, an decrease in the level of expression of filamin B (FLNB), lymphocyte antigen 9 (LY9), or keratin 19 in the biological sample as compared to the control sample is an indication that the subject is responding to treatment for prostate cancer.
[0083] In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) further include detection of prostate specific antigen (PSA) for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
[0084] The invention also provides methods for diagnosing prostate cancer comprising determining a level of expression of keratin 7 or keratin 15 in a biological sample obtained from a subject; and comparing the level of expression of keratin 7 or keratin 15 in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample, wherein an modulation in the level of expression of keratin 7 or keratin 15 in the biological sample as compared to the control sample is an indication that the subject is afflicted with prostate cancer.
[0085] The invention provides methods of prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of keratin 7 or keratin 15 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 7 or keratin 15 present in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample, wherein a modulation in the level of expression of keratin 7 or keratin 15 in the biological sample obtained from the subject with the level of expression of keratin 7 or keratin 15 in a control sample is an indication that the subject is predisposed to developing prostate cancer.
[0086] The invention provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of keratin 7 or keratin 15 present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of keratin 7 or keratin 15 in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of keratin 7 or keratin 15 in the first sample with the expression level of keratin 7 or keratin 15 in the second sample, wherein a modulation in the level of expression of keratin 7 or keratin 15 in the second sample as compared to keratin 7 or keratin 15 in the first sample is an indication that the therapy is modulating prostate cancer in the subject.
[0087] The invention also provides methods for diagnosing prostate cancer comprising determining a level of expression of keratin 19 in a biological sample obtained from a subject; and comparing the level of expression of keratin 19 in the biological sample obtained from the subject with the level of expression of keratin 19 in a control sample, wherein an increase in the level of expression of keratin 19 in the biological sample as compared to a normal control sample is an indication that the subject is afflicted with prostate cancer.
[0088] The invention provides methods prognosing whether a subject is predisposed to developing prostate cancer, the method comprising determining the level of expression of keratin 19 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 19 present in the biological sample obtained from the subject with the level of expression of keratin 19 in a control sample, wherein a modulation in the level of expression of keratin 19 in the biological sample obtained from the subject with the level of expression of keratin 19 in a normal control sample is an indication that the subject is predisposed to developing prostate cancer.
[0089] The invention provides methods for monitoring the treatment of prostate cancer in a subject, the methods comprising determining a level of expression of keratin 19 present in a first sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject; determining a level of expression of keratin 19 in a second sample obtained from the subject following administration of at least a portion of the treatment regimen to the subject; and comparing the level of expression of keratin 19 in the first sample with the expression level of keratin 19 in the second sample, wherein a decrease in the level of expression of keratin 19 in the second sample as compared to keratin 19 in the first sample is an indication that the subject is responding to treatment for prostate cancer.
[0090] In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of filamin B for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of LY9 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of PSA for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of filamin B for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 4 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 8 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of keratin 18 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer. In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level of keratin 7, 15, or 19 further include detection of tubulin-beta 3 for the diagnosing, prognosing, and monitoring the treatment of prostate cancer.
[0091] In certain embodiments, keratin 7, 15, or 19 is keratin 7. In certain embodiments, keratin 7, 15, or 19 is keratin 15. In certain embodiments, keratin 7, 15, or 19 is keratin 19. In certain embodiments, keratin 7, 15, or 19 is keratin 7 and 15. In certain embodiments, keratin 7, 15, or 19 is keratin 7 and 19. In certain embodiments, keratin 7, 15, or 19 is keratin 15 and 19. In certain embodiments, keratin 7, 15, or 19 is keratin 7, 15, and 19.
[0092] In certain embodiments, filamin B, LY9, or keratin 19 is filamin B. In certain embodiments, filamin B, LY9, or keratin 19 is LY9. In certain embodiments, filamin B, LY9, or keratin 19 is keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B and LY9. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B and keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is LY9, and keratin 19. In certain embodiments, filamin B, LY9, or keratin 19 is filamin B, LY9, and keratin 19.
[0093] In certain embodiments, the control sample is a sample from a normal subject or normal tissue. In certain embodiments, the control sample is a sample from the same subject from an earlier time point than the biological sample. In certain embodiments, the control sample is a sample from a subject with benign prostatic hyperplasia (BPH).
[0094] In certain embodiments, diagnosing includes differentiating between normal prostate and prostate cancer. In certain embodiments, diagnosing includes differentiating between benign prostate hyperplasia and prostate cancer.
[0095] The invention provides methods of characterizing prostate cancer status in a subject, the method comprising determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) present in a biological sample obtained from the subject; and comparing the level of expression of the one or more markers present in the biological sample obtained from the subject with the level of expression of the one or more markers in a control sample, wherein the level of expression of the one or more markers in the biological sample obtained from the subject compared to the level of expression of the corresponding marker in a control sample is an indication of the prostate cancer status in the subject.
[0096] The invention provides methods of characterizing prostate cancer status in a subject, the method comprising determining the level of expression of keratin 7, 15, or 19 present in a biological sample obtained from the subject; and comparing the level of expression of keratin 7, 15, or 19 present in the biological sample obtained from the subject with the level of expression of keratin 7, 15, or 19 in a control sample, wherein the level of expression of keratin 7, 15, or 19 in the biological sample obtained from the subject compared to the level of expression of keratin 7, 15, or 19 in a control sample is an indication of the prostate cancer status in the subject.
[0097] In certain embodiments, the methods further comprises detection of the level of expression of prostate specific antigen (PSA) in the biological sample in which the expression level of filamin B or LY9 is detected in the methods of characterization of prostate cancer. In certain embodiments, the method further includes comparing the level of expression of PSA in the biological sample with the level of PSA in a control sample. In certain embodiments, the results from the detection of the expression level of PSA is used in conjunction with the results from detection of the level of one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the methods of characterization of prostate cancer.
[0098] In certain embodiments, the control sample is a sample from a normal subject or normal tissue. In certain embodiments, the control sample is a sample from the same subject from an earlier time point than the biological sample. In certain embodiments, the control sample is a sample from a subject with benign prostatic hyperplasia (BPH). In certain embodiments, the control sample is a sample from a subject with androgen dependent prostate cancer. In certain embodiments, the control sample is a sample from a subject with androgen independent prostate cancer. In certain embodiments, the control sample is a sample from a subject with an aggressive prostate cancer. In certain embodiments, the control sample is a sample from a subject with a non-aggressive prostate cancer.
[0099] In certain embodiments of the invention, characterizing includes differentiating between normal prostate and prostate cancer. In certain embodiments, characterizing includes differentiating between benign prostate hyperplasia and prostate cancer. In certain embodiments, characterizing includes differentiating between androgen sensitive and androgen insensitive prostate cancer. In certain embodiments, characterizing includes differentiating between aggressive prostate cancer and non-aggressive prostate cancer. In certain embodiments, characterizing includes differentiating between any two or more of normal prostate, prostate cancer, benign prostate hyperplasia, androgen sensitive prostate cancer, androgen insensitive prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer and non-metastatic prostate cancer. In certain embodiments, characterizing includes detecting a change in status from androgen independent prostate cancer to androgen dependent prostate cancer. In certain embodiments, characterizing includes detecting a change in status from androgen independent prostate cancer to androgen dependent prostate cancer in response prior to a change in response to treatment. In certain embodiments, characterizing includes detecting a change in the size or relative aggressiveness of the prostate cancer. In certain embodiments, characterizing includes detecting a change from non-metastatic to metastatic prostate cancer.
[0100] In certain embodiments of the invention, an increase in the expression level of keratin 19 is an indication of increased pathology of prostate cancer or increased likelihood of developing prostate cancer. In certain embodiments of the invention, a decrease in the expression level of keratin 19 is an indication of decreased pathology of prostate cancer or decreased likelihood of developing prostate cancer. In certain embodiments of the invention, no significant change in the expression level of keratin 19 is an indication of no significant change in prostate cancer status.
[0101] In certain embodiments of the invention, an increase in the expression level of filamin B or LY9 is an indication of increased pathology of prostate cancer or increased likelihood of developing prostate cancer. In certain embodiments of the invention, an decrease in the expression level of filamin B or LY9 is an indication of decreased pathology of prostate cancer or decreased likelihood of developing prostate cancer. In certain embodiments of the invention, no significant change in the expression level of filamin B or LY9 is an indication of no significant change in prostate cancer status.
[0102] In certain embodiments, methods of the invention further comprise obtaining a biological sample from a subject.
[0103] In certain embodiments, methods of the invention further comprise selecting a subject for having or being suspected of having prostate cancer.
[0104] In certain embodiments, methods of the invention further comprise selection of a regimen for treatment of the subject including one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, and chemotherapy.
[0105] In certain embodiments, the method further comprises selection of the one ore more specific treatment regimens for the subject based on the results of the methods.
[0106] In certain embodiments, the method further comprises changing the treatment regimen of the subject based on the results of the methods.
[0107] In certain embodiments, the method further comprises a change in hormone based therapy based on monitoring of the subject based on the results of the methods.
[0108] In certain embodiments, the method further comprises not treating the subject with one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, or chemotherapy for an interval prior to performing a subsequent diagnostic, prognostic, or monitoring method provided herein.
[0109] The invention provides methods of treating a subject with prostate cancer by determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), present in a first sample obtained from the subject having prostate cancer; determining a level of expression of the one or more markers in a second sample obtained from the subject after administration of at least a portion of a treatment for prostate cancer; comparing the level of expression of the one or more markers in the first sample with the expression level of the one or more markers in the second sample, wherein a modulated level of expression of the one or more markers in the second sample as compared to the one or more markers in the first sample is an indication that the subject is an indication of modulation of prostate cancer in the subject; and selecting a treatment for the subject based on the expression level of the one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9). For example, a decrease in the level of filamin B, LY9, or keratin 19 is an indication that the subject is responding to treatment. An increase in the level of filamin B, LY9, or keratin 19 is an indication that the subject is not responding to treatment.
[0110] As used herein, modulation is understood as a change in an expression level of a marker, particularly a statistically significant change in an expression level of a marker as compared to an appropriate control. The meaning of an increase or a decrease in an expression level of the marker as compared to a control depends, at least, on the specific identity of the marker and the control used. Such considerations are well understood by those of skill in the art. The meaning of the modulation in the expression level(s) of markers can be determined based on the teachings provided herein.
[0111] In certain embodiments, the treatment method further comprises determining a level of expression of PSA in the first sample and determining a level of expression of PSA in the second sample. In certain embodiments, the treatment of the subject is maintained upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indicating that the subject was responsive to the treatment. In certain embodiments, the treatment of the subject is discontinued upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indicating that disease is no longer present or minimized such that treatment is no longer required. In certain embodiments, a new treatment of the subject is initiated upon detection of a decrease in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, e.g., resection after shrinkage of the tumor. In certain embodiments, the treatment of the subject is discontinued upon detection of an increase in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, indication of a lack of response or discontinuation of response to the treatment. In certain embodiments, a new treatment of the subject is initiated upon detection of an increase in the expression level of at least one of filamin B, LY9, keratin 19, or PSA in the second sample, e.g., due to lack of response or discontinuation of response to treatment. One of skill in the art can select appropriate methods of treatment of a subject based, at least in part, on his response, or non-response, to treatments being used as determined by the expression level of the markers.
[0112] The invention provides method of selecting a subject with prostate cancer for administration of active treatment, rather than watchful waiting, by determining a level of expression of filamin B, LY9, or keratin 19, present in a first sample obtained from the subject having prostate cancer wherein the subject has not been actively treated for prostate cancer; determining a level of expression of filamin B, LY9, or keratin 19 in a second sample obtained from the subject; comparing the level of expression of filamin B, LY9, or keratin 19 in the first sample obtained at an earlier time point with the expression level of filamin B, LY9, or keratin 19 in the second sample; wherein a decreased level of expression of filamin B, LY9, or keratin 19 in the second sample as compared to filamin B, LY9, or keratin 19 in the first sample is an indication that the subject should not be administered active treatment for prostate cancer; and selecting against active treatment of a subject for prostate cancer.
[0113] The invention also provides methods of selecting a subject with prostate cancer for administration of active treatment by determining a level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), present in a first sample obtained from the subject having prostate cancer wherein the subject has not been actively treated for prostate cancer; determining a level of expression of the corresponding one or more markers in a second sample obtained from the subject; comparing the level of expression of the one or more markers in the first sample obtained at an earlier time point with the expression level of the one or more markers in the second sample; wherein an modulated level of expression of the one or more markers in the second sample as compared to the one or more markers in the first sample is considered in determining if a subject should be actively treated for prostate cancer.
[0114] In certain embodiments, actively treating the subject for prostate cancer comprises treating the subject with one or more therapies such as hormone therapy, chemotherapy, radiation therapy, and surgery.
[0115] In certain embodiments, methods of subject selection further comprise determining a level of expression of PSA in the first sample and determining a level of expression of PSA in the second sample. In certain embodiments, a decreased level of expression of PSA in the second sample as compared to the level of expression of PSA in the first sample is an indication that the subject should not be administered active treatment for prostate cancer. In certain embodiments, an increased level of expression of PSA in the second sample as compared to the level of expression of PSA in the first sample is an indication that the subject should be administered active treatment for prostate cancer.
[0116] In certain embodiments of any of the methods provided herein, filamin B or LY9 is understood as filamin B and LY9. In certain embodiments of any of the methods provided herein, filamin B or LY9 is understood as filamin B. In certain embodiments of any of the methods provided herein, filamin B or LY9 is understood as LY9.
[0117] In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 15. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7 and 15. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 15 and 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7 and 19. In certain embodiments of any of the methods provided herein, keratin 7, 15, or 19 is understood as keratin 7, 15, and 19.
[0118] In certain embodiments, one or more markers selected from any group provided herein does not include keratin 4. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 7. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 8. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 15. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 18. In certain embodiments, one or more markers selected from any group provided herein does not include keratin 19. In certain embodiments, one or more markers selected from any group provided herein does not include tubulin-beta 3. In certain embodiments, one or more markers selected from any group provided herein does not include filamin B. In certain embodiments, one or more markers selected from any group provided herein does not include LY9. In certain embodiments, one or more markers selected from any group provided herein does not include PSA.
[0119] In certain embodiments of any of the methods provided herein, the methods further comprising obtaining a biological sample from the subject.
[0120] The invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in the test cell; comparing the level of expression of the one or more markers in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of the one or more markers in the test cell, thereby identifying a compound for treating a disorder in a subject. In certain embodiments, the methods further include identifying a compound that modulates the level of expression of PSA.
[0121] The invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of keratin 7, 15, or 19 in the test cell; comparing the level of expression of keratin 7, 15, or 19 in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of keratin 7, 15, or 19 in the test cell, thereby identifying a compound for treating a disorder in a subject.
[0122] The invention provides methods of identifying a compound for treating prostate cancer comprising obtaining a test cell; contacting the test cell with a test compound; determining the level of expression of filamin B or LY9 in the test cell; comparing the level of expression of filamin B or LY9 in the test cell with a control cell not contacted by the test compound; and selecting a test compound that modulates the level of expression of filamin B or LY9 in the test cell, thereby identifying a compound for treating a disorder in a subject.
[0123] In certain embodiments, the methods of identifying a compound for treating prostate cancer further include identifying a compound that modulates the level of expression of PSA.
[0124] In certain embodiments, the test cell is contacted with the agent in vitro.
[0125] In certain embodiments, the test cell is contacted with the agent in vivo. In certain embodiments, the test cell is present in a xenogenic model of cancer. In certain embodiments, the test cell is present in an animal model of prostate cancer. In certain embodiments, the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) is detected in the test cell by detection of the expression level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a biological sample in the organism containing the test cell.
[0126] The invention provides kits for the diagnosis, monitoring, or characterization of prostate cancer comprising at least one reagent specific for the detection of the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) in a sample.
[0127] In certain embodiments, the kit further comprises instructions for the diagnosis, monitoring, or characterization of prostate cancer based on the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9). In certain embodiments, the kit includes instructions to detect the level of expression of PSA in the same sample in which the level of expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) is detected. In certain embodiments, the kit includes at least one reagent specific for the detection of the level of expression of PSA. In certain embodiments, the kits include at least one antibody or nucleic acid for binding to f one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) for use in the methods provided herein. In certain embodiments, the kit includes at least one antibody or nucleic acid for binding to keratin 7 and one antibody or nucleic acid for binding to keratin 15. In certain embodiments, the kits further include at least one antibody or nucleic acid for binding to PSA for use in the methods provided herein. The kits may further provide instructions for practicing the methods provided herein.
[0128] Where applicable or not specifically disclaimed, any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0129] FIG. 1: Schematic representing the underlying principles of the Interrogative Platform Technology provided in WO2012119129.
[0130] FIGS. 2A-C: Causal associations of Keratins, including (A-B) KRT8, KRT18 and (C) KRT19 in human prostate cancer cells as inferred by the Interrogative Platform Technology.
[0131] FIGS. 3A-D: Mechanistic insight into regulation of keratins by mitochondrial function inferred by the Interrogative Platform Technology. (A-B) KRT8-KRT15 association is abolished upon ubidecaronone treatment. Note change of direction of arrow between and positions of KRT7 and KRT15 before treatment (A) and after treatment (B). (C) Tubulin-beta 3 interacts with a number of proteins. (D) Expression levels of keratin 19 in biological samples from subjects with prostate cancer or control samples.
[0132] FIG. 4: Inference of filamin B (FLNB) as a hub of activity in prostate cancer and as a biomarker using the Interrogative Platform Technology provided in WO2012119129.
[0133] FIG. 5: Portion of an inference map showing filamin B is connected directly to LY9, which is, in turn, connected to at least one other marker.
[0134] FIGS. 6A-B: Validation of filamin B levels in human serum samples. Levels of (A) filamin B and (B) PSA were elevated in prostate cancer samples when compared to normal serum. Data represents percent average change, with normal donors set to 100% on a log scale.
[0135] FIG. 7: Validation of LY9 levels in human serum samples. Levels of LY9 were elevated in prostate cancer samples when compared to normal serum. Data represents percent average change, with normal donors set to 100% on a log scale.
[0136] FIGS. 8A-C: Validation of (A) filamin B, (B) LY9, and (C) PSA levels in human serum samples. Data are shown as ng/ml of the marker in serum.
[0137] FIGS. 9A-B: ROC curve analysis of sensitivity and false positive rate (FPR) of PSA, FLNB and the combination of PSA and FLNB (A) and area under the curve values (AUC) calculated (B) based on the analysis. The combination of PSA and FLNB was more sensitive than either marker alone.
[0138] FIGS. 10A-B: ROC curve analysis of PSA, FLNB, LY9 and combinations of PSA, FLNB, and LY9 using linear (A) and non-linear (B) scoring functions. The combination of PSA, LY9, and FLNB was more sensitive than any marker alone.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0139] As used herein, each of the following terms has the meaning associated with it in this section.
[0140] A "patient" or "subject" to be treated by the method of the invention can mean either a human or non-human animal, preferably a mammal. By "subject" is meant any animal, including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. A human subject may be referred to as a patient. It should be noted that clinical observations described herein were made with human subjects and, in at least some embodiments, the subjects are human.
[0141] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease, e.g., the amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment, e.g., is sufficient to ameliorate at least one sign or symptom of the disease, e.g., to prevent progression of the disease or condition, e.g., prevent tumor growth, decrease tumor size, induce tumor cell apoptosis, reduce tumor angiogenesis, prevent metastasis. When administered for preventing a disease, the amount is sufficient to avoid or delay onset of the disease. The "therapeutically effective amount" will vary depending on the compound, its therapeutic index, solubility, the disease and its severity and the age, weight, etc., of the patient to be treated, and the like. For example, certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment. Administration of a therapeutically effective amount of a compound may require the administration of more than one dose of the compound.
[0142] "Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Prevention does not require that the disease or condition never occurs in the subject. Prevention includes delaying the onset or severity of the disease or condition.
[0143] The term "prophylactic" or "therapeutic" treatment refers to administration to the subject of one or more agents or interventions to provide the desired clinical effect. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing at least one sign or symptom of the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or maintain at least one sign or symptom of the existing unwanted condition or side effects therefrom).
[0144] As used herein, "treatment", particularly "active treatment" refers to performing an intervention to treat prostate cancer in a subject, e.g., reduce at least one of the growth rate, reduction of tumor burden, reduce or maintain the tumor size, or the malignancy (e.g., likelihood of metastasis) of the tumor; or to increase apoptosis in the tumor by one or more of administration of a therapeutic agent, e.g., chemotherapy or hormone therapy; administration of radiation therapy (e.g., pellet implantation, brachytherapy), or surgical resection of the tumor, or any combination thereof appropriate for treatment of the subject based on grade and stage of the tumor and other routine considerations. Active treatment is distinguished from "watchful waiting" (i.e., not active treatment) in which the subject and tumor are monitored, but no interventions are performed to affect the tumor. Watchful waiting can include administration of agents that alter effects caused by the tumor (e.g., incontinence, erectile dysfunction) that are not administered to alter the growth or pathology of the tumor itself.
[0145] The term "therapeutic effect" refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or in the enhancement of desirable physical or mental development and conditions in an animal or human. A therapeutic effect can be understood as a decrease in tumor growth, decrease in tumor growth rate, stabilization or decrease in tumor burden, stabilization or reduction in tumor size, stabilization or decrease in tumor malignancy, increase in tumor apoptosis, and/or a decrease in tumor angiogenesis.
[0146] The terms "disorders", "diseases", and "abnormal state" are used inclusively and refer to any deviation from the normal structure or function of any part, organ, or system of the body (or any combination thereof). A specific disease is manifested by characteristic symptoms and signs, including biological, chemical, and physical changes, and is often associated with a variety of other factors including, but not limited to, demographic, environmental, employment, genetic, and medically historical factors. Certain characteristic signs, symptoms, and related factors can be quantitated through a variety of methods to yield important diagnostic information. As used herein the disorder, disease, or abnormal state is an abnormal prostate state, including benign prostate hyperplasia and cancer, particularly prostate cancer. The abnormal prostate state of prostate cancer can be further subdivided into stages and grades of prostate cancer as provided, for example in Prostate. In: Edge S B, Byrd D R, Compton C C, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, N.Y.: Springer, 2010, pp 457-68 (incorporated herein by reference). Further, abnormal prostate states can be classified as one or more of benign prostate hyperplasia (BPH), androgen sensitive prostate cancer, androgen insensitive or resistant prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
[0147] A subject at "increased risk for developing prostate cancer" may or may not develop prostate cancer. Identification of a subject at increased risk for developing prostate cancer should be monitored for additional signs or symptoms of prostate cancer. The methods provided herein for identifying a subject with increased risk for developing prostate cancer can be used in combination with assessment of other known risk factors or signs of prostate cancer including, but not limited to decreased urinary stream, urgency, hesitancy, nocturia, incomplete bladder emptying, and age.
[0148] The term "expression" is used herein to mean the process by which a polypeptide is produced from DNA. The process involves the transcription of the gene into mRNA and the translation of this mRNA into a polypeptide. Depending on the context in which used, "expression" may refer to the production of RNA, or protein, or both.
[0149] The terms "level of expression of a gene", "gene expression level", "level of a marker", and the like refer to the level of mRNA, as well as pre-mRNA nascent transcript(s), transcript processing intermediates, mature mRNA(s) and degradation products, or the level of protein, encoded by the gene in the cell.
[0150] The term "specific identification" is understood as detection of a marker of interest with sufficiently low background of the assay and cross-reactivity of the reagents used such that the detection method is diagnostically useful. In certain embodiments, reagents for specific identification of a marker bind to only one isoform of the marker. In certain embodiments, reagents for specific identification of a marker bind to more than one isoform of the marker. In certain embodiments, reagents for specific identification of a marker bind to all known isoforms of the marker.
[0151] The term "modulation" refers to upregulation (i.e., activation or stimulation), down-regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. A "modulator" is a compound or molecule that modulates, and may be, e.g., an agonist, antagonist, activator, stimulator, suppressor, or inhibitor.
[0152] The term "control sample," as used herein, refers to any clinically relevant comparative sample, including, for example, a sample from a healthy subject not afflicted with an oncological disorder, e.g., prostate cancer, or a sample from a subject from an earlier time point, e.g., prior to treatment, an earlier tumor assessment time point, at an earlier stage of treatment. A control sample can be a purified sample, protein, and/or nucleic acid provided with a kit. Such control samples can be diluted, for example, in a dilution series to allow for quantitative measurement of levels of analytes, e.g., markers, in test samples. A control sample may include a sample derived from one or more subjects. A control sample may also be a sample made at an earlier time point from the subject to be assessed. For example, the control sample could be a sample taken from the subject to be assessed before the onset of an oncological disorder, e.g., prostate cancer, at an earlier stage of disease, or before the administration of treatment or of a portion of treatment. The control sample may also be a sample from an animal model, or from a tissue or cell lines derived from the animal model of oncological disorder, e.g., prostate cancer. The level of activity or expression of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), lymphocyte antigen 9 (LY9), and PSA in a control sample consists of a group of measurements may be determined, e.g., based on any appropriate statistical measure, such as, for example, measures of central tendency including average, median, or modal values. Different from a control is preferably statistically significantly different from a control.
[0153] The term "control level" refers to an accepted or pre-determined level of a marker in a subject sample. A control level can be a range of values. Marker levels can be compared to a single control value, to a range of control values, to the upper level of normal, or to the lower level of normal as appropriate for the assay.
[0154] In one embodiment, the control is a standardized control, such as, for example, a control which is predetermined using an average of the levels of expression of one or more markers from a population of subjects having no cancer, especially subjects having no prostate cancer. In still other embodiments of the invention, a control level of a marker in a non-cancerous sample(s) derived from the subject having cancer. For example, when a biopsy or other medical procedure reveals the presence of cancer in one portion of the tissue, the control level of a marker may be determined using the non-affected portion of the tissue, and this control level may be compared with the level of the marker in an affected portion of the tissue.
[0155] In certain embodiments, the control can be from a subject, or a population of subject, having an abnormal prostate state. For example, the control can be from a subject suffering from benign prostate hyperplasia (BPH), androgen sensitive prostate cancer, androgen insensitive or resistant prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, or non-metastatic prostate cancer. It is understood that not all markers will have different levels for each of the abnormal prostate states listed. It is understood that a combination of maker levels may be most useful to distinguish between abnormal prostate states, possibly in combination with other diagnostic methods. Further, marker levels in biological samples can be compared to more than one control sample (e.g., normal, abnormal, from the same subject, from a population control). Marker levels can be used in combination with other signs or symptoms of an abnormal prostate state to provide a diagnosis for the subject.
[0156] A control can also be a sample from a subject at an earlier time point, e.g., a baseline level prior to suspected presence of disease, before the diagnosis of a disease, at an earlier assessment time point during watchful waiting, before the treatment with a specific agent (e.g., chemotherapy, hormone therapy) or intervention (e.g., radiation, surgery). In certain embodiments, a change in the level of the marker in a subject can be more significant than the absolute level of a marker, e.g., as compared to control.
[0157] As used herein, a sample obtained at an "earlier time point" is a sample that was obtained at a sufficient time in the past such that clinically relevant information could be obtained in the sample from the earlier time point as compared to the later time point. In certain embodiments, an earlier time point is at least four weeks earlier. In certain embodiments, an earlier time point is at least six weeks earlier. In certain embodiments, an earlier time point is at least two months earlier. In certain embodiments, an earlier time point is at least three months earlier. In certain embodiments, an earlier time point is at least six months earlier. In certain embodiments, an earlier time point is at least nine months earlier. In certain embodiments, an earlier time point is at least one year earlier. Multiple subject samples (e.g., 3, 4, 5, 6, 7, or more) can be obtained at regular or irregular intervals over time and analyzed for trends in changes in marker levels. Appropriate intervals for testing for a particular subject can be determined by one of skill in the art based on ordinary considerations.
[0158] As used herein, "changed as compared to a control" sample or subject is understood as having a level of the analyte or diagnostic or therapeutic indicator (e.g., marker) to be detected at a level that is statistically different than a sample from a normal, untreated, or abnormal state control sample. Changed as compared to control can also include a difference in the rate of change of the level of one or more markers obtained in a series of at least two subject samples obtained over time. Determination of statistical significance is within the ability of those skilled in the art, e.g., the number of standard deviations from the mean that constitute a positive or negative result.
[0159] As used herein, the term "obtaining" is understood herein as manufacturing, purchasing, or otherwise coming into possession of.
[0160] As used herein, "detecting", "detection", "determining", and the like are understood that an assay performed for identification of a specific marker in a sample, e.g., one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), lymphocyte antigen 9 (LY9), and PSA. The amount of marker expression or activity detected in the sample can be none or below the level of detection of the assay or method.
[0161] As used herein, "greater predictive value" is understood as an assay that has significantly greater sensitivity and/or specificity, preferably greater sensitivity and specificity, than the test to which it is compared. The predictive value of a test can be determined using an ROC analysis. In an ROC analysis a test that provides perfect discrimination or accuracy between normal and disease states would have an area under the curve (AUC)=1, whereas a very poor test that provides no better discrimination than random chance would have AUC=0.5. As used herein, a test with a greater predictive value will have a statistically improved AUC as compared to another assay. The assays are preformed in an appropriate subject population.
[0162] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
[0163] The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to."
[0164] The term "or" is used inclusively herein to mean, and is used interchangeably with, the term "and/or," unless context clearly indicates otherwise. For example, as used herein, filamin B or LY9 is understood to include filamin B alone, LY9 alone, and the combination of filamin B and LY9.
[0165] The term "such as" is used herein to mean, and is used interchangeably, with the phrase "such as but not limited to."
[0166] Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
[0167] The recitation of a listing of chemical group(s) in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
[0168] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
[0169] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
[0170] As used herein, "one or more" is understood as each value 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and any value greater than 10.
[0171] Reference will now be made in detail to exemplary embodiments of the invention. While the invention will be described in conjunction with the exemplary embodiments, it will be understood that it is not intended to limit the invention to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.
Keratins
[0172] Keratin 4
[0173] Keratin 4, also known as as K4; CK4; CK-4; CYK4, is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in differentiated layers of the mucosal and esophageal epithelia with family member KRT13. Mutations in these genes have been associated with White Sponge Nevus, characterized by oral, esophageal, and anal leukoplakia. The type II cytokeratins are clustered in a region of chromosome 12q12-q13.
[0174] As used herein, keratin 4 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 4 is 3851 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3851 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 4, GenBank Accession No. NM--002272 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 1 and 2. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0175] It is understood that the invention includes the use of any fragments of keratin 4 sequences as long as the fragment can allow for the specific identification of keratin 4. Moreover, it is understood that there are naturally occurring variants of keratin 4 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Keratin 7
[0176] Keratin 7, also known as as CK7, K2C7, K7, SCL, CK-7; cytokeratin 7; cytokeratin-7; keratin, 55K type II cytoskeletal; keratin, simple epithelial type I, K7; keratin, type II cytoskeletal 7; keratin-7; sarcolectin; type II mesothelial keratin K7; and type-II keratin Kb7, is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.
[0177] As used herein, keratin 7 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 7 is 3855 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3855 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 7, GenBank Accession No. NM--005556 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 3 and 4. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0178] It is understood that the invention includes the use of any fragments of keratin 7 sequences as long as the fragment can allow for the specific identification of keratin 7. Moreover, it is understood that there are naturally occurring variants of keratin 7 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Keratin 8
[0179] Keratin 8, also known as K8; KO; CK8; CK-8; CYK8; K2C8; CARD2 is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene.
[0180] As used herein, keratin 8 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 8 is 3856 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3856 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 8, variant 1, GenBank Accession No. NM--001256282 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 5 and 6; and homo sapiens keratin 8, variant 3, GenBank Acession No. NM--001256293 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 7 and 8. (The GenBank numbers are incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0181] It is understood that the invention includes the use of either on of or both of the variants of keratin 8 provided in the sequence listing and any fragments of keratin 8 sequences as long as the fragment can allow for the specific identification of keratin 8. Moreover, it is understood that there are naturally occurring variants of keratin 8 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Keratin 15
[0182] Keratin 15, also known as as K15; CK15; K1CO, is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region on chromosome 17q21.2.
[0183] As used herein, keratin 15 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 15 is 3866 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3866 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 15, GenBank Accession No. NM--002275 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 9 and 10. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0184] It is understood that the invention includes the use of any fragments of keratin 15 sequences as long as the fragment can allow for the specific identification of keratin 15. Moreover, it is understood that there are naturally occurring variants of keratin 15 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Keratin 18
[0185] Keratin 18, also known as as K18; CYK18, encodes the type I intermediate filament chain keratin 18. Keratin 18, together with its filament partner keratin 8, are perhaps the most commonly found members of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.
[0186] As used herein, keratin 15 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 18 is 3875 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3875 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 18, variant 1, GenBank Accession No. NM--000224 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 11 and 12, and homo sapiens keratin 18, variant 2, GenBank Accession No. 199187 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 13 and 14. (The GenBank numbers are incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0187] It is understood that the invention includes the use of either on of or both of the variants of keratin 18 provided in the sequence listing and any fragments of keratin 18 sequences as long as the fragment can allow for the specific identification of keratin 18. Moreover, it is understood that there are naturally occurring variants of keratin 18 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Keratin 19
[0188] Keratin 19, also known as K19; CK19; K1CS, is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically expressed in the periderm, the transiently superficial layer that envelopes the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17q12-q21.
[0189] As used herein, keratin 19 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human keratin 19 is 3880 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/3880 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens keratin 19, GenBank Accession No. NM--002276 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 15 and 16. (The GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0190] It is understood that the invention includes the use of any fragments of keratin 19 sequences as long as the fragment can allow for the specific identification of keratin 19. Moreover, it is understood that there are naturally occurring variants of keratin 19 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Tubulin-Beta 3
[0191] Tubulin-beta 3, also known as CDCBM; TUBB4; beta-4; CFEOM3A, is a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6.
[0192] As used herein, Tubulin-beta 3 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI Gene ID for human Tubulin-beta 3 is 10381 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/10381 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority). Homo sapiens Tubulin-beta 3, variant 2, GenBank Accession No. NM--001197181 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 17 and 18. Homo sapiens Tubulin-beta 3, variant 1, GenBank Accession No. NM--006086 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 19 and 20. (The GenBank numbers are incorporated herein by reference in the versions available on the filing date of the application to which this application claims priority.)
[0193] It is understood that the invention includes the use of any fragments of Tubulin-beta 3 sequences as long as the fragment can allow for the specific identification of Tubulin-beta 3. Moreover, it is understood that there are naturally occurring variants of Tubulin-beta 3 which may or may not be associated with a specific disease state, the use of which are also included in this application.
Filamin B
[0194] Filamin B is also known as filamin-3, beta-filamin, ABP-280 homolog, filamin homolog 1, thyroid autoantigen, actin binding protein 278, actin-binding-like protein, Larsen syndrome 1 (autosomal dominant), AOI; FH1; SCT; TAP; LRS1; TABP; FLN-B; FLN1L; ABP-278; and ABP-280. The gene encodes a member of the filamin family. The encoded protein interacts with glycoprotein Ib alpha as part of the process to repair vascular injuries. The platelet glycoprotein Ib complex includes glycoprotein Ib alpha, and it binds the actin cytoskeleton. Mutations in this gene have been found in several conditions: atelosteogenesis type 1 and type 3; boomerang dysplasia; autosomal dominant Larsen syndrome; and spondylocarpotarsal synostosis syndrome. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.
[0195] As used herein, filamin B refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI gene ID for filamin B is 2317 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/2317 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
[0196] Homo sapiens filamin B, beta (FLNB), RefSeqGene on chromosome 3, locus NG--012801 is shown in SEQ ID NO: 21. Homo sapiens filamin B, beta (FLNB), transcript variant 1, GenBank Accession No. NM--001164317.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 22 and 23. Homo sapiens filamin B, beta (FLNB), transcript variant 3, GenBank Accession No. NM--001164318.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 24 and 25. Homo sapiens filamin B, beta (FLNB), transcript variant 4, GenBank Accession No. NM--001164319.1 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 26 and 27. Homo sapiens filamin B, beta (FLNB), transcript variant 2, GenBank Accession No. NM--001457.3 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 28 and 29. (Each GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0197] It is understood that the invention includes the use of any combination of one or more of the filamin B sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of filamin B. Methods of the invention and reagents can be used to detect single isoforms of filamin B, combinations of filamin β isoforms, or all of the filamin B isoforms simultaneously. Unless specified, filamin B can be considered to refer to one or more isoforms of filamin B, including total filamin B. Moreover, it is understood that there are naturally occurring variants of filamin B, which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
Lymphocyte Antigen 9
[0198] Lymphocyte antigen 9 (LY9) is also known as RP11-312J18.1, CD229, SLAMF3, hly9, mLY9, T-lymphocyte surface antigen Ly-9; and cell surface molecule Ly-9. LY9 belongs to the SLAM family of immunomodulatory receptors (see SLAMF1; MIM 603492) and interacts with the adaptor molecule SAP (SH2D1A; MIM 300490) (Graham et al., 2006).
[0199] As used herein, LY9 refers to both the gene and the protein unless clearly indicated otherwise by context. The NCBI gene ID for LY9 is 4063 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/4063 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
[0200] Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 2, GenBank Accession No. NM--001033667 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 30 and 31. Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 3, GenBank Accession No. NM--001261456 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 32 and 33. Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 4, GenBank Accession No. NM--001261457 amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 34 and 35. Homo sapiens lymphocyte antigen 9 (LY9), transcript variant 1, GenBank Accession No. NM--002348 is shown amino acid and nucleotide sequences, respectively, are provided in SEQ ID NOs: 36 and 37. (Each GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority.)
[0201] It is understood that the invention includes the use of any combination of one or more of the LY9 sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of LY9. Methods of the invention and reagents can be used to detect single isoforms of LY9, combinations of LY9 isoforms, or all of the LY9 isoforms simultaneously. Unless specified, LY9 can be considered to refer to one or more isoforms of LY9, including total LY9. Moreover, it is understood that there are naturally occurring variants of LY9, which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
Prostate Specific Antigen
[0202] Prostate-specific antigen (PSA) is also known as kallikrein-3, seminin, P-30 antigen, semenogelase, gamma-seminoprotein, APS, hK3, and KLK2A1. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its protein product is a protease present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. Serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms.
[0203] As used herein, PSA refers to both the gene and the protein, in both processed and unprocessed forms, unless clearly indicated otherwise by context. The NCBI gene ID for PSA is 354 and detailed information can be found at www.ncbi.nlm.nih.gov/gene/354 (incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
[0204] Homo sapiens PSA is located on chromosome 19 at 19q13.41Sequence: NC--000019.9 (51358171.51364020). Four splice variants of human PSA are known: Prostate-specific antigen isoform 3 preproprotein, NM--001030047.1; Prostate-specific antigen isoform 4 preproprotein, NM--001030048.1; Prostate-specific antigen isoform 6 preproprotein, NM--001030050.1; and Prostate-specific antigen isoform 1 preproprotein, NM--001648.2. (Each GenBank number is incorporated herein by reference in the version available on the filing date of the application to which this application claims priority).
[0205] It is understood that the invention includes the use of any combination of one or more of the PSA sequences provided in the sequence listing or any fragments thereof as long as the fragment can allow for the specific identification of PSA. Methods of the invention and reagents can be used to detect single isoforms of PSA, combinations of PSA isoforms, or all of the PSA isoforms simultaneously. Unless specified, PSA can be considered to refer to one or more isoforms of PSA, including total PSA. Moreover, it is understood that there are naturally occurring variants of PSA, which may or may not be associated with a specific disease state, the use of which are also included in the instant application.
Treatment of Disease States
[0206] The present invention provides methods for use of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9) to treat disease states in a subject, e.g., a mammal, e.g., a human.
[0207] The present invention also provides methods for treatment of a subject with prostate cancer with a therapeutic, e.g., a nucleic acid based therapeutic, that modulates the expression or activity of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
[0208] The invention also provides methods for selection and/or administration of known treatment agents, especially hormone based therapies vs. non-hormone based therapies, and aggressive or active treatment vs. "watchful waiting", depending on the detection of a change in the level of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), as compared to a control. The selection of treatment regimens can further include the detection of PSA to assist in selection of the therapeutic methods. Selection of treatment methods can also include other diagnostic considerations and patient characteristics including results from imaging studies, tumor size or growth rates, risk of poor outcomes, disruption of daily activities, and age.
[0209] As used herein, the term "aggressive oncological disorder", such as aggressive prostate cancer, refers to an oncological disorder involving a fast-growing tumor. An aggressive oncological disorder typically does not respond, responds poorly, or loses response to therapeutic treatment. For example, an prostate cancer may be considered to become an aggressive prostate cancer upon loss of response to hormone therapy, necessitating treatment with chemotherapy, surgery, and/or radiation. As used herein, an aggressive prostate cancer, for example, is one that will likely or has metastasized. As used herein, an aggressive prostate cancer is one that will result in significant changes in quality of life as the tumor grows. Active treatment is therapeutically indicated for an aggressive oncological disorder, e.g., aggressive prostate cancer.
[0210] As used herein, the term "non-aggressive oncological disorder" such as a non-aggressive prostate cancer, refers to an oncological disorder involving a slow-growing tumor. A non-aggressive oncological disorder typically responds favorably or moderately to therapeutic treatment or grows so slowly that immediate treatment is not warranted. A non-aggressive prostate tumor is one that a person skilled in the art, e.g., an oncologist, may decide to not actively treat with routine interventions for the treatment of cancer, e.g., chemotherapy, radiation, surgery, as the active treatment may do more harm than the disease, particularly in an older subject. A non-aggressive prostate tumor is one that a person skilled in the art may decide to monitor with "watchful waiting" rather than subjecting the person to any active therapeutic interventions to alter the presence or growth of the tumor (e.g., radiation, surgery, chemotherapy, hormone therapy).
Diagnostic/Prognostic Uses of the Invention
[0211] The invention provides methods for diagnosing an abnormal prostate state, e.g., BPH or an oncological disease state, e.g., prostate cancer, in a subject. The invention further provides methods for prognosing or monitoring progression or monitoring response of an abnormal prostate state, e.g., BPH or prostate cancer, to a therapeutic treatment during active treatment or watchful waiting.
[0212] The invention provides, in one embodiment, methods for diagnosing an oncological disorder, e.g., prostate cancer. The methods of the present invention can be practiced in conjunction with any other method used by the skilled practitioner to prognose the occurrence or recurrence of an oncologic disorder and/or the survival of a subject being treated for an oncologic disorder. The diagnostic and prognostic methods provided herein can be used to determine if additional and/or more invasive tests or monitoring should be performed on a subject. It is understood that a disease as complex as an oncological disorder is rarely diagnosed using a single test. Therefore, it is understood that the diagnostic, prognostic, and monitoring methods provided herein are typically used in conjunction with other methods known in the art. For example, the methods of the invention may be performed in conjunction with a morphological or cytological analysis of the sample obtained from the subject, imaging analysis, and/or physical exam. Cytological methods would include immunohistochemical or immunofluorescence detection (and quantitation if appropriate) of any other molecular marker either by itself, in conjunction with other markers. Other methods would include detection of other markers by in situ PCR, or by extracting tissue and quantitating other markers by real time PCR. PCR is defined as polymerase chain reaction.
[0213] Methods for assessing tumor progression during watchful waiting or the efficacy of a treatment regimen, e.g., chemotherapy, radiation therapy, surgery, hormone therapy, or any other therapeutic approach useful for treating an oncologic disorder in a subject are also provided. In these methods the amount of marker in a pair of samples (a first sample obtained from the subject at an earlier time point or prior to the treatment regimen and a second sample obtained from the subject at a later time point, e.g., at a later time point when the subject has undergone at least a portion of the treatment regimen) is assessed. It is understood that the methods of the invention include obtaining and analyzing more than two samples (e.g., 3, 4, 5, 6, 7, 8, 9, or more samples) at regular or irregular intervals for assessment of marker levels. Pairwise comparisons can be made between consecutive or non-consecutive subject samples. Trends of marker levels and rates of change of marker levels can be analyzed for any two or more consecutive or non-consecutive subject samples.
[0214] The invention also provides a method for determining whether an oncologic disorder, e.g., prostate cancer, is aggressive. The method comprises determining the amount of a marker present in a sample and comparing the amount to a control amount of the marker present in one or more control samples, as defined in Definitions, thereby determining whether an oncologic disorder is aggressive. Marker levels can be compared to marker levels in samples obtained at different times from the same subject or marker levels from normal or abnormal prostate state subjects. A rapid increase in the level of marker may be indicative of a more aggressive cancer than a slow increase or no increase or change in the marker level.
[0215] The methods of the invention may also be used to select a compound that is capable of modulating, i.e., decreasing, the aggressiveness of an oncologic disorder, e.g., prostate cancer. In this method, a cancer cell is contacted with a test compound, and the ability of the test compound to modulate the expression and/or activity of a marker in the invention in the cancer cell is determined, thereby selecting a compound that is capable of modulating aggressiveness of an oncologic disorder.
[0216] Using the methods described herein, a variety of molecules, may be screened in order to identify molecules which modulate, e.g., increase or decrease the expression and/or activity of a marker of the invention, i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), optionally in combination with PSA. Compounds so identified can be provided to a subject in order to inhibit the aggressiveness of an oncologic disorder in the subject, to prevent the recurrence of an oncologic disorder in the subject, or to treat an oncologic disorder in the subject.
Markers of the Invention
[0217] The invention relates to markers (hereinafter "biomarkers", "markers" or "markers of the invention"). The preferred markers of the invention are one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9). Methods of the invention also include use of the marker PSA in conjunction with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9).
[0218] The invention provides nucleic acids and proteins (e.g., isolated nucleic acids and isolated proteins or fragments thereof) that are encoded by, or correspond to, the markers (hereinafter "marker nucleic acids" and "marker proteins," respectively). These markers are particularly useful in screening for the presence of an altered prostate state, e.g., BPH or prostate cancer, in assessing aggressiveness and metastatic potential of an oncologic disorder, assessing the androgen dependent status of an oncological disorder, assessing whether a subject is afflicted with an oncological disorder, identifying a composition for treating an oncological disorder, assessing the efficacy of a compound for treating an oncological disorder, monitoring the progression of an oncological disorder, prognosing the aggressiveness of an oncological disorder, prognosing the survival of a subject with an oncological disorder, prognosing the recurrence of an oncological disorder, and prognosing whether a subject is predisposed to developing an oncological disorder.
[0219] In some embodiments of the present invention, other biomarkers can be used in connection with the methods of the present invention. As used herein, the term "one or more biomarkers" is intended to mean that one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B (FLNB), and lymphocyte antigen 9 (LY9), are assayed, optionally in combination with PSA, and, in various embodiments, more than one other biomarker may be assayed, such as two, three, four, five, six, seven, eight, nine, or more biomarkers in the list may be assayed. One or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and keratin 19 can be assayed in combination with one or more of filamin B, LY9, and PSA. Filamin B can be used in conjunction with one or more other biomarkers, e.g., LY9 or PSA, known to be associated with prostate cancer. LY9 can be used in conjunction with one or more other biomarkers, e.g., filamin B or PSA, known to be associated with prostate cancer. That is, any combination of the filamin B and LY9 biomarkers, optionally with PSA can be used, e.g., filamin B; LY9; filamin B and PSA; filamin B and LY9; LY9 and PSA; filamin B, LY9, and PSA; all of which can optionally be combined with other markers, e.g., one or more of keratins 4, 7, 8, 15, 18, 19, or tubulin-beta 3.
[0220] Methods, kits, and panels provided herein include any combination of 1, 2, 3, 4, 5, 6, 7, 8, or 9 markers of the set filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3. Such combinations include any of the following marker sets:
[0221] Marker sets with one member: filamin B; LY9; keratin 4; keratin 7; keratin 8; keratin 15; keratin 18; keratin 19; and tubulin-beta 3. Any single marker can be used in combination with PSA.
[0222] Marker sets with two members: filamin B, LY9; filamin B, keratin 4; filamin B, keratin 7; filamin B, keratin 8; filamin B, keratin 15; filamin B, keratin 18; filamin B, keratin 19; filamin B, tubulin-beta 3; LY9, keratin 4; LY9, keratin 7; LY9, keratin 8; LY9, keratin 15; LY9, keratin 18; LY9, keratin 19; LY9, tubulin-beta 3; keratin 4, keratin 7; keratin 4, keratin 8; keratin 4, keratin 15; keratin 4, keratin 18; keratin 4, keratin 19; keratin 4, tubulin-beta 3; keratin 7, keratin 8; keratin 7, keratin 15; keratin 7, keratin 18; keratin 7, keratin 19; keratin 7, tubulin-beta 3; keratin 8, keratin 15; keratin 8, keratin 18; keratin 8, keratin 19; keratin 8, tubulin-beta 3; keratin 15, keratin 18; keratin 15, keratin 19; keratin 15, tubulin-beta 3; keratin 18, tubulin-beta 3; keratin 18, keratin 19; and keratin 19, tubulin-beta 3. Any marker set can be used in combination with PSA.
[0223] Marker sets with three members: filamin B, LY9, keratin 4; filamin B, LY9, keratin 7; filamin B, LY9, keratin 8; filamin B, LY9, keratin 15; filamin B, LY9, keratin 18; filamin B, LY9, keratin 19; filamin B, LY9, tubulin-beta 3; filamin B, keratin 4, keratin 7; filamin B, keratin 4, keratin 8; filamin B, keratin 4, keratin 15; filamin B, keratin 4, keratin 18; filamin B, keratin 4, keratin 19; filamin B, keratin 4, tubulin-beta 3; filamin B, keratin 7, keratin 8; filamin B, keratin 7, keratin 15; filamin B, keratin 7, keratin 18; filamin B, keratin 7, keratin 19; filamin B, keratin 7, tubulin-beta 3; filamin B, keratin 8, keratin 15; filamin B, keratin 8, keratin 18; filamin B, keratin 8, keratin 19; filamin B, keratin 8, tubulin-beta 3; filamin B, keratin 15, keratin 18; filamin B, keratin 15, keratin 19; filamin B, keratin 15, tubulin-beta 3; filamin B, keratin 18, keratin 19; filamin B, keratin 18, tubulin-beta 3; filamin B, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7; LY9, keratin 4, keratin 8; LY9, keratin 4, keratin 15; LY9, keratin 4, keratin 18; LY9, keratin 4, keratin 19; LY9, keratin 4, tubulin-beta 3; LY9, keratin 7, keratin 8; LY9, keratin 7, keratin 15; LY9, keratin 7, keratin 18; LY9, keratin 7, keratin 19; LY9, keratin 7, tubulin-beta 3; LY9, keratin 8, keratin 15; LY9, keratin 8, keratin 18; LY9, keratin 8, keratin 19; LY9, keratin 8, tubulin-beta 3; LY9, keratin 15, keratin 18; LY9, keratin 15, keratin 19; LY9, keratin 15, tubulin-beta 3; LY9, keratin 18, keratin 19; LY9, keratin 18, tubulin-beta 3; LY9, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8; keratin 4, keratin 7, keratin 15; keratin 4, keratin 7, keratin 18; keratin 4, keratin 7, keratin 19; keratin 4, keratin 7, tubulin-beta 3; keratin 4, keratin 8, keratin 15; keratin 4, keratin 8, keratin 18; keratin 4, keratin 8, keratin 19; keratin 4, keratin 8, tubulin-beta 3; keratin 4, keratin 15, keratin 18; keratin 4, keratin 15, keratin 19; keratin 4, keratin 15, tubulin-beta 3; keratin 4, keratin 18, keratin 19; keratin 4, keratin 19, tubulin-beta 3; keratin 7, keratin 8, keratin 15; keratin 7, keratin 8, keratin 18; keratin 7, keratin 8, keratin 19; keratin 7, keratin 8, tubulin-beta 3; keratin 7, keratin 8, tubulin-beta 3; keratin 7, keratin 15, keratin 18; keratin 7, keratin 15, keratin 19; keratin 7, keratin 15, tubulin-beta 3; keratin 7, keratin 18, keratin 19; keratin 7, keratin 18, tubulin-beta 3; keratin 15, keratin 18, keratin 19; keratin 15, keratin 18, tubulin-beta 3; and keratin 18, keratin 19, tubulin-beta 3. Any marker set can be used in combination with PSA.
[0224] Marker sets with four members: filamin B, LY9, keratin 4, keratin 7; filamin B, LY9, keratin 4, keratin 8; filamin B, LY9, keratin 4, keratin 15; filamin B, LY9, keratin 4, keratin 18; filamin B, LY9, keratin 4, keratin 19; filamin B, LY9, keratin 4, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8; filamin B, keratin 4, keratin 7, keratin 15; filamin B, keratin 4, keratin 7, keratin 18; filamin B, keratin 4, keratin 7, tubulin-beta 3; filamin B, keratin 4, keratin 7, tubulin-beta 3; filamin B, keratin 7, keratin 8, keratin 15; filamin B, keratin 7, keratin 8, keratin 18; filamin B, keratin 7, keratin 8, keratin 19; filamin B, keratin 7, keratin 8, tubulin-beta 3; filamin B, keratin 8, keratin 15, keratin 18; filamin B, keratin 8, keratin 15, keratin 19; filamin B, keratin 8, keratin 15, tubulin-beta 3; filamin B, keratin 15, keratin 18, keratin 19; filamin B, keratin 15, keratin 18, tubulin-beta 3; filamin B, keratin 18, keratin 19, and tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8; LY9, keratin 4, keratin 7, keratin 15; LY9, keratin 4, keratin 7, keratin 18; LY9, keratin 4, keratin 7, keratin 19; LY9, keratin 4, keratin 7, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15; LY9, keratin 7, keratin 8, keratin 18; LY9, keratin 7, keratin 8, keratin 19; LY9, keratin 7, keratin 8, tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18; LY9, keratin 8, keratin 15, keratin 19; LY9, keratin 8, keratin 15, tubulin-beta 3; LY9, keratin 15, keratin 18, keratin 19; LY9, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 18, keratin 19, and tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15; keratin 4, keratin 7, keratin 8, keratin 18; keratin 4, keratin 7, keratin 8, keratin 19; keratin 4, keratin 7, keratin 8, tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18; keratin 4, keratin 8, keratin 15, keratin 19; keratin 4, keratin 8, keratin 15, tubulin-beta 3; keratin 4, keratin 15, keratin 18, keratin 19; keratin 4, keratin 15, keratin 18, tubulin-beta 3; keratin 4, keratin 18, keratin 19, tubulin-beta 3; keratin 8, keratin 15, keratin 18, keratin 19; keratin 8, keratin 15, keratin 18, tubulin-beta 3; and keratin 15, keratin 18, keratin 19, tubulin-beta 3. Any marker set can be used in combination with PSA.
[0225] Marker sets with five members: keratin 8, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; keratin 4, keratin 15, keratin 18, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18 tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 8, keratin 18, keratin 19 tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 19 tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, and tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, keratin 19; filamin B, keratin 15, keratin 18, keratin 19 tubulin-beta 3; filamin B, keratin 8, keratin 18, keratin 19 tubulin-beta 3; filamin B, keratin 8, keratin 15, keratin 19 tubulin-beta 3; filamin B, keratin 8, keratin 15, keratin 18, and tubulin-beta 3; filamin B, keratin 8, keratin 15, keratin 18, keratin 19; filamen B, LY9, keratin 18, keratin 19 tubulin-beta 3; filamen B, LY9, keratin 15, keratin 19 tubulin-beta 3; filamen B, LY9, keratin 15, keratin 18, tubulin-beta 3; filamen B, LY9, keratin 15, keratin 18, keratin 19; filamen B, keratin 4, keratin 18, keratin 19 tubulin-beta 3; filamen B, keratin 4, keratin 15, keratin 19 tubulin-beta 3; filamen B, keratin 4, keratin 15, keratin 18, tubulin-beta 3; filamen B, keratin 4, keratin 15, keratin 18, keratin 19; filamen B keratin 7, keratin 18, keratin 19 tubulin-beta 3; filamen B keratin 7, keratin 15, keratin 19, tubulin-beta 3; filamen B keratin 7, keratin 15, keratin 18, tubulin-beta 3; filamen B keratin 7, keratin 15, keratin 18, keratin 19; filamen B, keratin 8, keratin 18, keratin 19 tubulin-beta 3; filamen B, keratin 8, keratin 15, keratin 19 tubulin-beta 3; filamen B, keratin 8, keratin 15, keratin 18 tubulin-beta 3; filamen B, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 4, keratin 18, keratin 19 and tubulin-beta 3; LY9, keratin 4, keratin 15, keratin 19 tubulin-beta 3; LY9, keratin 4, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 15, keratin 18, keratin 19; LY9, keratin 7, keratin 18, keratin 19 tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 19 tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 18, and tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 18, keratin 19; LY9, keratin 8, keratin 18, keratin 19 tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 19 tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, and tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, keratin 19; keratin 4, keratin 7, keratin 18, keratin 19 tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 19 tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, and tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, keratin 19; keratin 4, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 19 tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, and tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, keratin 19; keratin 7, keratin 8, keratin 18, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 19 tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18, and tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; filamen B, LY9, keratin 4, keratin 19, tubulin-beta 3; filamen B, LY9, keratin 4, keratin 18, ubulin-beta 3; filamen B, LY9, keratin 4, keratin 18, keratin 19; filamen B, LY9, keratin 7, keratin 19, tubulin-beta 3; filamen B, LY9, keratin 7, keratin 18, tubulin-beta 3; filamen B, LY9, keratin 7, keratin 18, keratin 19; filamen B, LY9, keratin 8, keratin 19, tubulin-beta 3; filamen B, LY9, keratin 8, keratin 18, tubulin-beta 3; filamen B, LY9, keratin 8, keratin 18, keratin 19; filamen B, LY9, keratin 15, keratin 19, tubulin-beta 3; filamen B, LY9, keratin 15, keratin 18, tubulin-beta 3; filamen B, LY9, keratin 15, keratin 18, keratin 19; filamen B, keratin 4, keratin 7, keratin 19, tubulin-beta 3; filamen B, keratin 4, keratin 7, keratin 18, tubulin-beta 3; filamen B, keratin 4, keratin 7, keratin 18, keratin 19; filamen B, keratin 4, keratin 8, keratin 19, tubulin-beta 3; filamen B, keratin 4, keratin 8, keratin 18, tubulin-beta 3; filamen B, keratin 4, keratin 8, keratin 18, keratin 19; filamen B, keratin 4, keratin 15, keratin 19, tubulin-beta 3; filamen B, keratin 4, keratin 15, keratin 18, tubulin-beta 3; filamen B, keratin 4, keratin 15, keratin 18, keratin 19; filamen B, keratin 7, keratin 8, keratin 19, tubulin-beta 3; filamen B, keratin 7, keratin 8, keratin 18, tubulin-beta 3; filamen B, keratin 7, keratin 8, keratin 18, keratin 19; filamen B, keratin 8, keratin 15, keratin 19, tubulin-beta 3; filamen B, keratin 8, keratin 15, keratin 18, tubulin-beta 3; filamen B, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 4, keratin 7, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 18, keratin 19; LY9, keratin 4, keratin 8, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 18, keratin 19; LY9, keratin 4, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 15, keratin 18, keratin 19; LY9, keratin 7, keratin 8, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 18, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 18, keratin 19; LY9, keratin 7, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 18, keratin 19; LY9, keratin 8, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 8, keratin 15, keratin 18, keratin 19; keratin 4, keratin 7, keratin 8, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 18, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 18, keratin 19; keratin 4, keratin 7, keratin 15, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, keratin 19; keratin 4, keratin 8, keratin 15, keratin 19, tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, keratin 19; keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; and keratin 7, keratin 8, keratin 15, keratin 18, keratin 19. Any marker set can be used in combination with PSA.
[0226] Marker sets with six members: keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3; keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3; keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 4, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19; LY9, keratin 4, keratin 7, keratin 18, keratin 19, and tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 15, keratin 19, and tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19; LY9, keratin 4, keratin 7, keratin 8, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19; LY9, keratin 4, keratin 7, keratin 8, keratin 15, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 19; and LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18. Any marker set can be used in combination with PSA.
[0227] Marker sets with seven members: keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; filamin B, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; filamin B, LY9, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19; filamin B, LY9, keratin 4, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 18, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19; filamin B, LY9, keratin 4, keratin 7, keratin 18, keratin 19, and tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 15, keratin 19, and tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 15, keratin 18, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 18, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 19; and filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18. Any marker set can be used in combination with PSA.
[0228] Marker sets with eight members: LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 15, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 18, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 19, tubulin-beta 3; filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, tubulin-beta 3; and filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19. Any marker set can be used in combination with PSA.
[0229] Marker sets with nine members: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3.
[0230] Any marker set can be used in combination with PSA.
[0231] The invention provides for the use of various combinations and sub-combinations of markers. It is understood that any single marker or combination of the markers provided herein can be used in the invention unless clearly indicated otherwise. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0232] Throughout the application, one or more of filamin B, LY9 and keratin 19 is understood as any of: filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9 and keratin 19; or filamin B, LY9, and keratin 19. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0233] Throughout the application, combination of the filamin B and LY9 with PSA is understood as any of filamin B; LY9; filamin B and PSA; filamin B and LY9; LY9 and PSA; filamin B, LY9, and PSA.
[0234] Throughout the application, one or more prostate cancer markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 is understood as any of keratin 4; keratin 7; keratin 8; keratin 15; keratin 18; tubulin beta-3; keratin 4 and keratin 7; keratin 4 and keratin 8; keratin 4 and keratin 15; keratin 4 and keratin 18; keratin 4 and tubulin beta-3; keratin 7 and keratin 8; keratin 7 and keratin 15; keratin 7 and keratin 18; keratin and tubulin beta-3; keratin 8 and keratin 15; keratin 8 and keratin 18; keratin 8 and tubulin beta-3; keratin 15 and keratin 18; keratin 15 and tubulin beta-3; keratin 18 and tubulin beta-3; keratin 4, keratin 7 and keratin 8; keratin 4, keratin 7 and keratin 15; keratin 4, keratin 7 and keratin 18; keratin 4, keratin 7 and tubulin beta-3; keratin 4, keratin 8 and keratin 15; keratin 4, keratin 8 and keratin 18; keratin 4, keratin 8 and tubulin beta-e; keratin 4, keratin 15 and keratin 18; keratin 4, keratin 15 and tubulin beta-e; keratin 4, keratin 18 and tubulin beta-3; kertin 4, keratin 7, keratin 8 and keratin 15; keratin 4, keratin 7, keratin 8 and keratin 18; keratin 4, keratin 7, keratin 8 and tubulin beta-3; keratin 4, keratin 8, keratin 15 and keratin 18; keratin 4, keratin 8, keratin 15 and tubulin beta-3; keratin 4, keratin 15, keratin 18 and tubulin beta-3; keratin 4, keratin 7, keratin 8, keratin 15 and keratin 18; keratin 4, keratin 7, keratin 8, keratin 15, and tubulin beta-3; keratin 4, keratin 7, keratin 8, keratin 18, and tubulin beta-3; keratin 4, keratin 7, keratin 15, keratin 18, and tubulin beta-3; keratin 4, keratin 8, keratin 15, keratin 18, and tubulin beta-3; or keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0235] Throughout the application, one or more prostate cancer markers selected from the group consisting of keratin 7, 15, and 19 is understood as any of keratin 7; keratin 15; keratin 19; keratin 7 and 15; keratin 7 and 19; keratin 15 and 19; and keratin 7, 15, and 19. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0236] Throughout the application, one or more prostate cancer markers selected from the group consisting of keratin 7, 8, and 15 is understood as any of keratin 7; keratin 8; keratin 15; keratin 7 and 8; keratin 7 and 15; keratin 8 and 15; and keratin 7, 8, and 15. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0237] Throughout the application, one or more prostate cancer markers selected from the group consisting of keratin 7 and 15 is understood as any of keratin 7; keratin 15; or keratin 7 and 15. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0238] Throughout the application, one or more prostate cancer markers selected from the group consisting filamin B, LY9, or keratin 19 is understood as any of filamin B; LY9; keratin 19; filamin B and LY9; filamin B and keratin 19; LY9, and keratin 19; and filamin B, LY9, and keratin 19. Further, any single marker or combination of the markers of the invention can be used in conjunction with PSA.
[0239] In certain embodiments, methods of diagnosing, prognosing, and monitoring the treatment of prostate cancer by detecting the level sets of markers including of keratin 7, 15, or 19 and filamin B; keratin 7, 15, 19 or LY9; keratin 7, 15, 19, or PSA; keratin 4, 7, 15, or 19; keratin 7, 8, 15, or 19; keratin 7, 15, 18, or 19; and keratin 7, 15, 19, or tubulin-beta 3.
[0240] A "marker" is a gene whose altered level of expression in a tissue or cell from its expression level in normal or healthy tissue or cell is associated with a disease state, such as an abnormal prostate state. In a preferred embodiment, the marker is detected in a blood sample, e.g., serum or plasma. In one embodiment, the marker is detected in serum. In one embodiment, the marker is detected in plasma. In certain embodiments, the serum or plasma can be further processed to remove abundant blood proteins (e.g., albumin) or proteins that are not marker proteins prior to analysis. A "marker nucleic acid" is a nucleic acid (e.g., mRNA, cDNA) encoded by or corresponding to a marker of the invention. Such marker nucleic acids include DNA (e.g., cDNA) comprising the entire or a partial sequence of any of the nucleic acid sequences provided herein or the complement of such a sequence. The marker nucleic acids also include RNA comprising the entire or a partial sequence of any of the nucleic acid sequences provided herein or the complement of such a sequence, wherein all thymidine residues are replaced with uridine residues. A "marker protein" is a protein encoded by or corresponding to a marker of the invention. A marker protein comprises the entire or a partial sequence of any of the amino acid sequences provided herein. The terms "protein" and "polypeptide" are used interchangeably.
[0241] A "biological sample" or a "subject sample" is a body fluid or tissue in which a prostate cancer related marker may be present. In certain embodiments the sample is blood or a blood product (e.g., serum or plasma). In certain embodiments, the sample is a tissue sample, e.g., a tissue sample from at or near the site of the prostate hyperplasia or tumor, or the suspected prostate hyperplasia or tumor. A tissue sample can be obtained, for example, during biopsy or surgical resection of the prostate. A tissue sample can include one or more of normal tissue, hyperplasia, and cancerous tissue. Methods of distinguishing between such tissue types are known, e.g., histological analysis, immunohistochemical analysis. In certain embodiments, the control sample can be a normal portion of sample tissue removed from a subject.
[0242] An "oncological disorder-associated" body fluid is a fluid which, when in the body of a subject, contacts, or passes through oncological cells or into which cells or proteins shed from oncological cells are capable of passing. Exemplary oncological disorder-associated body fluids include blood fluids (e.g. whole blood, blood serum, blood having platelets removed therefrom), and are described in more detail below. Many oncological disorder-associated body fluids can have oncological cells therein, particularly when the cells are metastasizing. Cell-containing fluids which can contain oncological cells include, but are not limited to, whole blood, blood having platelets removed therefrom, lymph, prostatic fluid, urine, and semen.
[0243] The "normal" level of expression of a marker is the level of expression of the marker in cells of a human subject or patient or a population of subjects not afflicted with an oncological disorder or an abnormal prostate state, e.g., BPH or prostate cancer.
[0244] An "over-expression", "higher level of expression", "higher level", and the like of a marker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least 25% more, at least 50% more, at least 75% more, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten times the expression level of the marker in a control sample (e.g., sample from a healthy subject not having the marker associated disease, i.e., an abnormal prostate state) and preferably, the average expression level of the marker or markers in several control samples.
[0245] A "lower level of expression" or "lower level" of a marker refers to an expression level in a test sample that is less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the expression level of the marker in a control sample (e.g., sample from a healthy subjects not having the marker associated disease, i.e., an abnormal prostate state) and preferably, the average expression level of the marker in several control samples.
[0246] A "transcribed polynucleotide" or "nucleotide transcript" is a polynucleotide (e.g. an mRNA, hnRNA, a cDNA, or an analog of such RNA or cDNA) which is complementary to or having a high percentage of identity (e.g., at least 80% identity) with all or a portion of a mature mRNA made by transcription of a marker of the invention and normal post-transcriptional processing (e.g. splicing), if any, of the RNA transcript, and reverse transcription of the RNA transcript.
[0247] "Complementary" refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds ("base pairing") with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine. A first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. More preferably, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.
[0248] "Identical" or "identity" as used herein, refers to nucleotide sequence similarity between two regions of the same nucleic acid strand or between regions of two different nucleic acid strands. When a nucleotide residue position in both regions is occupied by the same nucleotide residue, then the regions are identical at that position. A first region is identical to a second region if at least one nucleotide residue position of each region is occupied by the same residue. Identity between two regions is expressed in terms of the proportion of nucleotide residue positions of the two regions that are occupied by the same nucleotide residue. By way of example, a region having the nucleotide sequence 5'-ATTGCC-3' and a region having the nucleotide sequence 5'-TATGGC-3' share 50% identity. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residue positions of each of the portions are occupied by the same nucleotide residue. More preferably, all nucleotide residue positions of each of the portions are occupied by the same nucleotide residue.
[0249] "Proteins of the invention" encompass marker proteins and their fragments; variant marker proteins and their fragments; peptides and polypeptides comprising an at least a 15 amino acid segment of a marker or variant marker protein; and fusion proteins comprising a marker or variant marker protein, or an at least a 15 amino acid segment of a marker or variant marker protein. In certain embodiments, a protein of the invention is a peptide sequence or epitope large enough to permit the specific binding of an antibody to the marker.
[0250] The invention further provides antibodies, antibody derivatives and antibody fragments which specifically bind with the marker proteins and fragments of the marker proteins of the present invention. Unless otherwise specified herewithin, the terms "antibody" and "antibodies" broadly encompass naturally-occurring forms of antibodies (e.g., IgG, IgA, IgM, IgE) and recombinant antibodies such as single-chain antibodies, chimeric and humanized antibodies and multi-specific antibodies, as well as fragments and derivatives of all of the foregoing, which fragments and derivatives have at least an antigenic binding site. Antibody derivatives may comprise a protein or chemical moiety conjugated to an antibody.
[0251] In certain embodiments, the positive or negative fold change refers to that of any gene described herein.
[0252] As used herein, "positive fold change" refers to "up-regulation" or "increase (of expression)" of a gene that is listed herein.
[0253] As used herein, "negative fold change" refers to "down-regulation" or "decrease (of expression)" of a gene that is listed herein.
[0254] Various aspects of the invention are described in further detail in the following subsections.
Isolated Nucleic Acid Molecules
[0255] One aspect of the invention pertains to isolated nucleic acid molecules, including nucleic acids which encode a marker protein or a portion thereof. Isolated nucleic acids of the invention also include nucleic acid molecules sufficient for use as hybridization probes to identify marker nucleic acid molecules, and fragments of marker nucleic acid molecules, e.g., those suitable for use as PCR primers for the amplification of a specific product or mutation of marker nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.
[0256] An "isolated" nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. In one embodiment, an "isolated" nucleic acid molecule (preferably a protein-encoding sequences) is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. In another embodiment, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule that is substantially free of cellular material includes preparations having less than about 30%, 20%, 10%, or 5% of heterologous nucleic acid (also referred to herein as a "contaminating nucleic acid").
[0257] A nucleic acid molecule of the present invention can be isolated using standard molecular biology techniques and the sequence information in the database records described herein. Using all or a portion of such nucleic acid sequences, nucleic acid molecules of the invention can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook et al., ed., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).
[0258] A nucleic acid molecule of the invention can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, nucleotides corresponding to all or a portion of a nucleic acid molecule of the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.
[0259] In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which has a nucleotide sequence complementary to the nucleotide sequence of a marker nucleic acid or to the nucleotide sequence of a nucleic acid encoding a marker protein. A nucleic acid molecule which is complementary to a given nucleotide sequence is one which is sufficiently complementary to the given nucleotide sequence that it can hybridize to the given nucleotide sequence thereby forming a stable duplex.
[0260] Moreover, a nucleic acid molecule of the invention can comprise only a portion of a nucleic acid sequence, wherein the full length nucleic acid sequence comprises a marker nucleic acid or which encodes a marker protein. Such nucleic acids can be used, for example, as a probe or primer. The probe/primer typically is used as one or more substantially purified oligonucleotides. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 15, more preferably at least about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 or more consecutive nucleotides of a nucleic acid of the invention.
[0261] Probes based on the sequence of a nucleic acid molecule of the invention can be used to detect transcripts or genomic sequences corresponding to one or more markers of the invention. In certain embodiments, the probes hybridize to nucleic acid sequences that traverse splice junctions. The probe comprises a label group attached thereto, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as part of a diagnostic test kit or panel for identifying cells or tissues which express or mis-express the protein, such as by measuring levels of a nucleic acid molecule encoding the protein in a sample of cells from a subject, e.g., detecting mRNA levels or determining whether a gene encoding the protein or its translational control sequences have been mutated or deleted.
[0262] The invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a marker protein (e.g., protein having the sequence provided in the sequence listing), and thus encode the same protein.
[0263] It will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequence can exist within a population (e.g., the human population). Such genetic polymorphisms can exist among individuals within a population due to natural allelic variation and changes known to occur in cancer. An allele is one of a group of genes which occur alternatively at a given genetic locus. In addition, it will be appreciated that DNA polymorphisms that affect RNA expression levels can also exist that may affect the overall expression level of that gene (e.g., by affecting regulation or degradation).
[0264] As used herein, the phrase "allelic variant" refers to a nucleotide sequence which occurs at a given locus or to a polypeptide encoded by the nucleotide sequence.
[0265] As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding a polypeptide corresponding to a marker of the invention. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of a given gene. Alternative alleles can be identified by sequencing the gene of interest in a number of different individuals. This can be readily carried out by using hybridization probes to identify the same genetic locus in a variety of individuals. Any and all such nucleotide variations and resulting amino acid polymorphisms or variations that are the result of natural allelic variation and that do not alter the functional activity are intended to be within the scope of the invention.
[0266] In another embodiment, an isolated nucleic acid molecule of the invention is at least 15, 20, 25, 30, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 550, 650, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3500, 4000, 4500, or more nucleotides in length and hybridizes under stringent conditions to a marker nucleic acid or to a nucleic acid encoding a marker protein. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% (65%, 70%, preferably 75%) identical to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in sections 6.3.1-6.3.6 of Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989). A preferred, non-limiting example of stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65° C.
Nucleic Acid Therapeutics
[0267] Nucleic acid therapeutics are well known in the art. Nucleic acid therapeutics include both single stranded and double stranded (i.e., nucleic acid therapeutics having a complementary region of at least 15 nucleotides in length that may be one or two nucleic acid strands) nucleic acids that are complementary to a target sequence in a cell. Nucleic acid therapeutics can be delivered to a cell in culture, e.g., by adding the nucleic acid to culture media either alone or with an agent to promote uptake of the nucleic acid into the cell. Nucleic acid therapeutics can be delivered to a cell in a subject, i.e., in vivo, by any route of administration. The specific formulation will depend on the route of administration.
[0268] As used herein, and unless otherwise indicated, the term "complementary," when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.
[0269] Sequences can be "fully complementary" with respect to each when there is base-pairing of the nucleotides of the first nucleotide sequence with the nucleotides of the second nucleotide sequence over the entire length of the first and second nucleotide sequences. However, where a first sequence is referred to as "substantially complementary" with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs as is common in double stranded nucleic acid therapeutics, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as "fully complementary" for the purposes described herein.
[0270] "Complementary" sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs includes, but not limited to, G:U Wobble or Hoogstein base pairing.
[0271] The terms "complementary," "fully complementary", and "substantially complementary" herein may be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between an antisense nucleic acid or the antisense strand of dsRNA and a target sequence, as will be understood from the context of their use.
[0272] As used herein, a polynucleotide that is "substantially complementary to at least part of" a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding filamin B, LY9, a keratin, tubulin-beta 3, or PSA) including a 5' UTR, an open reading frame (ORF), or a 3' UTR. For example, a polynucleotide is complementary to at least a part of filamin B, LY9, a keratin, tubulin-beta 3, or PSA mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding filamin B, LY9, a keratin, tubulin-beta 3, or PSA.
[0273] Nucleic acid therapeutics typically include chemical modifications to improve their stability and to modulate their pharmacokinetic and pharmacodynamic properties. For example, the modifications on the nucleotides can include, but are not limited to, LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-- allyl, 2'-fluoro, 2'-deoxy, 2'-hydroxyl, and combinations thereof.
[0274] Nucleic acid therapeutics may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both (in nucleic acid therapeutics including a sense strand) in any position of the strand. For instance, the internucleotide linkage modification may occur on every nucleotide on the sense strand or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.
Single Stranded Nucleic Acid Therapeutics
[0275] Antisense nucleic acid therapeutic agent single stranded nucleic acid therapeutics, typically about 16 to 30 nucleotides in length and are complementary to a target nucleic acid sequence in the target cell, either in culture or in an organism. Patents directed to antisense nucleic acids, chemical modifications, and therapeutic uses are provided, for example, in U.S. Pat. No. 5,898,031 related to chemically modified RNA-containing therapeutic compounds, and U.S. Pat. No. 6,107,094 related methods of using these compounds as therapeutic agent. U.S. Pat. No. 7,432,250 related to methods of treating patients by administering single-stranded chemically modified RNA-like compounds; and U.S. Pat. No. 7,432,249 related to pharmaceutical compositions containing single-stranded chemically modified RNA-like compounds. U.S. Pat. No. 7,629,321 is related to methods of cleaving target mRNA using a single-stranded oligonucleotide having a plurality RNA nucleosides and at least one chemical modification. Each of the patents listed in the paragraph are incorporated herein by reference.
Double Stranded Nucleic Acid Therapeutics
[0276] In many embodiments, the duplex region is 15-30 nucleotide pairs in length. In some embodiments, the duplex region is 17-23 nucleotide pairs in length, 17-25 nucleotide pairs in length, 23-27 nucleotide pairs in length, 19-21 nucleotide pairs in length, or 21-23 nucleotide pairs in length.
[0277] In certain embodiments, each strand has 15-30 nucleotides.
[0278] The RNAi agents that are used in the methods of the invention include agents with chemical modifications as disclosed, for example, in Publications WO 2009/073809 and WO/2012/037254, the entire contents of each of which are incorporated herein by reference.
[0279] An "RNAi agent," "double stranded RNAi agent," double-stranded RNA (dsRNA) molecule, also referred to as "dsRNA agent," "dsRNA", "siRNA", "iRNA agent," as used interchangeably herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary, as defined below, nucleic acid strands. As used herein, an RNAi agent can also include dsiRNA (see, e.g., US Patent publication 20070104688, incorporated herein by reference). In general, the majority of nucleotides of each strand are ribonucleotides, but as described herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, an "RNAi agent" may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by "RNAi agent" for the purposes of this specification and claims.
[0280] The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3'-end of one strand and the 5'-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a "hairpin loop." Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3'-end of one strand and the 5'-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a "linker." The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi agent may comprise one or more nucleotide overhangs. The term "siRNA" is also used herein to refer to an RNAi agent as described above.
[0281] In another aspect, the agent is a single-stranded antisense RNA molecule. An antisense RNA molecule is complementary to a sequence within the target mRNA. Antisense RNA can inhibit translation in a stoichiometric manner by base pairing to the mRNA and physically obstructing the translation machinery, see Dias, N. et al., (2002) Mol Cancer Ther 1:347-355. The antisense RNA molecule may have about 15-30 nucleotides that are complementary to the target mRNA. For example, the antisense RNA molecule may have a sequence of at least 15, 16, 17, 18, 19, 20 or more contiguous nucleotides complementary to the filamin B or LY9 sequences provided herein.
[0282] The term "antisense strand" refers to the strand of a double stranded RNAi agent which includes a region that is substantially complementary to a target sequence (e.g., a human TTR mRNA). As used herein, the term "region complementary to part of an mRNA encoding transthyretin" refers to a region on the antisense strand that is substantially complementary to part of a TTR mRNA sequence. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most tolerated in the terminal regions and, if present, are generally in a terminal region or regions, e.g., within 6, 5, 4, 3, or 2 nucleotides of the 5' and/or 3' terminus.
[0283] The term "sense strand," as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.
[0284] The invention also includes molecular beacon nucleic acids having at least one region which is complementary to a nucleic acid of the invention, such that the molecular beacon is useful for quantitating the presence of the nucleic acid of the invention in a sample. A "molecular beacon" nucleic acid is a nucleic acid comprising a pair of complementary regions and having a fluorophore and a fluorescent quencher associated therewith. The fluorophore and quencher are associated with different portions of the nucleic acid in such an orientation that when the complementary regions are annealed with one another, fluorescence of the fluorophore is quenched by the quencher. When the complementary regions of the nucleic acid are not annealed with one another, fluorescence of the fluorophore is quenched to a lesser degree. Molecular beacon nucleic acids are described, for example, in U.S. Pat. No. 5,876,930.
Isolated Proteins and Antibodies
[0285] One aspect of the invention pertains to isolated marker proteins and biologically active portions thereof, as well as polypeptide fragments suitable for use as immunogens to raise antibodies directed against a marker protein or a fragment thereof. In one embodiment, the native marker protein can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, a protein or peptide comprising the whole or a segment of the marker protein is produced by recombinant DNA techniques. Alternative to recombinant expression, such protein or peptide can be synthesized chemically using standard peptide synthesis techniques.
[0286] An "isolated" or "purified" protein or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of protein in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein"). When the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. When the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.
[0287] Biologically active portions of a marker protein include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the marker protein, which include fewer amino acids than the full length protein, and exhibit at least one activity of the corresponding full-length protein. Typically, biologically active portions comprise a domain or motif with at least one activity of the corresponding full-length protein. A biologically active portion of a marker protein of the invention can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Moreover, other biologically active portions, in which other regions of the marker protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the native form of the marker protein.
[0288] Preferred marker proteins are encoded by nucleotide sequences provided in the sequence listing. Other useful proteins are substantially identical (e.g., at least about 40%, preferably 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to one of these sequences and retain the functional activity of the corresponding naturally-occurring marker protein yet differ in amino acid sequence due to natural allelic variation or mutagenesis.
[0289] To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. Preferably, the percent identity between the two sequences is calculated using a global alignment. Alternatively, the percent identity between the two sequences is calculated using a local alignment. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions (e.g., overlapping positions)×100). In one embodiment the two sequences are the same length. In another embodiment, the two sequences are not the same length.
[0290] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the BLASTN and BLASTX programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleotide searches can be performed with the BLASTN program, score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the invention. BLAST protein searches can be performed with the BLASTP program, score=50, wordlength=3 to obtain amino acid sequences homologous to a protein molecules of the invention. To obtain gapped alignments for comparison purposes, a newer version of the BLAST algorithm called Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, which is able to perform gapped local alignments for the programs BLASTN, BLASTP and BLASTX. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., BLASTX and BLASTN) can be used. See http://www.ncbi.nlm.nih.gov. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444-2448. When using the FASTA algorithm for comparing nucleotide or amino acid sequences, a PAM120 weight residue table can, for example, be used with a k-tuple value of 2.
[0291] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, only exact matches are counted.
[0292] Another aspect of the invention pertains to antibodies directed against a protein of the invention. In preferred embodiments, the antibodies specifically bind a marker protein or a fragment thereof. The terms "antibody" and "antibodies" as used interchangeably herein refer to immunoglobulin molecules as well as fragments and derivatives thereof that comprise an immunologically active portion of an immunoglobulin molecule, (i.e., such a portion contains an antigen binding site which specifically binds an antigen, such as a marker protein, e.g., an epitope of a marker protein). An antibody which specifically binds to a protein of the invention is an antibody which binds the protein, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the protein. Examples of an immunologically active portion of an immunoglobulin molecule include, but are not limited to, single-chain antibodies (scAb), F(ab) and F(ab')2 fragments.
[0293] An isolated protein of the invention or a fragment thereof can be used as an immunogen to generate antibodies. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments for use as immunogens. The antigenic peptide of a protein of the invention comprises at least 8 (preferably 10, 15, 20, or 30 or more) amino acid residues of the amino acid sequence of one of the proteins of the invention, and encompasses at least one epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with the protein. Preferred epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity sequence analysis, hydrophilicity sequence analysis, or similar analyses can be used to identify hydrophilic regions. In preferred embodiments, an isolated marker protein or fragment thereof is used as an immunogen.
[0294] The invention provides polyclonal and monoclonal antibodies. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope. Preferred polyclonal and monoclonal antibody compositions are ones that have been selected for antibodies directed against a protein of the invention. Particularly preferred polyclonal and monoclonal antibody preparations are ones that contain only antibodies directed against a marker protein or fragment thereof. Methods of making polyclonal, monoclonal, and recombinant antibody and antibody fragments are well known in the art.
Predictive Medicine
[0295] The present invention pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining the level of expression of one or more marker proteins or nucleic acids, in order to determine whether an individual is at risk of developing a disease or disorder, such as, without limitation, an oncological disorder, e.g., prostate cancer. Such assays can be used for prognostic or predictive purposes to thereby prophylactically treat an individual prior to the onset of the disorder.
[0296] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs or other compounds administered either to inhibit an oncological disorder, e.g., prostate cancer, or to treat or prevent any other disorder (i.e. in order to understand any carcinogenic effects that such treatment may have)) on the expression or activity of a marker of the invention in clinical trials. These and other agents are described in further detail in the following sections.
[0297] A. Diagnostic Assays
[0298] An exemplary method for detecting the presence or absence or change of expression level of a marker protein or nucleic acid in a biological sample involves obtaining a biological sample (e.g. an oncological disorder-associated body fluid) from a test subject and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA). The detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo.
[0299] Methods provided herein for detecting the presence, absence, change of expression level of a marker protein or nucleic acid in a biological sample include obtaining a biological sample from a subject that may or may not contain the marker protein or nucleic acid to be detected, contacting the sample with a marker-specific binding agent (i.e., one or more marker-specific binding agents) that is capable of forming a complex with the marker protein or nucleic acid to be detected, and contacting the sample with a detection reagent for detection of the marker--marker-specific binding agent complex, if formed. It is understood that the methods provided herein for detecting an expression level of a marker in a biological sample includes the steps to perform the assay. In certain embodiments of the detection methods, the level of the marker protein or nucleic acid in the sample is none or below the threshold for detection.
[0300] The methods include formation of either a transient or stable complex between the marker and the marker-specific binding agent. The methods require that the complex, if formed, be formed for sufficient time to allow a detection reagent to bind the complex and produce a detectable signal (e.g., fluorescent signal, a signal from a product of an enzymatic reaction, e.g., a peroxidase reaction, a phosphatase reaction, a beta-galactosidase reaction, or a polymerase reaction).
[0301] In certain embodiments, all markers are detected using the same method. In certain embodiments, all markers are detected using the same biological sample (e.g., same body fluid or tissue). In certain embodiments, different markers are detected using various methods. In certain embodiments, markers are detected in different biological samples.
[0302] 1. Protein Detection
[0303] In certain embodiments of the invention, the marker to be detected is a protein. Proteins are detected using a number of assays in which a complex between the marker protein to be detected and the marker specific binding agent would not occur naturally, for example, because one of the components is not a naturally occurring compound or the marker for detection and the marker specific binding agent are not from the same organism (e.g., human marker proteins detected using marker-specific binding antibodies from mouse, rat, or goat). In a preferred embodiment of the invention, the marker protein for detection is a human marker protein. In certain detection assays, the human markers for detection are bound by marker-specific, non-human antibodies, thus, the complex would not be formed in nature. The complex of the marker protein can be detected directly, e.g., by use of a labeled marker-specific antibody that binds directly to the marker, or by binding a further component to the marker-marker-specific antibody complex. In certain embodiments, the further component is a second marker-specific antibody capable of binding the marker at the same time as the first marker-specific antibody. In certain embodiments, the further component is a secondary antibody that binds to a marker-specific antibody, wherein the secondary antibody preferably linked to a detectable label (e.g., fluorescent label, enzymatic label, biotin). When the secondary antibody is linked to an enzymatic detectable label (e.g., a peroxidase, a phosphatase, a beta-galactosidase), the secondary antibody is detected by contacting the enzymatic detectable label with an appropriate substrate to produce a colorimetric, fluorescent, or other detectable, preferably quantitatively detectable, product. Antibodies for use in the methods of the invention can be polyclonal, however, in a preferred embodiment monoclonal antibodies are used. An intact antibody, or a fragment or derivative thereof (e.g., Fab or F(ab')2) can be used in the methods of the invention. Such strategies of marker protein detection are used, for example, in ELISA, RIA, western blot, and immunofluorescence assay methods.
[0304] In certain detection assays, the marker present in the biological sample for detection is an enzyme and the detection reagent is an enzyme substrate. For example, the enzyme can be a protease and the substrate can be any protein that includes an appropriate protease cleavage site. Alternatively, the enzyme can be a kinase and the substrate can be any substrate for the kinase. In preferred embodiments, the substrate which forms a complex with the marker enzyme to be detected is not the substrate for the enzyme in a human subject.
[0305] In certain embodiments, the marker-marker-specific binding agent complex is attached to a solid support for detection of the marker. The complex can be formed on the substrate or formed prior to capture on the substrate. For example, in an ELISA, RIA, immunoprecipitation assay, western blot, immunofluorescence assay, in gel enzymatic assay the marker for detection is attached to a solid support, either directly or indirectly. In an ELISA, RIA, or immunofluorescence assay, the marker is typically attached indirectly to a solid support through an antibody or binding protein. In a western blot or immunofluorescence assay, the marker is typically attached directly to the solid support. For in-gel enzyme assays, the marker is resolved in a gel, typically an acrylamide gel, in which a substrate for the enzyme is integrated.
[0306] 2. Nucleic Acid Detection
[0307] In certain embodiments of the invention, the marker is a nucleic acid. Nucleic acids are detected using a number of assays in which a complex between the marker nucleic acid to be detected and a marker-specific probe would not occur naturally, for example, because one of the components is not a naturally occurring compound. In certain embodiments, the analyte comprises a nucleic acid and the probe comprises one or more synthetic single stranded nucleic acid molecules, e.g., a DNA molecule, a DNA-RNA hybrid, a PNA, or a modified nucleic acid molecule containing one or more artificial bases, sugars, or backbone moieties. In certain embodiments, the synthetic nucleic acid is a single stranded is a DNA molecule that includes a fluorescent label. In certain embodiments, the synthetic nucleic acid is a single stranded oligonucleotide molecule of about 12 to about 50 nucleotides in length. In certain embodiments, the nucleic acid to be detected is an mRNA and the complex formed is an mRNA hybridized to a single stranded DNA molecule that is complementary to the mRNA. In certain embodiments, an RNA is detected by generation of a DNA molecule (i.e., a cDNA molecule) first from the RNA template using the single stranded DNA that hybridizes to the RNA as a primer, e.g., a general poly-T primer to transcribe poly-A RNA. The cDNA can then be used as a template for an amplification reaction, e.g., PCR, primer extension assay, using a marker-specific probe. In certain embodiments, a labeled single stranded DNA can be hybridized to the RNA present in the sample for detection of the RNA by fluorescence in situ hybridization (FISH) or for detection of the RNA by northern blot.
[0308] For example, in vitro techniques for detection of mRNA include northern hybridizations, in situ hybridizations, and rtPCR. In vitro techniques for detection of genomic DNA include Southern hybridizations. Techniques for detection of mRNA include PCR, northern hybridizations and in situ hybridizations. Methods include both qualitative and quantitative methods.
[0309] A general principle of such diagnostic, prognostic, and monitoring assays involves preparing a sample or reaction mixture that may contain a marker, and a probe, under appropriate conditions and for a time sufficient to allow the marker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture. These assays can be conducted in a variety of ways known in the art, e.g., ELISA assay, PCR, FISH.
[0310] 3. Detection of Expression Levels
[0311] Marker levels can be detected based on the absolute expression level or a normalized or relative expression level. Detection of absolute marker levels may be preferable when monitoring the treatment of a subject or in determining if there is a change in the prostate cancer status of a subject. For example, the expression level of one or more markers can be monitored in a subject undergoing treatment for prostate cancer, e.g., at regular intervals, such a monthly intervals. A modulation in the level of one or more markers can be monitored over time to observe trends in changes in marker levels. Expression levels of one or more of filamin B, LY9, or keratin 19 in the subject may be higher than the expression level of those markers in a normal sample, but may be lower than the prior expression level, thus indicating a benefit of the treatment regimen for the subject. Similarly, rates of change of marker levels can be important in a subject who is not subject to active treatment for prostate cancer (e.g., watchful waiting). Changes, or not, in marker levels may be more relevant to treatment decisions for the subject than marker levels present in the population. Rapid changes in marker levels in a subject who otherwise appears to have a normal prostate may be indicative of an abnormal prostate state, even if the markers are within normal ranges for the population.
[0312] As an alternative to making determinations based on the absolute expression level of the marker, determinations may be based on the normalized expression level of the marker. Expression levels are normalized by correcting the absolute expression level of a marker by comparing its expression to the expression of a gene that is not a marker, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, e.g., a non-cancer sample, or between samples from different sources.
[0313] Alternatively, the expression level can be provided as a relative expression level as compared to an appropriate control, e.g., population control, adjacent normal tissue control, earlier time point control, etc. Preferably, the samples used in the baseline determination will be from non-cancer cells. The choice of the cell source is dependent on the use of the relative expression level. Using expression found in normal tissues as a mean expression score aids in validating whether the marker assayed is cancer specific (versus normal cells). In addition, as more data is accumulated, the mean expression value can be revised, providing improved relative expression values based on accumulated data. Expression data from cancer cells provides a means for grading the severity of the cancer state.
Diagnostic, Prognostic, and Treatment Methods
[0314] The invention provides methods for detecting an abnormal prostate state in a subject by
[0315] (1) contacting a biological sample from a subject with a panel of one or more detection reagents wherein each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate-cancer related protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0316] (2) measuring the amount of each prostate-cancer related marker detected in the biological sample by each detection reagent; and
[0317] (3) comparing the level of expression of the one or more prostate-cancer related protein in the biological sample obtained from the subject with a level of expression of the one or more prostate-cancer related protein in a normal control sample, thereby detecting an abnormal prostate state.
[0318] In certain embodiments, detecting an abnormal prostate state comprises diagnosing prostate cancer status in a subject. In certain embodiments, an abnormal prostate state comprises identifying a predisposed to developing prostate cancer.
[0319] The invention provides methods for monitoring the treatment of prostate cancer in a subject by
[0320] (1) contacting a first biological sample obtained from the subject prior to administering at least a portion of a treatment regimen to the subject with a panel of one or more detection reagents wherein each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0321] (2) contacting a second biological sample obtained from the subject after administering at least a portion of a treatment regimen to the subject with a panel of one or more detection reagents wherein each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0322] (3) measuring the amount of prostate-cancer related marker detected in each the first biological sample and the second biological sample by each detection reagent; and
[0323] (4) comparing the level of expression of the one or more prostate-cancer related markers in the first sample with the expression level of the one or more prostate-cancer related markers in the second sample, thereby monitoring the treatment of prostate cancer in the subject.
[0324] The invention provides method of selecting for administration of active treatment or against administration of active treatment of prostate cancer in a subject by
[0325] (1) contacting a first biological sample obtained from the subject prior to administering a treatment regimen to the subject with a panel of one or more detection reagents wherein each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0326] (2) contacting a second biological sample obtained from the subject prior to administering a treatment regimen to the subject with a panel of one or more detection reagents wherein each detection reagent is specific for one prostate-cancer related protein; wherein the prostate-cancer related proteins are selected from the prostate protein set as follows: filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3;
[0327] (3) measuring the amount of prostate-cancer related marker detected in each the first biological sample and the second biological sample by each detection reagent; and
[0328] (4) comparing the level of expression of the one or more prostate-cancer related markers in the first sample with the expression level of the one or more prostate-cancer related markers in the second sample, wherein selecting for administration of active treatment or against administration of active treatment of prostate cancer is based on the presence or absence of changes in the level of expression of one or more markers between the first sample and the second sample.
[0329] In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is two or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is three or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is four or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is five or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is six or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is seven or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is eight or more markers. In certain embodiments of the diagnostic and monitoring methods provided herein, one or more prostate-cancer related markers is nine or more markers.
[0330] In certain embodiments of the diagnostic methods provided herein, an increase in the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample as compared to the level of expression of the one or more prostate-cancer related markers in a normal control sample is an indication that the subject is afflicted with prostate cancer. In certain embodiments of the diagnostic methods provided herein, no increase in the detected expression level of one or more of filamin B, LY9, and keratin 19 in the biological sample as compared to the expression level in a normal control sample is an indication that the subject is not afflicted with prostate cancer or not predisposed to developing prostate cancer.
[0331] In certain embodiments of the diagnostic methods provided herein, an increase in the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the biological sample as compared to the level of expression of the one or more prostate-cancer related markers in a normal control sample is an indication that the subject is predisposed to developing prostate cancer.
[0332] In certain embodiments of the monitoring methods provided herein, no increase in the detected level of expression of any of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication that the therapy is efficacious for treating prostate cancer in the subject. In certain embodiments the monitoring methods provided herein, further comprise comparing the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the first sample or the level of expression of one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample with the expression of the one or more prostate-cancer related markers in a control sample.
[0333] In certain embodiments of the monitoring methods provided herein, an increase in the level of expression of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication for selection of active treatment of prostate cancer in the subject. In certain embodiments of the monitoring methods provided herein, no increase in the detected level of expression of any of the one or more prostate-cancer related markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers in the first sample is an indication against selection of active treatment of prostate cancer in the subject. In certain embodiments of the monitoring methods provided herein, wherein an increased expression level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the expression level in the first sample is an indication that the therapy is not efficacious in the treatment of prostate cancer.
[0334] In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is selected from the group of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is selected from the group of keratin 7, keratin 8, and keratin 15. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is selected from the group of keratin 7, keratin 15, and keratin 19. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers is keratin 7 or keratin 15. In certain embodiments of the diagnostic and monitoring methods provided herein, the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the biological sample is compared to the level of the one or more prostate-cancer related markers in a normal control sample is indicative of a modulation in prostate cancer status.
[0335] In certain embodiments of the monitoring methods provided herein, modulation of the level of expression of the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample as compared to the level of expression of the one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample is indicative of a change in prostate cancer status in response to treatment of the prostate cancer in the subject. In certain embodiments of the monitoring methods provided herein, the methods further comprise comparing the level of expression of one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; or the level of expression of one or more prostate-cancer related markers selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample to the level of expression of one or more prostate-cancer related markers in a normal control sample.
[0336] In certain embodiments the diagnostic methods provided herein further comprise detecting the level of expression of prostate specific antigen (PSA) in the biological sample and preferably further comprise comparing the level of expression of PSA in the biological sample to a PSA expression level in a normal control sample. In certain embodiments, the combination of PSA level with one or more of the prostate-cancer maker levels increases the predictive value of the method.
[0337] In certain embodiments the monitoring methods provided herein further comprise detecting the level of expression of prostate specific antigen (PSA) in the first sample and the second sample, and preferably further comprising comparing the level of expression of PSA in the first sample with the level of expression of PSA in the second sample. In certain monitoring methods, the change in PSA level in combination with the change in prostate-cancer maker level increases the predictive value of the method.
[0338] In certain embodiments the diagnostic and monitoring methods provided herein further comprise comparing the detected level of the one or more prostate markers in the biological samples with one or more control samples wherein the control sample is one or more of a sample from the same subject at an earlier time point than the biological sample, a sample from a subject with benign prostatic hyperplasia (BPH), a sample from a subject with non-metastatic prostate cancer, a sample from a subject with metastatic prostate cancer, a sample from a subject with androgen sensitive prostate cancer, a sample from a subject with androgen insensitive prostate cancer, a sample from a subject with aggressive prostate cancer, and sample obtained from a subject with non-aggressive prostate cancer. Comparison of the marker levels in the biological samples with control samples from subjects with various normal and abnormal prostate states facilitates the differentiation between various prostate states including normal prostate and prostate cancer, benign prostate hyperplasia and prostate cancer, benign prostate hyperplasia and normal prostate, androgen dependent and androgen independent prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, aggressive prostate cancer and non-aggressive prostate cancer, or between any two or more prostate states including normal prostate, prostate cancer, benign prostate hyperplasia, androgen dependent prostate cancer, androgen independent prostate cancer, aggressive prostate cancer, non-aggressive prostate cancer, metastatic prostate cancer, and non-metastatic prostate cancer.
[0339] In certain embodiments the diagnostic and monitoring methods provided herein further comprising detecting the size of the prostate tumor in the subject. In certain embodiments the monitoring methods provided herein further comprise detecting a change in the size or relative aggressiveness of the tumor. In certain embodiments, the size of the prostate tumor in the subject is detected prior to administering the at least a portion of a treatment regimen to the subject. In certain embodiments, the size of the prostate tumor in the subject is detected after administering the at least a portion of a treatment regimen to the subject. Certain monitoring methods, further comprise comparing the size of the prostate tumor in the subject prior to administering the at least a portion of a treatment regimen to the subject to the size of the prostate tumor in the subject after administering the at least a portion of a treatment regimen to the subject.
[0340] In certain embodiments the diagnostic and monitoring methods provided herein further comprising obtaining a subject sample.
[0341] In certain embodiments the diagnostic and monitoring methods provided herein further comprising selecting a treatment regimen for the subject based on the level expression of one or more of the prostate-cancer related markers provided in claims 1.
[0342] In certain embodiments the diagnostic and monitoring methods provided herein further comprising selecting a subject for having or being suspected of having prostate cancer.
[0343] In certain embodiments the diagnostic and monitoring methods provided herein further comprising treating the subject with a regimen including one or more treatments selected from the group consisting of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, and chemotherapy.
[0344] In certain embodiments the diagnostic and monitoring methods provided herein further comprising selecting the one or more specific treatment regimens for the subject based on the results of the diagnostic and monitoring methods provided herein. In certain embodiments, the treatment method is maintained based on the results from the diagnostic or prognostic methods. n certain embodiments, the treatment method is changed based on the results from the diagnostic or prognostic methods.
[0345] In certain embodiments, a change the treatment regimen comprises changing a hormone based therapy treatment. In certain embodiments, treatments for prostate cancer include one or more of surgery, radiation, hormone therapy, antibody therapy, therapy with growth factors, cytokines, or chemotherapy based on the results of a method of any one of claims 1-64 for an interval prior to performing a subsequent diagnostic, prognostic, or monitoring method provided herein.
[0346] In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises isolating a component of the biological sample.
[0347] In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises labeling a component of the biological sample.
[0348] In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises amplifying a component of a biological sample.
[0349] In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises forming a complex with a probe and a component of a biological sample. In certain embodiments, forming a complex with a probe comprises forming a complex with at least one non-naturally occurring reagent. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises processing the biological sample. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level of at least two markers comprises a panel of markers. In certain embodiments of the diagnostic and monitoring methods provided herein, the method of detecting a level comprises attaching the marker to be detected to a solid surface.
[0350] The invention provides methods of selecting for administration of active treatment or against administration of active treatment of prostate cancer in a subject comprising:
[0351] (1) detecting a level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta in a first sample obtained from the subject having prostate cancer wherein the subject has not been actively treated for prostate cancer;
[0352] (2) detecting a level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in a second sample from the subject;
[0353] (3) comparing the level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the first sample with the level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the second sample;
[0354] wherein selecting for administration of active treatment or against administration of active treatment of prostate cancer is based on the presence or absence of changes in the level of expression of one or more markers between the first sample and the second sample.
[0355] In certain embodiments, the method further comprising obtaining a third sample obtained from the subject, detecting a level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the third sample, and comparing the level of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 in the third sample with the level of the one or more markers in the first sample or the one or more markers in the second sample.
[0356] In certain embodiments, an increased level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample is an indication that the therapy is not efficacious in the treatment of prostate cancer.
[0357] In certain embodiments, an increased of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample is an indication for selecting active treatment for prostate cancer.
[0358] In certain embodiments, the method further comprises comparing the level of one or more markers selected from the group consisting of filamin B, LY9, and keratin 19 in the first sample or the level of one or more markers selected from the group consisting of filamin B, LY9, and keratin 19 in the second sample with the level of one or more of filamin B, LY9, and keratin 19 in a control sample. In certain embodiments, the method comprises detecting the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; detecting the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample; and comparing the level of the one or more of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample with the one or more of the level of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample. In certain embodiments, the method comprises detection of a subset of keratins such as keratin 7, keratin 8, and keratin 15; keratin 7, 15, and 19; and keratin 7 or keratin 15. In certain embodiments, the method further comprises comparing the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the first sample; or the level of expression of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in the second sample to the level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, and tubulin beta-3 in a control sample.
[0359] In certain embodiments, no change in the level of expression of one or more markers selected from the group consisting of filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3 between the first sample and the second sample is an indication for selecting against active treatment for prostate cancer.
[0360] In certain embodiments, the methods further comprise detecting the level of prostate specific antigen (PSA) in the first sample and the second sample, and then preferably further comprising comparing the level of PSA in the first sample with the level of PSA in the second sample.
[0361] In certain embodiments, a decrease in the level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample in combination with a decrease in the level of PSA in the second sample as compared to the level of PSA in the first sample has greater predictive value that the therapy is efficacious in treating prostate cancer in the subject than analysis of a single marker alone.
[0362] In certain embodiments, a decrease in the level of one or more of filamin B, LY9, and keratin 19 in the second sample as compared to the level of one or more of filamin B, LY9, and keratin 19 in the first sample in combination with a decrease in the level of expression of PSA in the second sample as compared to the level of PSA in the first sample has greater predictive value that for selecting against active treatment for prostate cancer than analysis of a single marker alone.
Monitoring Clinical Trials
[0363] Monitoring the influence of agents (e.g., drug compounds) on the level of expression of a marker of the invention can be applied not only in basic drug screening or monitoring the treatment of a single subject, but also in clinical trials. For example, the effectiveness of an agent to affect marker expression can be monitored in clinical trials of subjects receiving treatment for an oncological disorder. In a preferred embodiment, the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of one or more selected markers of the invention (e.g., filamin B, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, optionally in combination with PSA) in the pre-administration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression of the marker(s) in the post-administration samples; (v) comparing the level of expression of the marker(s) in the pre-administration sample with the level of expression of the marker(s) in the post-administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased expression of the marker gene(s) during the course of treatment may indicate ineffective dosage and the desirability of increasing the dosage. Conversely, decreased expression of the marker gene(s) may indicate efficacious treatment and no need to change dosage.
Kits
[0364] The invention also provides compositions and kits for diagnosing, prognosing, or monitoring a disease or disorder, recurrence of a disorder, or survival of a subject being treated for a disorder (e.g., an abnormal prostate state, BPH, an oncologic disorder, e.g., prostate cancer). These kits include one or more of the following: a detectable antibody that specifically binds to a marker of the invention, a detectable antibody that specifically binds to a marker of the invention, reagents for obtaining and/or preparing subject tissue samples for staining, and instructions for use.
[0365] The invention also encompasses kits for detecting the presence of a marker protein or nucleic acid in a biological sample. Such kits can be used to determine if a subject is suffering from or is at increased risk of developing an abnormal prostate state. For example, the kit can comprise a labeled compound or agent capable of detecting a marker protein or nucleic acid in a biological sample and means for determining the amount of the protein or mRNA in the sample (e.g., an antibody which binds the protein or a fragment thereof, or an oligonucleotide probe which binds to DNA or mRNA encoding the protein). Kits can also include instructions for use of the kit for practicing any of the methods provided herein or interpreting the results obtained using the kit based on the teachings provided herein. The kits can also include reagents for detection of a control protein in the sample not related to the abnormal prostate state, e.g., actin for tissue samples, albumin in blood or blood derived samples for normalization of the amount of the marker present in the sample. The kit can also include the purified marker for detection for use as a control or for quantitation of the assay performed with the kit.
[0366] Kits include panel of reagents for use in a method to diagnose prostate cancer in a subject (or to identify a subject predisposed to developing prostate cancer, etc.), the panel comprising at least two detection reagents, wherein each detection reagent is specific for one prostate cancer-specific protein, wherein said prostate cancer-specific proteins are selected from the prostate cancer-specific protein sets provided herein.
[0367] For antibody-based kits, the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a first marker protein; and, optionally, (2) a second, different antibody which binds to either the first marker protein or the first antibody and is conjugated to a detectable label. In certain embodiments, the kit includes (1) a second antibody (e.g., attached to a solid support) which binds to a second marker protein; and, optionally, (2) a second, different antibody which binds to either the second marker protein or the second antibody and is conjugated to a detectable label. The first and second marker proteins are different. In an embodiment, the first and second markers are markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and PSA. In certain embodiments, neither the first marker nor the second marker is PSA. In certain embodiments, the kit comprises a third antibody which binds to a third marker protein which is different from the first and second marker proteins, and a second different antibody that binds to either the third marker protein or the antibody that binds the third marker protein wherein the third marker protein is different from the first and second marker proteins.
[0368] For oligonucleotide-based kits, the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a marker protein or (2) a pair of primers useful for amplifying a marker nucleic acid molecule. In certain embodiments, the kit can further include, for example: (1) an oligonucleotide, e.g., a second detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a second marker protein or (2) a pair of primers useful for amplifying the second marker nucleic acid molecule. The first and second markers are different. In an embodiment, the first and second markers are markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and PSA. In certain embodiments, neither the first marker nor the second marker is PSA. In certain embodiments, the kit can further include, for example: (1) an oligonucleotide, e.g., a third detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a third marker protein or (2) a pair of primers useful for amplifying the third marker nucleic acid molecule wherein the third marker is different from the first and second markers. In certain embodiments, the kit includes a third primer specific for each nucleic acid marker to allow for detection using quantitative PCR methods.
[0369] For chromatography methods, the kit can include markers, including labeled markers, to permit detection and identification of one or more markers of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and optionally PSA, by chromatography. In certain embodiments, kits for chromatography methods include compounds for derivatization of one or more markers of the invention. In certain embodiments, kits for chromatography methods include columns for resolving the markers of the method.
[0370] Reagents specific for detection of a marker of the invention, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, LY9, and PSA, allow for detection and quantitation of the marker in a complex mixture, e.g., serum, tissue sample. In certain embodiments, the reagents are species specific. In certain embodiments, the reagents are not species specific. In certain embodiments, the reagents are isoform specific. In certain embodiments, the reagents are not isoform specific. In certain embodiments, the reagents detect total keratin 8, keratin 18, filamin B, PSA, or LY9.
[0371] In certain embodiments, the kits for the diagnosis, monitoring, or characterization of prostate cancer comprise at least one reagent specific for the detection of the level of expression of at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9. In certain embodiments, the kits further comprise instructions for the diagnosis, monitoring, or characterization of prostate cancer based on the level of expression of the at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9. In certain embodiments, the kits further comprise instructions to detect the level of PSA in a sample in which the at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 is detected. In certain embodiments, the kits further comprise at least one reagent for the specific detection of PSA.
[0372] The invention provides kits comprising at least one reagent specific for the detection of a level of expression of at least one marker selected from the group consisting of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, filamin B, and LY9 and at least one reagent specific for the detection of a level of expression of PSA.
[0373] In certain embodiments, the kits can also comprise, e.g., a buffering agents, a preservative, a protein stabilizing agent, reaction buffers. The kit can further comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate). The kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample. The controls can be control serum samples or control samples of purified proteins or nucleic acids, as appropriate, with known levels of target markers. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
[0374] The kits of the invention may optionally comprise additional components useful for performing the methods of the invention.
Panels
[0375] The invention provides panels of reagents for detection of one or more prostate-related marker in a subject sample and at least one control reagent. In certain embodiments, the control reagent is to detect the marker for detection in the biological sample wherein the panel is provided with a control sample containing the marker for use as a positive control and optionally to quantitate the amount of marker present in the biological sample. In certain embodiments, the panel includes a detection reagent for a maker not related to an abnormal prostate state that is known to be present or absent in the biological sample to provide a positive or negative control, respectively. The panel can be provided with reagents for detection of a control protein in the sample not related to the abnormal prostate state, e.g., actin for tissue samples, albumin in blood or blood derived samples for normalization of the amount of the marker present in the sample. The panel can be provided with a purified marker for detection for use as a control or for quantitation of the assay performed with the panel.
[0376] In a preferred embodiment, the panel includes reagents for detection of two or more markers of the invention (e.g., 2, 3, 4, 5, 6, 7, 8, 9), preferably in conjunction with a control reagent. In the panel, each marker is detected by a reagent specific for that marker. In certain embodiments, the panel further includes a reagent for the detection of PSA. In certain embodiments, the panel includes replicate wells, spots, or portions to allow for analysis of various dilutions (e.g., serial dilutions) of biological samples and control samples. In a preferred embodiment, the panel allows for quantitative detection of one or more markers of the invention.
[0377] In certain embodiments, the panel is a protein chip for detection of one or more markers. In certain embodiments, the panel is an ELISA plate for detection of one or more markers. In certain embodiments, the panel is a plate for quantitative PCR for detection of one or more markers.
[0378] In certain embodiments, the panel of detection reagents is provided on a single device including a detection reagent for one or more markers of the invention and at least one control sample. In certain embodiments, the panel of detection reagents is provided on a single device including a detection reagent for two or more markers of the invention and at least one control sample. In certain embodiments, multiple panels for the detection of different markers of the invention are provided with at least one uniform control sample to facilitate comparison of results between panels.
Screening Assays
[0379] The invention also provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., proteins, peptides, peptidomimetics, peptoids, small molecules or other drugs), which modulate the state of the diseased cell by modulating the expression and/or activity of a marker of the invention, i.e., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, or LY9; optionally in combination with PSA. Such assays typically comprise a reaction between a marker of the invention and one or more assay components. The other components may be either the test compound itself, or a combination of test compounds and a natural binding partner of a marker of the invention. Compounds identified via assays such as those described herein may be useful, for example, for modulating, e.g., inhibiting, ameliorating, treating, or preventing the disease. Compounds identified for modulating the expression level of one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, filamin B, or LY9; optionally in combination with PSA, are preferably further tested for activity useful in the treatment of cancer, preferably prostate cancer, e.g., inhibiting tumor cell growth, inhibiting tumor angiogenesis, inducing tumor cell apoptosis, etc.
[0380] The test compounds used in the screening assays of the present invention may be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. Test compounds may also be obtained by any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann et al., 1994, J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the `one-bead one-compound` library method; and synthetic library methods using affinity chromatography selection. The biological library and peptoid library approaches are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997, Anticancer Drug Des. 12:145).
[0381] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233.
[0382] Libraries of compounds may be presented in solution (e.g., Houghten, 1992, Biotechniques 13:412-421), or on beads (Lam, 1991, Nature 354:82-84), chips (Fodor, 1993, Nature 364:555-556), bacteria and/or spores, (Ladner, U.S. Pat. No. 5,223,409), plasmids (Cull et al, 1992, Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith, 1990, Science 249:386-390; Devlin, 1990, Science 249:404-406; Cwirla et al, 1990, Proc. Natl. Acad. Sci. 87:6378-6382; Felici, 1991, J. Mol. Biol. 222:301-310; Ladner, supra.).
[0383] The screening methods of the invention comprise contacting a cell, e.g., a diseased cell, especially a prostate cancer cell, with a test compound and determining the ability of the test compound to modulate the expression and/or activity of filamin B, LY9, or keratin 19, optionally in combination with PSA, in the cell. The expression and/or activity of filamin B, LY9, or keratin 19; optionally in combination with PSA, can be determined using any methods known in the art, such as those described herein.
[0384] In another embodiment, the invention provides assays for screening candidate or test compounds which are substrates of a marker of the invention or biologically active portions thereof. In yet another embodiment, the invention provides assays for screening candidate or test compounds which bind to a marker of the invention or biologically active portions thereof. Determining the ability of the test compound to directly bind to a marker can be accomplished, for example, by any method known in the art.
[0385] This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model. For example, an agent capable of modulating the expression and/or activity of a marker of the invention identified as described herein can be used in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein can be used in an animal model to determine the mechanism of action of such an agent. Furthermore, this invention pertains to uses of novel agents identified by the above-described screening assays for treatment as described above.
[0386] This invention is further illustrated by the following examples which should not be construed as limiting. The contents of all references and published patents and patent applications cited throughout the application are hereby incorporated by reference.
Exemplification of the Invention
[0387] This invention is further illustrated by the following examples which should not be construed as limiting. The contents of all references, GenBank Accession and Gene numbers, and published patents and patent applications cited throughout the application are hereby incorporated by reference.
Example 1
Identification of Keratins and Tubulin as Prostate Cancer Markers
[0388] Extracellular Keratins are known to influence the cell proliferation and metastasis of epithelial derived prostate cancers. Androgen refractory prostate cancers exhibit differential expression keratin 8 (K8) when compared to normal tissue. Modulation and degradation of keratins is in turn mediated by mitochondrial generation of Reactive Oxygen Species (ROS). Despite these advances a systematic approach to understanding of keratins and other EC proteins in prostate cancer metastasis and proliferation is lacking. An interrogative systems biology based discovery platform disclosed in WO2012119129 (incorporated herein by reference), and shown schematically in FIG. 1, provides new mechanistic insights into understanding mitochondrial role in behavior of prostate cancer cells. The discovery platform involves discovery across a hierarchy of systems including in vitro human cell based models and human serum samples from prostate cancer patients and downstream data integration and mathematical modeling employing an Artificial Intelligence (AI) based informatic module. For cellular models, androgen sensitive LnCAP cell line and metastatic, androgen refractory PC3 cell line were treated with ubidecarenone (coenzyme Q10) in order to engage the mitochondrial machinery. Proteomic signatures were captured using a 2D LC-MS orbitrap technology. Total protein signatures were input to an AI based informatics module to generate causal protein networks (FIGS. 2A-C). Wet lab assays that specifically measure mitochondrial ROS, ATP and caspase 3 activation confirmed changes in intracellular levels of these markers. Several novel protein causal interactions that govern induction of mitochondrial machinery by ubidecarenone in PC3 cells were observed. Causal protein maps revealed association of keratins 8 and 15 in PC3 models and not LnCAP. The keratin 8/15 association was lost upon treatment with ubidecarenone, and a direct association of keratins 7 and 15 was established (FIGS. 3A-D). These results suggest that a change in the interaction among keratins 7, 8, and 15 is particularly useful in demonstrating a response to treatment or a change in prostate cancer status in a subject. Further, keratins 8 and 15 were differentially associated in the androgen refractory, metastatic PC3 cell line and the androgen sensitive LnCAP cell line. This indicates that keratins 8 and 15 could be useful do differentiate between prostate cancer states, e.g., between androgen sensitive and metastatic, androgen refractory prostate cancer.
[0389] An increase in the expression of keratin 19 in relation to prostate cancer was confirmed using a panel of serum samples from subjects suffering from prostate cancer as compared to an appropriate matched control population.
[0390] Thus novel mechanistic insight into prostate cancer proliferation and mitochondrial role in modulating metastasis was gained with a novel chemical systems biology approach.
[0391] The results provided herein demonstrate that modulation of keratin and potential causal association in androgen refractory prostate cancer was inferred by the Platform technology. This provides a potential mechanisms of keratin regulation in response to modulation of mitochondrial function was deciphered by the Platform technology. Thus, novel drivers of cancer pathophysiology were validated in patient serum samples.
Example 2
Identification of Filamin B as a Prostate Cancer Marker
[0392] An interrogative systems biology based discovery platform was used to obtain mechanistic insights into understanding mitochondrial role in behavior of prostate cancer cells. The Platform technology, which is described in detail in WO2012119129, involves discovery across a hierarchy of systems including in vitro human cell based models and human serum samples from prostate cancer patients and downstream data integration and mathematical modeling employing an Artificial Intelligence (AI) based informatics module.
[0393] The results provided herein demonstrate the modulation of filamin B and LY9, and potential causal association in androgen refractory prostate cancer that was inferred using the Platform technology. The application provides potential mechanisms of filamin B and LY9 regulation in response to modulation of mitochondrial function was deciphered by the Platform technology and provides validation of the markers in patient serum samples.
[0394] Using the Platform methods, human prostate cancer cells PC3 (androgen insensitive, metastatic) and LnCap (androgen sensitive) were modeled in cancer microenvironments including hypoxia, reduced environments, and hyperglycemia and in presence of coenzyme Q10. Normal cells (human dermal fibroblasts (HDFa) and SV40 transformed human liver cells (THLE2)) were modeled under similar conditions mentioned above. Proteomics of cellular proteins and proteins secreted in the supernatant were carried out by LCMS. Data were input into the Bayesian Network Inference (BNI) algorithms REFS®.
[0395] Causal associations between proteins were derived by the BNI. Differential network analysis was employed to tease out the hubs of activity in prostate cancer when compared to normal cells in normal microenviroments. Filamin B was identified as differential hub of activity in PC3 and not in LnCap and normal cells. That is, Filamin B was found to differ between androgen sensitive LnCAP cell line and metastatic, androgen refractory PC3 cell line. This indicates that Filamin B could be useful do differentiate between prostate cancer states, e.g., between androgen sensitive and metastatic, androgen refractory prostate cancer. The interaction matrix placing filamin B at the center of an interaction hub is shown in FIG. 4. The interaction of LY9 with filamin B is shown in FIG. 5.
Example 3
Validation of Filamin B as a Prostate Cancer Marker in Human Samples
[0396] Having identified filamin B as a prostate cancer marker using the platform technology, human serum samples from normal subjects and subjects with prostate cancer were used to confirm filamin B as a prostate cancer marker.
[0397] Specifically, human serum samples were procured from a commercial vendor that sources human serum. Twenty samples were from normal donors and 20 samples were from patients diagnosed with prostate cancer. Prostate cancer samples were from patients with different prognosis and aggressiveness of cancers reported. Clinical characteristics of the subjects are provided in the table.
TABLE-US-00001 Prostate Cancer Control Group Median Age 61 (47-86) 58 (45-72) Ethnicity Caucasian 75% 85% African American 15% 10% Hispanic 10% 5% Tumor Stage Stage I 20% Stage II 35% Stage III 5% Stage IV 40%
[0398] Commercially available ELISA tests for filamin B and PSA were procured from commercial source. The assays were performed using the manufactures' instructions. The results from the assay are shown in FIGS. 6A-B. The results show the differential levels of FlnB and PSA in patients with a diagnosis for prostate cancer as compared to control subjects without prostate cancer.
[0399] As shown, both filamin B and PSA levels were elevated in serum samples from patients diagnosed with prostate cancer. The correlation between PSA and FlnB expression in serum samples is 0.20075, indicating a relatively low correlation between the variables. This demonstrates that filamin B and PSA are useful for the detection of prostate cancer in different subjects. These results demonstrate that filamin B is useful for the diagnosis of prostate cancer, and that filamin B is useful for improving the detection of prostate cancer by PSA. Additional samples can be analyzed to further refine the results.
Example 4
Stratification of Subjects with Prostate Cancer using LY9
[0400] The same human serum samples used in Example 4 were further tested to detect the presence of LY9. A commercially available ELISA test for LY9 was procured from commercial source. The assay was performed using the manufactures' instructions. The results from the assay are shown in FIG. 7. The results show the differential levels of LY9 in patients with a diagnosis for prostate cancer as compared to control subjects without prostate cancer. As shown, samples from subjects with prostate cancer were found to have higher levels of LY9 as compared to normal subjects. Results from assays of expression levels of both filamin B and LY9 in human serum with results expressed as ng/ml of protein are shown in FIGS. 8A-C. Additional samples can be analyzed to further refine the results.
Example 5
Analysis of Filamin B Levels Improves the Detection of Prostate Cancer as Compared to PSA Alone
[0401] Having demonstrated that level of filamin B is increased in the serum of subjects with prostate cancer, the results were analyzed in conjunction with the study of PSA levels in the same samples to determine the predictive value of filamin B and PSA together was better than either of the markers alone. Receiver operating characteristic (ROC) curve analysis of sensitivity and false positive rate (FPR) of PSA, filamin B, and the combination of PSA and filamin B was generated. The curves and the area under the curve (AUC) values are shown in FIGS. 9A and B. The goal of this analysis is to gauge the predictive power of the test independent of a specific cut-off. When using an ROC analysis, a test that provides perfect discrimination or accuracy between normal and disease states would have AUC=1, whereas a very poor test that provides no better discrimination than random chance would have AUC=0.5
[0402] As demonstrated by the analysis, filamin B alone performs very well and most importantly somewhat orthogonal to PSA. PSA is reported to have a very high false positive rate, e.g., about 75% (as reported in, Gilligan, The new data on prostate cancer screening: What should we do now? Cleveland Clin. J. Med. 76: 446-448, 2009, incorporated herein by reference). That is, it has a high sensitivity and low specificity. In the specific study presented, the AUC for FLNB is lower than that for PSA. However, the correlation level of 0.20075 determined in Example 3, indicates a relatively low correlation between the variables. That is, subjects identified as having an elevated filamin B level did not necessarily have a high PSA level, and the reverse was also true, suggesting that the markers in combination can provide a predictive test than either marker alone.
[0403] This was confirmed in the ROC analysis. As shown, the combination of PSA and filamin B was found to have a higher AUC indicating better discrimination of the test than PSA alone, and to be more predictive than either of the markers alone. The combination of PSA and filamin B is very good and provides a drastic increase PSA test specificity, which is the main problem with the test.
Example 6
Analysis of Filamin B, LY9, and PSA Levels Together Improves the Detection of Prostate Cancer as Compared to any Marker Alone
[0404] Having demonstrated that each filamin B, LY9, and PSA are all elevated in serum samples from subjects with prostate cancer, the ROC curve analysis was performed comparing each of the three markers individually to the combination of all three markers using a linear scoring function, and comparing the combination of filamin B and LY9, and the combination of filamin B and PSA, against the combination of all three markers using a non-linear scoring function to determine which combinations of the markers were more effective than each single marker for the detection of prostate cancer in a subject. As shown, the combination of all three markers was more predictive than any of the markers alone (FIG. 10A). The combination of filamin B with PSA, either with or without LY9, was more predictive than the combination of filamin B with LY9 (FIG. 10B). Additional samples can be analyzed to further refine the results. The AUC results are summarized in the table.
TABLE-US-00002 Marker AUC LY9 0.85 FLNB 0.78 PSA 0.87 LY9 + FLNB + PSA 0.98
Example 7
Stratification of Subjects with Prostate Cancer using Keratin 4, Keratin 7, Keratin 8, Keratin 15, Keratin 18, Keratin 19, Tubulin-beta 3
[0405] As demonstrated in Examples 3 and 4 respectively, filamin B levels and LY9 levels can be used to distinguish subjects who are or are not suffering from prostate cancer. Further, as demonstrated in Examples 6 and 7, the analysis of both filamin B and PSA, optionally further in combination with LY9, is more sensitive than an analysis based on either marker alone.
[0406] A series of subject samples are obtained from an appropriate source, e.g., a commercial source, wherein the samples were obtained from subjects with different stages of prostate cancer, e.g., aggressive prostate cancer, androgen sensitive, androgen insensitive, metastatic; or from subjects not suffering from prostate cancer, e.g., subjects with normal prostate or subjects with BPH. The samples are analyzed for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA. The level of the expression of the makers, alone and in various combinations, correlate with the presence or absence of disease, and with the severity of prostate cancer. For example, an increase in the expression level of one or more of keratin 19, filamin B, LY9, and PSA, as compared to a normal sample from a subject not suffering from prostate cancer, is indicative of prostate cancer in the subject. Expression levels of keratins 7, 8, and 15 may also be particularly useful in the stratification of subjects with prostate cancer.
Example 8
Monitoring of Prostate Cancer Treatment using Keratin 4, Keratin 7, Keratin 8, Keratin 15, Keratin 18, Keratin 19, Tubulin-beta 3
[0407] At the time of diagnosis with prostate cancer, subjects are invited to participate in a trial. A subject sample, e.g., blood, is obtained. Periodically, throughout the monitoring, watchful waiting, or active treatment of the subject, e.g., chemotherapy, radiation therapy, surgery, hormone therapy, a new subject sample is obtained. At the end of the study, all subject samples are tested for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA. The subject samples are matched to the medical records of the subjects to correlate marker levels with prostate cancer status at the time of diagnosis, rate of progression of disease, response of subjects to one or more interventions, and transitions between androgen dependent and independent status. An increase in the expression level of one or more of keratin 19, filamin B, LY9, and PSA, as compared to a normal sample from a subject not suffering from prostate cancer, is indicative of prostate cancer in the subject. Expression levels of keratins 7, 8, and 15 may also be particularly useful in the diagnosis and monitoring of subjects with prostate cancer.
Example 9
Detection and Monitoring of Prostate Cancer using keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3
[0408] Despite its limitations, including a positive predictive value of only 25-40%, PSA remains the only generally accepted biomarker for prostate cancer. Moreover, as prostate cancer is most commonly a slow growing tumor in men of advanced age, treatment of the cancer may do more harm to the subject than the tumor itself would. Therefore, the tests together for the expression level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA are used for the detection an monitoring of prostate cancer. The level of the expression of the makers, alone and in various combinations are used in detection, including in routine, preventative, screening methods in men having an increased risk of prostate cancer (e.g., increased age, family history, race, etc.) or in monitoring of subjects diagnosed with prostate cancer prior to or during treatment may be useful to better identify subjects in need of further, potentially more invasive, diagnostic tests, e.g., prostate exam or biopsy, digital rectal exam; or more aggressive treatment. Detection of levels of expression of the markers, or various combinations thereof, may also be indicative of a good or poor response to a specific treatment regimen prior to changes in other signs or symptoms, e.g., loss of tumor response to hormone therapy.
[0409] In routine screening methods for prostate cancer, a serum sample from a subject is tested for the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA. The levels are compared to one or more appropriate controls, e.g., other normal subjects, subjects with prostate cancer. Detection of an abnormal level of one or more of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19; indicates that the subject should be considered for further tests for the presence of prostate cancer. Changes in the level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19, in the subject may be more indicative of a change in prostate cancer status than comparison to a population control.
[0410] In determining a therapeutic regimen for a subject with prostate cancer not yet being actively treated for prostate cancer (i.e., watchful waiting) can be tested at regular intervals to determine if there is a change in the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA. An modulation in the level of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 8, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA indicates that the subject should be considered for further tests to monitor the prostate cancer and more active therapeutic interventions should be considered.
[0411] In a subject undergoing treatment for prostate cancer (e.g., hormone therapy, chemotherapy, radiation therapy, surgery) is tested prior to the initiation of the treatment and during and/or after the treatment to determine if the treatment results in a decrease in the level of expression of at least one of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, tubulin-beta 3, preferably at least one of keratin 7, keratin 15, and keratin 19; and optionally further at least one of filamin B, LY9, and PSA. A decrease in the level of keratin 19, filamin B, LY9, or PSA is indicative of response to treatment. Expression levels of keratins 7, 8, and 15 may also be particularly useful in the diagnosis and monitoring of subjects with prostate cancer.
Example 10
Stratification of Subjects with Prostate Cancer using Filamin B, PSA, or LY9
[0412] As demonstrated in Examples 3 and 4 respectively, filamin B levels and LY9 levels can be used to distinguish subjects who are or are not suffering from prostate cancer. Further, as demonstrated in Examples 6 and 7, the analysis of both filamin B and PSA, optionally further in combination with LY9, is more sensitive than an analysis based on either marker alone.
[0413] A series of subject samples are obtained from an appropriate source, e.g., a commercial source, wherein the samples were obtained from subjects with different stages of prostate cancer, e.g., aggressive prostate cancer, androgen sensitive, androgen insensitive, metastatic; or from subjects not suffering from prostate cancer, e.g., subjects with normal prostate or subjects with BPH. The samples are analyzed for the expression level of filamin B and PSA, and optionally the level of LY9, and further with one or more of keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19. The level of filamin B, LY9, and PSA, alone and in various combinations, optionally with other markers, e.g., keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, correlate with the presence or absence of disease, and with the severity of prostate cancer.
Example 11
Monitoring of Prostate Cancer Treatment using Filamin B, PSA, or LY9
[0414] At the time of diagnosis with prostate cancer, subjects are invited to participate in a trial. A subject sample, e.g., blood, is obtained. Periodically, throughout the monitoring, watchful waiting, or active treatment of the subject, e.g., chemotherapy, radiation therapy, surgery, hormone therapy, a new subject sample is obtained. At the end of the study, all subject samples are tested for the level of filamin B, PSA, and optionally in further combination with one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3. The subject samples are matched to the medical records of the subjects to correlate filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, or tubulin-beta 3 levels, as appropriate, with prostate cancer status at the time of diagnosis, rate of progression of disease, response of subjects to one or more interventions, and transitions between androgen dependent and independent status.
Example 12
Detection and Monitoring of Prostate Cancer using Filamin B, PSA, or LY9
[0415] Despite its limitations, including a positive predictive value of only 25-40%, PSA remains the only generally accepted biomarker for prostate cancer. Moreover, as prostate cancer is most commonly a slow growing tumor in men of advanced age, treatment of the cancer may do more harm to the subject than the tumor itself would. As demonstrated herein, there is a low correlation between elevated levels of filamin B and PSA in subjects with prostate cancer. Further, elevated levels of LY9 have been demonstrated to be associated with prostate cancer. Therefore, the tests together, particularly filamin B and PSA, optionally in combination with one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, in detection, including in routine, preventative, screening methods in men having an increased risk of prostate cancer (e.g., increased age, family history, race, etc.) or in monitoring of subjects diagnosed with prostate cancer prior to or during treatment may be useful to better identify subjects in need of further, potentially more invasive, diagnostic tests, e.g., prostate exam or biopsy, digital rectal exam; or more aggressive treatment. Detection of levels of expression of filamin B, PSA, LY9 keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19, may also be indicative of a good or poor response to a specific treatment regimen prior to changes in other signs or symptoms, e.g., loss of tumor response to hormone therapy.
[0416] In routine screening methods for prostate cancer, a serum sample from a subject is tested for the level of expression of both filamin B and PSA, and optionally one or more of LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19. The levels are compared to one or more appropriate controls, e.g., other normal subjects, subjects with prostate cancer. Detection of an abnormal level of one or more of filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3, especially keratin 19 indicates that the subject should be considered for further tests for the presence of prostate cancer. Changes in the level of filamin B, optionally in combination with one or more of PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, or tubulin-beta 3, especially keratin 19 with PSA in the subject may be more indicative of a change in prostate cancer status than comparison to a population control.
[0417] In determining a therapeutic regimen for a subject with prostate cancer not yet being actively treated for prostate cancer (i.e., watchful waiting) can be tested at regular intervals to determine if there is a change in the level of expression of filamin B, PSA, LY9 keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3. An increase in the level of filamin B, PSA, keratin 19, or LY9 indicates that the subject should be considered for further tests to monitor the prostate cancer and more active therapeutic interventions should be considered.
[0418] In a subject undergoing treatment for prostate cancer (e.g., hormone therapy, chemotherapy, radiation therapy, surgery) is tested prior to the initiation of the treatment and during and/or after the treatment to determine if the treatment results in a change in the level of expression of one or more of filamin B, PSA, LY9, keratin 4, keratin 7, keratin 8, keratin 15, keratin 18, keratin 19, and tubulin-beta 3. A decrease in the level of filamin B, PSA, keratin 19, or LY9 is indicative of response to treatment.
EQUIVALENTS
[0419] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.
Sequence CWU
1
1
451520PRTHomo sapiens 1Met Ile Ala Arg Gln Gln Cys Val Arg Gly Gly Pro Arg
Gly Phe Ser 1 5 10 15
Cys Gly Ser Ala Ile Val Gly Gly Gly Lys Arg Gly Ala Phe Ser Ser
20 25 30 Val Ser Met Ser
Gly Gly Ala Gly Arg Cys Ser Ser Gly Gly Phe Gly 35
40 45 Ser Arg Ser Leu Tyr Asn Leu Arg Gly
Asn Lys Ser Ile Ser Met Ser 50 55
60 Val Ala Gly Ser Arg Gln Gly Ala Cys Phe Gly Gly Ala
Gly Gly Phe 65 70 75
80 Gly Thr Gly Gly Phe Gly Gly Gly Phe Gly Gly Ser Phe Ser Gly Lys
85 90 95 Gly Gly Pro Gly
Phe Pro Val Cys Pro Ala Gly Gly Ile Gln Glu Val 100
105 110 Thr Ile Asn Gln Ser Leu Leu Thr Pro
Leu His Val Glu Ile Asp Pro 115 120
125 Glu Ile Gln Lys Val Arg Thr Glu Glu Arg Glu Gln Ile Lys
Leu Leu 130 135 140
Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Gln Phe Leu Glu Gln 145
150 155 160 Gln Asn Lys Val Leu
Glu Thr Lys Trp Asn Leu Leu Gln Gln Gln Thr 165
170 175 Thr Thr Thr Ser Ser Lys Asn Leu Glu Pro
Leu Phe Glu Thr Tyr Leu 180 185
190 Ser Val Leu Arg Lys Gln Leu Asp Thr Leu Gly Asn Asp Lys Gly
Arg 195 200 205 Leu
Gln Ser Glu Leu Lys Thr Met Gln Asp Ser Val Glu Asp Phe Lys 210
215 220 Thr Lys Tyr Glu Glu Glu
Ile Asn Lys Arg Thr Ala Ala Glu Asn Asp 225 230
235 240 Phe Val Val Leu Lys Lys Asp Val Asp Ala Ala
Tyr Leu Asn Lys Val 245 250
255 Glu Leu Glu Ala Lys Val Asp Ser Leu Asn Asp Glu Ile Asn Phe Leu
260 265 270 Lys Val
Leu Tyr Asp Ala Glu Leu Ser Gln Met Gln Thr His Val Ser 275
280 285 Asp Thr Ser Val Val Leu Ser
Met Asp Asn Asn Arg Asn Leu Asp Leu 290 295
300 Asp Ser Ile Ile Ala Glu Val Arg Ala Gln Tyr Glu
Glu Ile Ala Gln 305 310 315
320 Arg Ser Lys Ala Glu Ala Glu Ala Leu Tyr Gln Thr Lys Val Gln Gln
325 330 335 Leu Gln Ile
Ser Val Asp Gln His Gly Asp Asn Leu Lys Asn Thr Lys 340
345 350 Ser Glu Ile Ala Glu Leu Asn Arg
Met Ile Gln Arg Leu Arg Ala Glu 355 360
365 Ile Glu Asn Ile Lys Lys Gln Cys Gln Thr Leu Gln Val
Ser Val Ala 370 375 380
Asp Ala Glu Gln Arg Gly Glu Asn Ala Leu Lys Asp Ala His Ser Lys 385
390 395 400 Arg Val Glu Leu
Glu Ala Ala Leu Gln Gln Ala Lys Glu Glu Leu Ala 405
410 415 Arg Met Leu Arg Glu Tyr Gln Glu Leu
Met Ser Val Lys Leu Ala Leu 420 425
430 Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Gly Glu
Glu Tyr 435 440 445
Arg Met Ser Gly Glu Cys Gln Ser Ala Val Ser Ile Ser Val Val Ser 450
455 460 Gly Ser Thr Ser Thr
Gly Gly Ile Ser Gly Gly Leu Gly Ser Gly Ser 465 470
475 480 Gly Phe Gly Leu Ser Ser Gly Phe Gly Ser
Gly Ser Gly Ser Gly Phe 485 490
495 Gly Phe Gly Gly Ser Val Ser Gly Ser Ser Ser Ser Lys Ile Ile
Ser 500 505 510 Thr
Thr Thr Leu Asn Lys Arg Arg 515 520 22147DNAHomo
sapiens 2actcaccggc ctgggccctg tcacttctct gatagctccc agctcgctct
ctgcagccat 60gattgccaga cagcagtgtg tccgaggcgg gccccggggc ttcagctgtg
gctcggccat 120tgtaggcggt ggcaagagag gtgccttcag ctcagtctcc atgtctggag
gtgctggccg 180atgctcttct gggggatttg gcagcagaag cctctacaac ctcaggggga
acaaaagcat 240ctccatgagt gtggctgggt cacgacaagg tgcctgcttt gggggtgctg
gaggctttgg 300cactggtggc tttggtggtg gatttggggg ctccttcagt ggtaagggtg
gccctggctt 360ccccgtctgc cccgctgggg gaattcagga ggtcaccatc aaccagagct
tgctcacccc 420cctccacgtg gagattgacc ctgagatcca gaaagtccgg acggaagagc
gcgaacagat 480caagctcctc aacaacaagt ttgcctcctt catcgacaag gtgcagttct
tagagcaaca 540gaataaggtc ctggagacca aatggaacct gctccagcag cagacgacca
ccacctccag 600caaaaacctt gagcccctct ttgagaccta cctcagtgtc ctgaggaagc
agctagatac 660cttgggcaat gacaaagggc gcctgcagtc tgagctgaag accatgcagg
acagcgtgga 720ggacttcaag actaagtatg aagaggagat caacaaacgc acagcagccg
agaatgactt 780tgtggtccta aagaaggacg tggatgctgc ctacctgaac aaggtggagt
tggaggccaa 840ggtggacagt cttaatgacg agatcaactt cctgaaggtc ctctatgatg
cggagctgtc 900ccagatgcag acccatgtca gcgacacgtc cgtggtcctt tccatggaca
acaaccgcaa 960cctggacctg gacagcatta ttgccgaggt ccgtgcccag tacgaggaga
ttgcccagag 1020gagcaaggct gaggctgaag ccctgtacca gaccaaggtc cagcagctcc
agatctcggt 1080tgaccaacat ggtgacaacc tgaagaacac caagagtgaa attgcagagc
tcaacaggat 1140gatccagagg ctgcgggcag agatcgagaa catcaagaag cagtgccaga
ctcttcaggt 1200atccgtggct gatgcagagc agcgaggtga gaatgccctt aaagatgccc
acagcaagcg 1260cgtagagctg gaggctgccc tgcagcaggc caaggaggag ctggcacgaa
tgctgcgtga 1320gtaccaggag ctcatgagtg tgaagctggc cttggacatc gagatcgcca
cctaccgcaa 1380actgctggag ggcgaggagt acagaatgtc tggagaatgc cagagtgccg
tgagcatctc 1440tgtggtcagc ggtagcacca gcactggagg catcagcgga ggattaggaa
gtggctccgg 1500gtttggcctg agtagtggct ttggctccgg ctctggaagt ggctttgggt
ttggtggcag 1560tgtctctggc agttccagca gcaagatcat ctctaccacc accctgaaca
agagacgata 1620gaggagacga ggtccctgca gctcactgtg tccagctggg cccagcactg
gtgtctctgt 1680gcttccttca cttcacctcc atcctctgtc tctggggctc atcttactag
tatcccctcc 1740actatcccat gggctctctc tgccccagga tgatcttctg tgctgggaca
gggactctgc 1800ctcttggagt ttggtagcta cttcttgatt tgggcctggt gacccacctg
gaatgggaag 1860gatgtcagct gacctctcac ctcccatgga cagagaagaa aatgaccagg
agtgtcatct 1920ccagaattat tggggtcaca tatgtccctt cccagtccaa tgccatctcc
cactagatcc 1980tgtattatcc atctacatca gaaccaaact acttctccaa cacccggcag
cacttggccc 2040tgcaagctta ggatgagaac cacttagtgt cccattctac tcctctcatt
ccctcttatc 2100catctgcagg tgaatcttca ataaaatgct tttgtcattc attctga
21473469PRTHomo sapiens 3Met Ser Ile His Phe Ser Ser Pro Val
Phe Thr Ser Arg Ser Ala Ala 1 5 10
15 Phe Ser Gly Arg Gly Ala Gln Val Arg Leu Ser Ser Ala Arg
Pro Gly 20 25 30
Gly Leu Gly Ser Ser Ser Leu Tyr Gly Leu Gly Ala Ser Arg Pro Arg
35 40 45 Val Ala Val Arg
Ser Ala Tyr Gly Gly Pro Val Gly Ala Gly Ile Arg 50
55 60 Glu Val Thr Ile Asn Gln Ser Leu
Leu Ala Pro Leu Arg Leu Asp Ala 65 70
75 80 Asp Pro Ser Leu Gln Arg Val Arg Gln Glu Glu Ser
Glu Gln Ile Lys 85 90
95 Thr Leu Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu
100 105 110 Glu Gln Gln
Asn Lys Leu Leu Glu Thr Lys Trp Thr Leu Leu Gln Glu 115
120 125 Gln Lys Ser Ala Lys Ser Ser Arg
Leu Pro Asp Ile Phe Glu Ala Gln 130 135
140 Ile Ala Gly Leu Arg Gly Gln Leu Glu Ala Leu Gln Val
Asp Gly Gly 145 150 155
160 Arg Leu Glu Ala Glu Leu Arg Ser Met Gln Asp Val Val Glu Asp Phe
165 170 175 Lys Asn Lys Tyr
Glu Asp Glu Ile Asn His Arg Thr Ala Ala Glu Asn 180
185 190 Glu Phe Val Val Leu Lys Lys Asp Val
Asp Ala Ala Tyr Met Ser Lys 195 200
205 Val Glu Leu Glu Ala Lys Val Asp Ala Leu Asn Asp Glu Ile
Asn Phe 210 215 220
Leu Arg Thr Leu Asn Glu Thr Glu Leu Thr Glu Leu Gln Ser Gln Ile 225
230 235 240 Ser Asp Thr Ser Val
Val Leu Ser Met Asp Asn Ser Arg Ser Leu Asp 245
250 255 Leu Asp Gly Ile Ile Ala Glu Val Lys Ala
Gln Tyr Glu Glu Met Ala 260 265
270 Lys Cys Ser Arg Ala Glu Ala Glu Ala Trp Tyr Gln Thr Lys Phe
Glu 275 280 285 Thr
Leu Gln Ala Gln Ala Gly Lys His Gly Asp Asp Leu Arg Asn Thr 290
295 300 Arg Asn Glu Ile Ser Glu
Met Asn Arg Ala Ile Gln Arg Leu Gln Ala 305 310
315 320 Glu Ile Asp Asn Ile Lys Asn Gln Arg Ala Lys
Leu Glu Ala Ala Ile 325 330
335 Ala Glu Ala Glu Glu Arg Gly Glu Leu Ala Leu Lys Asp Ala Arg Ala
340 345 350 Lys Gln
Glu Glu Leu Glu Ala Ala Leu Gln Arg Gly Lys Gln Asp Met 355
360 365 Ala Arg Gln Leu Arg Glu Tyr
Gln Glu Leu Met Ser Val Lys Leu Ala 370 375
380 Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu Leu
Glu Gly Glu Glu 385 390 395
400 Ser Arg Leu Ala Gly Asp Gly Val Gly Ala Val Asn Ile Ser Val Met
405 410 415 Asn Ser Thr
Gly Gly Ser Ser Ser Gly Gly Gly Ile Gly Leu Thr Leu 420
425 430 Gly Gly Thr Met Gly Ser Asn Ala
Leu Ser Phe Ser Ser Ser Ala Gly 435 440
445 Pro Gly Leu Leu Lys Ala Tyr Ser Ile Arg Thr Ala Ser
Ala Ser Arg 450 455 460
Arg Ser Ala Arg Asp 465 41753DNAHomo sapiens
4cagccccgcc cctacctgtg gaagcccagc cgcccgctcc cgcggataaa aggcgcggag
60tgtccccgag gtcagcgagt gcgcgctcct cctcgcccgc cgctaggtcc atcccggccc
120agccaccatg tccatccact tcagctcccc ggtattcacc tcgcgctcag ccgccttctc
180gggccgcggc gcccaggtgc gcctgagctc cgctcgcccc ggcggccttg gcagcagcag
240cctctacggc ctcggcgcct cacggccgcg cgtggccgtg cgctctgcct atgggggccc
300ggtgggcgcc ggcatccgcg aggtcaccat taaccagagc ctgctggccc cgctgcggct
360ggacgccgac ccctccctcc agcgggtgcg ccaggaggag agcgagcaga tcaagaccct
420caacaacaag tttgcctcct tcatcgacaa ggtgcggttt ctggagcagc agaacaagct
480gctggagacc aagtggacgc tgctgcagga gcagaagtcg gccaagagca gccgcctccc
540agacatcttt gaggcccaga ttgctggcct tcggggtcag cttgaggcac tgcaggtgga
600tgggggccgc ctggaggcgg agctgcggag catgcaggat gtggtggagg acttcaagaa
660taagtacgaa gatgaaatta accaccgcac agctgctgag aatgagtttg tggtgctgaa
720gaaggatgtg gatgctgcct acatgagcaa ggtggagctg gaggccaagg tggatgccct
780gaatgatgag atcaacttcc tcaggaccct caatgagacg gagttgacag agctgcagtc
840ccagatctcc gacacatctg tggtgctgtc catggacaac agtcgctccc tggacctgga
900cggcatcatc gctgaggtca aggcgcagta tgaggagatg gccaaatgca gccgggctga
960ggctgaagcc tggtaccaga ccaagtttga gaccctccag gcccaggctg ggaagcatgg
1020ggacgacctc cggaataccc ggaatgagat ttcagagatg aaccgggcca tccagaggct
1080gcaggctgag atcgacaaca tcaagaacca gcgtgccaag ttggaggccg ccattgccga
1140ggctgaggag cgtggggagc tggcgctcaa ggatgctcgt gccaagcagg aggagctgga
1200agccgccctg cagcggggca agcaggatat ggcacggcag ctgcgtgagt accaggaact
1260catgagcgtg aagctggccc tggacatcga gatcgccacc taccgcaagc tgctggaggg
1320cgaggagagc cggttggctg gagatggagt gggagccgtg aatatctctg tgatgaattc
1380cactggtggc agtagcagtg gcggtggcat tgggctgacc ctcgggggaa ccatgggcag
1440caatgccctg agcttctcca gcagtgcggg tcctgggctc ctgaaggctt attccatccg
1500gaccgcatcc gccagtcgca ggagtgcccg cgactgagcc gcctcccacc actccactcc
1560tccagccacc acccacaatc acaagaagat tcccacccct gcctcccatg cctggtccca
1620agacagtgag acagtctgga aagtgatgtc agaatagctt ccaataaagc agcctcattc
1680tgaggcctga gtgatccacg tgaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
1740aaaaaaaaaa aaa
17535511PRTHomo sapiens 5Met Asn Gly Val Ser Trp Ser Gln Asp Leu Gln Glu
Gly Ile Ser Ala 1 5 10
15 Trp Phe Gly Pro Pro Ala Ser Thr Pro Ala Ser Thr Met Ser Ile Arg
20 25 30 Val Thr Gln
Lys Ser Tyr Lys Val Ser Thr Ser Gly Pro Arg Ala Phe 35
40 45 Ser Ser Arg Ser Tyr Thr Ser Gly
Pro Gly Ser Arg Ile Ser Ser Ser 50 55
60 Ser Phe Ser Arg Val Gly Ser Ser Asn Phe Arg Gly Gly
Leu Gly Gly 65 70 75
80 Gly Tyr Gly Gly Ala Ser Gly Met Gly Gly Ile Thr Ala Val Thr Val
85 90 95 Asn Gln Ser Leu
Leu Ser Pro Leu Val Leu Glu Val Asp Pro Asn Ile 100
105 110 Gln Ala Val Arg Thr Gln Glu Lys Glu
Gln Ile Lys Thr Leu Asn Asn 115 120
125 Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu Glu Gln
Gln Asn 130 135 140
Lys Met Leu Glu Thr Lys Trp Ser Leu Leu Gln Gln Gln Lys Thr Ala 145
150 155 160 Arg Ser Asn Met Asp
Asn Met Phe Glu Ser Tyr Ile Asn Asn Leu Arg 165
170 175 Arg Gln Leu Glu Thr Leu Gly Gln Glu Lys
Leu Lys Leu Glu Ala Glu 180 185
190 Leu Gly Asn Met Gln Gly Leu Val Glu Asp Phe Lys Asn Lys Tyr
Glu 195 200 205 Asp
Glu Ile Asn Lys Arg Thr Glu Met Glu Asn Glu Phe Val Leu Ile 210
215 220 Lys Lys Asp Val Asp Glu
Ala Tyr Met Asn Lys Val Glu Leu Glu Ser 225 230
235 240 Arg Leu Glu Gly Leu Thr Asp Glu Ile Asn Phe
Leu Arg Gln Leu Tyr 245 250
255 Glu Glu Glu Ile Arg Glu Leu Gln Ser Gln Ile Ser Asp Thr Ser Val
260 265 270 Val Leu
Ser Met Asp Asn Ser Arg Ser Leu Asp Met Asp Ser Ile Ile 275
280 285 Ala Glu Val Lys Ala Gln Tyr
Glu Asp Ile Ala Asn Arg Ser Arg Ala 290 295
300 Glu Ala Glu Ser Met Tyr Gln Ile Lys Tyr Glu Glu
Leu Gln Ser Leu 305 310 315
320 Ala Gly Lys His Gly Asp Asp Leu Arg Arg Thr Lys Thr Glu Ile Ser
325 330 335 Glu Met Asn
Arg Asn Ile Ser Arg Leu Gln Ala Glu Ile Glu Gly Leu 340
345 350 Lys Gly Gln Arg Ala Ser Leu Glu
Ala Ala Ile Ala Asp Ala Glu Gln 355 360
365 Arg Gly Glu Leu Ala Ile Lys Asp Ala Asn Ala Lys Leu
Ser Glu Leu 370 375 380
Glu Ala Ala Leu Gln Arg Ala Lys Gln Asp Met Ala Arg Gln Leu Arg 385
390 395 400 Glu Tyr Gln Glu
Leu Met Asn Val Lys Leu Ala Leu Asp Ile Glu Ile 405
410 415 Ala Thr Tyr Arg Lys Leu Leu Glu Gly
Glu Glu Ser Arg Leu Glu Ser 420 425
430 Gly Met Gln Asn Met Ser Ile His Thr Lys Thr Thr Ser Gly
Tyr Ala 435 440 445
Gly Gly Leu Ser Ser Ala Tyr Gly Gly Leu Thr Ser Pro Gly Leu Ser 450
455 460 Tyr Ser Leu Gly Ser
Ser Phe Gly Ser Gly Ala Gly Ser Ser Ser Phe 465 470
475 480 Ser Arg Thr Ser Ser Ser Arg Ala Val Val
Val Lys Lys Ile Glu Thr 485 490
495 Arg Asp Gly Lys Leu Val Ser Glu Ser Ser Asp Val Leu Pro Lys
500 505 510 61807DNAHomo
sapiens 6attcagcaaa tgtttgcgga atgaatgggg tgagctggag ccaggacctg
caggaaggga 60tctccgcctg gttcggcccg cctgcctcca ctcctgcctc taccatgtcc
atcagggtga 120cccagaagtc ctacaaggtg tccacctctg gcccccgggc cttcagcagc
cgctcctaca 180cgagtgggcc cggttcccgc atcagctcct cgagcttctc ccgagtgggc
agcagcaact 240ttcgcggtgg cctgggcggc ggctatggtg gggccagcgg catgggaggc
atcaccgcag 300ttacggtcaa ccagagcctg ctgagccccc ttgtcctgga ggtggacccc
aacatccagg 360ccgtgcgcac ccaggagaag gagcagatca agaccctcaa caacaagttt
gcctccttca 420tagacaaggt acggttcctg gagcagcaga acaagatgct ggagaccaag
tggagcctcc 480tgcagcagca gaagacggct cgaagcaaca tggacaacat gttcgagagc
tacatcaaca 540accttaggcg gcagctggag actctgggcc aggagaagct gaagctggag
gcggagcttg 600gcaacatgca ggggctggtg gaggacttca agaacaagta tgaggatgag
atcaataagc 660gtacagagat ggagaacgaa tttgtcctca tcaagaagga tgtggatgaa
gcttacatga 720acaaggtaga gctggagtct cgcctggaag ggctgaccga cgagatcaac
ttcctcaggc 780agctatatga agaggagatc cgggagctgc agtcccagat ctcggacaca
tctgtggtgc 840tgtccatgga caacagccgc tccctggaca tggacagcat cattgctgag
gtcaaggcac 900agtacgagga tattgccaac cgcagccggg ctgaggctga gagcatgtac
cagatcaagt 960atgaggagct gcagagcctg gctgggaagc acggggatga cctgcggcgc
acaaagactg 1020agatctctga gatgaaccgg aacatcagcc ggctccaggc tgagattgag
ggcctcaaag 1080gccagagggc ttccctggag gccgccattg cagatgccga gcagcgtgga
gagctggcca 1140ttaaggatgc caacgccaag ttgtccgagc tggaggccgc cctgcagcgg
gccaagcagg 1200acatggcgcg gcagctgcgt gagtaccagg agctgatgaa cgtcaagctg
gccctggaca 1260tcgagatcgc cacctacagg aagctgctgg agggcgagga gagccggctg
gagtctggga 1320tgcagaacat gagtattcat acgaagacca ccagcggcta tgcaggtggt
ctgagctcgg 1380cctatggggg cctcacaagc cccggcctca gctacagcct gggctccagc
tttggctctg 1440gcgcgggctc cagctccttc agccgcacca gctcctccag ggccgtggtt
gtgaagaaga 1500tcgagacacg tgatgggaag ctggtgtctg agtcctctga cgtcctgccc
aagtgaacag 1560ctgcggcagc ccctcccagc ctacccctcc tgcgctgccc cagagcctgg
gaaggaggcc 1620gctatgcagg gtagcactgg gaacaggaga cccacctgag gctcagccct
agccctcagc 1680ccacctgggg agtttactac ctggggaccc cccttgccca tgcctccagc
tacaaaacaa 1740ttcaattgct tttttttttt ggtccaaaat aaaacctcag ctagctctgc
caatgtcaaa 1800aaaaaaa
18077483PRTHomo sapiens 7Met Ser Ile Arg Val Thr Gln Lys Ser
Tyr Lys Val Ser Thr Ser Gly 1 5 10
15 Pro Arg Ala Phe Ser Ser Arg Ser Tyr Thr Ser Gly Pro Gly
Ser Arg 20 25 30
Ile Ser Ser Ser Ser Phe Ser Arg Val Gly Ser Ser Asn Phe Arg Gly
35 40 45 Gly Leu Gly Gly
Gly Tyr Gly Gly Ala Ser Gly Met Gly Gly Ile Thr 50
55 60 Ala Val Thr Val Asn Gln Ser Leu
Leu Ser Pro Leu Val Leu Glu Val 65 70
75 80 Asp Pro Asn Ile Gln Ala Val Arg Thr Gln Glu Lys
Glu Gln Ile Lys 85 90
95 Thr Leu Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu
100 105 110 Glu Gln Gln
Asn Lys Met Leu Glu Thr Lys Trp Ser Leu Leu Gln Gln 115
120 125 Gln Lys Thr Ala Arg Ser Asn Met
Asp Asn Met Phe Glu Ser Tyr Ile 130 135
140 Asn Asn Leu Arg Arg Gln Leu Glu Thr Leu Gly Gln Glu
Lys Leu Lys 145 150 155
160 Leu Glu Ala Glu Leu Gly Asn Met Gln Gly Leu Val Glu Asp Phe Lys
165 170 175 Asn Lys Tyr Glu
Asp Glu Ile Asn Lys Arg Thr Glu Met Glu Asn Glu 180
185 190 Phe Val Leu Ile Lys Lys Asp Val Asp
Glu Ala Tyr Met Asn Lys Val 195 200
205 Glu Leu Glu Ser Arg Leu Glu Gly Leu Thr Asp Glu Ile Asn
Phe Leu 210 215 220
Arg Gln Leu Tyr Glu Glu Glu Ile Arg Glu Leu Gln Ser Gln Ile Ser 225
230 235 240 Asp Thr Ser Val Val
Leu Ser Met Asp Asn Ser Arg Ser Leu Asp Met 245
250 255 Asp Ser Ile Ile Ala Glu Val Lys Ala Gln
Tyr Glu Asp Ile Ala Asn 260 265
270 Arg Ser Arg Ala Glu Ala Glu Ser Met Tyr Gln Ile Lys Tyr Glu
Glu 275 280 285 Leu
Gln Ser Leu Ala Gly Lys His Gly Asp Asp Leu Arg Arg Thr Lys 290
295 300 Thr Glu Ile Ser Glu Met
Asn Arg Asn Ile Ser Arg Leu Gln Ala Glu 305 310
315 320 Ile Glu Gly Leu Lys Gly Gln Arg Ala Ser Leu
Glu Ala Ala Ile Ala 325 330
335 Asp Ala Glu Gln Arg Gly Glu Leu Ala Ile Lys Asp Ala Asn Ala Lys
340 345 350 Leu Ser
Glu Leu Glu Ala Ala Leu Gln Arg Ala Lys Gln Asp Met Ala 355
360 365 Arg Gln Leu Arg Glu Tyr Gln
Glu Leu Met Asn Val Lys Leu Ala Leu 370 375
380 Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu
Gly Glu Glu Ser 385 390 395
400 Arg Leu Glu Ser Gly Met Gln Asn Met Ser Ile His Thr Lys Thr Thr
405 410 415 Ser Gly Tyr
Ala Gly Gly Leu Ser Ser Ala Tyr Gly Gly Leu Thr Ser 420
425 430 Pro Gly Leu Ser Tyr Ser Leu Gly
Ser Ser Phe Gly Ser Gly Ala Gly 435 440
445 Ser Ser Ser Phe Ser Arg Thr Ser Ser Ser Arg Ala Val
Val Val Lys 450 455 460
Lys Ile Glu Thr Arg Asp Gly Lys Leu Val Ser Glu Ser Ser Asp Val 465
470 475 480 Leu Pro Lys
81901DNAHomo sapiens 8acaggccttt ccttacctcc ctccatgctg tccacttcct
ctgtaaagct ctcaaccctg 60tccccttccc cctctctcct gggaaagagc cctcccatgc
ctagctgctg ctcttaggga 120ccctgtggct aggtgcgcgg atggaaatcc aggatctccg
cctggttcgg cccgcctgcc 180tccactcctg cctctaccat gtccatcagg gtgacccaga
agtcctacaa ggtgtccacc 240tctggccccc gggccttcag cagccgctcc tacacgagtg
ggcccggttc ccgcatcagc 300tcctcgagct tctcccgagt gggcagcagc aactttcgcg
gtggcctggg cggcggctat 360ggtggggcca gcggcatggg aggcatcacc gcagttacgg
tcaaccagag cctgctgagc 420ccccttgtcc tggaggtgga ccccaacatc caggccgtgc
gcacccagga gaaggagcag 480atcaagaccc tcaacaacaa gtttgcctcc ttcatagaca
aggtacggtt cctggagcag 540cagaacaaga tgctggagac caagtggagc ctcctgcagc
agcagaagac ggctcgaagc 600aacatggaca acatgttcga gagctacatc aacaacctta
ggcggcagct ggagactctg 660ggccaggaga agctgaagct ggaggcggag cttggcaaca
tgcaggggct ggtggaggac 720ttcaagaaca agtatgagga tgagatcaat aagcgtacag
agatggagaa cgaatttgtc 780ctcatcaaga aggatgtgga tgaagcttac atgaacaagg
tagagctgga gtctcgcctg 840gaagggctga ccgacgagat caacttcctc aggcagctat
atgaagagga gatccgggag 900ctgcagtccc agatctcgga cacatctgtg gtgctgtcca
tggacaacag ccgctccctg 960gacatggaca gcatcattgc tgaggtcaag gcacagtacg
aggatattgc caaccgcagc 1020cgggctgagg ctgagagcat gtaccagatc aagtatgagg
agctgcagag cctggctggg 1080aagcacgggg atgacctgcg gcgcacaaag actgagatct
ctgagatgaa ccggaacatc 1140agccggctcc aggctgagat tgagggcctc aaaggccaga
gggcttccct ggaggccgcc 1200attgcagatg ccgagcagcg tggagagctg gccattaagg
atgccaacgc caagttgtcc 1260gagctggagg ccgccctgca gcgggccaag caggacatgg
cgcggcagct gcgtgagtac 1320caggagctga tgaacgtcaa gctggccctg gacatcgaga
tcgccaccta caggaagctg 1380ctggagggcg aggagagccg gctggagtct gggatgcaga
acatgagtat tcatacgaag 1440accaccagcg gctatgcagg tggtctgagc tcggcctatg
ggggcctcac aagccccggc 1500ctcagctaca gcctgggctc cagctttggc tctggcgcgg
gctccagctc cttcagccgc 1560accagctcct ccagggccgt ggttgtgaag aagatcgaga
cacgtgatgg gaagctggtg 1620tctgagtcct ctgacgtcct gcccaagtga acagctgcgg
cagcccctcc cagcctaccc 1680ctcctgcgct gccccagagc ctgggaagga ggccgctatg
cagggtagca ctgggaacag 1740gagacccacc tgaggctcag ccctagccct cagcccacct
ggggagttta ctacctgggg 1800accccccttg cccatgcctc cagctacaaa acaattcaat
tgcttttttt ttttggtcca 1860aaataaaacc tcagctagct ctgccaatgt caaaaaaaaa a
19019456PRTHomo sapiens 9Met Thr Thr Thr Phe Leu
Gln Thr Ser Ser Ser Thr Phe Gly Gly Gly 1 5
10 15 Ser Thr Arg Gly Gly Ser Leu Leu Ala Gly Gly
Gly Gly Phe Gly Gly 20 25
30 Gly Ser Leu Ser Gly Gly Gly Gly Ser Arg Ser Ile Ser Ala Ser
Ser 35 40 45 Ala
Arg Phe Val Ser Ser Gly Ser Gly Gly Gly Tyr Gly Gly Gly Met 50
55 60 Arg Val Cys Gly Phe Gly
Gly Gly Ala Gly Ser Val Phe Gly Gly Gly 65 70
75 80 Phe Gly Gly Gly Val Gly Gly Gly Phe Gly Gly
Gly Phe Gly Gly Gly 85 90
95 Asp Gly Gly Leu Leu Ser Gly Asn Glu Lys Ile Thr Met Gln Asn Leu
100 105 110 Asn Asp
Arg Leu Ala Ser Tyr Leu Asp Lys Val Arg Ala Leu Glu Glu 115
120 125 Ala Asn Ala Asp Leu Glu Val
Lys Ile His Asp Trp Tyr Gln Lys Gln 130 135
140 Thr Pro Thr Ser Pro Glu Cys Asp Tyr Ser Gln Tyr
Phe Lys Thr Ile 145 150 155
160 Glu Glu Leu Arg Asp Lys Ile Met Ala Thr Thr Ile Asp Asn Ser Arg
165 170 175 Val Ile Leu
Glu Ile Asp Asn Ala Arg Leu Ala Ala Asp Asp Phe Arg 180
185 190 Leu Lys Tyr Glu Asn Glu Leu Ala
Leu Arg Gln Gly Val Glu Ala Asp 195 200
205 Ile Asn Gly Leu Arg Arg Val Leu Asp Glu Leu Thr Leu
Ala Arg Thr 210 215 220
Asp Leu Glu Met Gln Ile Glu Gly Leu Asn Glu Glu Leu Ala Tyr Leu 225
230 235 240 Lys Lys Asn His
Glu Glu Glu Met Lys Glu Phe Ser Ser Gln Leu Ala 245
250 255 Gly Gln Val Asn Val Glu Met Asp Ala
Ala Pro Gly Val Asp Leu Thr 260 265
270 Arg Val Leu Ala Glu Met Arg Glu Gln Tyr Glu Ala Met Ala
Glu Lys 275 280 285
Asn Arg Arg Asp Val Glu Ala Trp Phe Phe Ser Lys Thr Glu Glu Leu 290
295 300 Asn Lys Glu Val Ala
Ser Asn Thr Glu Met Ile Gln Thr Ser Lys Thr 305 310
315 320 Glu Ile Thr Asp Leu Arg Arg Thr Met Gln
Glu Leu Glu Ile Glu Leu 325 330
335 Gln Ser Gln Leu Ser Met Lys Ala Gly Leu Glu Asn Ser Leu Ala
Glu 340 345 350 Thr
Glu Cys Arg Tyr Ala Thr Gln Leu Gln Gln Ile Gln Gly Leu Ile 355
360 365 Gly Gly Leu Glu Ala Gln
Leu Ser Glu Leu Arg Cys Glu Met Glu Ala 370 375
380 Gln Asn Gln Glu Tyr Lys Met Leu Leu Asp Ile
Lys Thr Arg Leu Glu 385 390 395
400 Gln Glu Ile Ala Thr Tyr Arg Ser Leu Leu Glu Gly Gln Asp Ala Lys
405 410 415 Met Ala
Gly Ile Gly Ile Arg Glu Ala Ser Ser Gly Gly Gly Gly Ser 420
425 430 Ser Ser Asn Phe His Ile Asn
Val Glu Glu Ser Val Asp Gly Gln Val 435 440
445 Val Ser Ser His Lys Arg Glu Ile 450
455 101861DNAHomo sapiens 10cactcaaggt gtgcaggcag ctgtgtttgt
caggaaggca gaaggagttg gctttgcttt 60aggggaggag acgaggtccc acaacaccct
ctgaagggta tataaggagc cccagcgtgc 120agcctggcct ggtacctcct gccagcatct
cttgggtttg ctgagaactc acgggctcca 180gctacctggc catgaccacc acatttctgc
aaacttcttc ctccaccttt gggggtggct 240caacccgagg gggttccctc ctggctgggg
gaggtggctt tggtgggggg agtctctctg 300ggggaggtgg aagccgaagt atctcagctt
cttctgctag gtttgtctct tcagggtcag 360gaggaggata tgggggtggc atgagggtct
gtggctttgg tggaggggct ggtagtgttt 420tcggtggagg ctttggaggg ggcgttggtg
ggggttttgg tggtggcttt ggtggtggcg 480atggtggtct cctctctggc aatgagaaaa
ttaccatgca gaacctcaat gaccgcctgg 540cctcctacct ggacaaggta cgtgccctgg
aggaggccaa tgctgacctg gaggtgaaga 600tccatgactg gtaccagaag cagaccccaa
ccagcccaga atgcgactac agccaatact 660tcaagaccat tgaagagctc cgggacaaga
tcatggccac caccatcgac aactcccggg 720tcatcctgga gatcgacaat gccaggctgg
ctgcggacga cttcaggctc aagtatgaga 780atgagctggc cctgcgccag ggcgttgagg
ctgacatcaa cggcttgcgc cgagtcctgg 840atgagctgac cctggccagg actgacctgg
agatgcagat cgagggcctg aatgaggagc 900tagcctacct gaagaagaac cacgaagagg
agatgaagga gttcagcagc cagctggccg 960gccaggtcaa tgtggagatg gacgcagcac
cgggtgtgga cctgacccgt gtgctggcag 1020agatgaggga gcagtacgag gccatggcgg
agaagaaccg ccgggatgtc gaggcctggt 1080tcttcagcaa gactgaggag ctgaacaaag
aggtggcctc caacacagaa atgatccaga 1140ccagcaagac ggagatcaca gacctgagac
gcacgatgca ggagctggag atcgagctgc 1200agtcccagct cagcatgaaa gctgggctgg
agaactcact ggccgagaca gagtgccgct 1260atgccacgca gctgcagcag atccaggggc
tcattggtgg cctggaggcc cagctgagtg 1320agctccgatg cgagatggag gctcagaacc
aggagtacaa gatgctgctt gacataaaga 1380cacggctgga gcaggagatc gctacttacc
gcagcctgct cgagggccag gatgccaaga 1440tggctggcat tggcatcagg gaagcctctt
caggaggtgg tggtagcagc agcaatttcc 1500acatcaatgt agaagagtca gtggatggac
aggtggtttc ttcccacaag agagaaatct 1560aagtgtctat tgcaggagaa acgtcccttg
ccactcccca ctctcatcag gccaagtgga 1620ggactggcca gagggcctgc acatgcaaac
tccagtccct gccttcagag agctgaaaag 1680ggtccctcgg tcttttattt cagggctttg
catgcgctct attccccctc tgcctctccc 1740caccttcttt ggagcaagga gatgcagctg
tattgtgtaa caagctcatt tgtacagtgt 1800ctgttcatgt aataaagaat tacttttcct
tttgcaaata aaaaaaaaaa aaaaaaaaaa 1860a
186111430PRTHomo sapiens 11Met Ser Phe
Thr Thr Arg Ser Thr Phe Ser Thr Asn Tyr Arg Ser Leu 1 5
10 15 Gly Ser Val Gln Ala Pro Ser Tyr
Gly Ala Arg Pro Val Ser Ser Ala 20 25
30 Ala Ser Val Tyr Ala Gly Ala Gly Gly Ser Gly Ser Arg
Ile Ser Val 35 40 45
Ser Arg Ser Thr Ser Phe Arg Gly Gly Met Gly Ser Gly Gly Leu Ala 50
55 60 Thr Gly Ile Ala
Gly Gly Leu Ala Gly Met Gly Gly Ile Gln Asn Glu 65 70
75 80 Lys Glu Thr Met Gln Ser Leu Asn Asp
Arg Leu Ala Ser Tyr Leu Asp 85 90
95 Arg Val Arg Ser Leu Glu Thr Glu Asn Arg Arg Leu Glu Ser
Lys Ile 100 105 110
Arg Glu His Leu Glu Lys Lys Gly Pro Gln Val Arg Asp Trp Ser His
115 120 125 Tyr Phe Lys Ile
Ile Glu Asp Leu Arg Ala Gln Ile Phe Ala Asn Thr 130
135 140 Val Asp Asn Ala Arg Ile Val Leu
Gln Ile Asp Asn Ala Arg Leu Ala 145 150
155 160 Ala Asp Asp Phe Arg Val Lys Tyr Glu Thr Glu Leu
Ala Met Arg Gln 165 170
175 Ser Val Glu Asn Asp Ile His Gly Leu Arg Lys Val Ile Asp Asp Thr
180 185 190 Asn Ile Thr
Arg Leu Gln Leu Glu Thr Glu Ile Glu Ala Leu Lys Glu 195
200 205 Glu Leu Leu Phe Met Lys Lys Asn
His Glu Glu Glu Val Lys Gly Leu 210 215
220 Gln Ala Gln Ile Ala Ser Ser Gly Leu Thr Val Glu Val
Asp Ala Pro 225 230 235
240 Lys Ser Gln Asp Leu Ala Lys Ile Met Ala Asp Ile Arg Ala Gln Tyr
245 250 255 Asp Glu Leu Ala
Arg Lys Asn Arg Glu Glu Leu Asp Lys Tyr Trp Ser 260
265 270 Gln Gln Ile Glu Glu Ser Thr Thr Val
Val Thr Thr Gln Ser Ala Glu 275 280
285 Val Gly Ala Ala Glu Thr Thr Leu Thr Glu Leu Arg Arg Thr
Val Gln 290 295 300
Ser Leu Glu Ile Asp Leu Asp Ser Met Arg Asn Leu Lys Ala Ser Leu 305
310 315 320 Glu Asn Ser Leu Arg
Glu Val Glu Ala Arg Tyr Ala Leu Gln Met Glu 325
330 335 Gln Leu Asn Gly Ile Leu Leu His Leu Glu
Ser Glu Leu Ala Gln Thr 340 345
350 Arg Ala Glu Gly Gln Arg Gln Ala Gln Glu Tyr Glu Ala Leu Leu
Asn 355 360 365 Ile
Lys Val Lys Leu Glu Ala Glu Ile Ala Thr Tyr Arg Arg Leu Leu 370
375 380 Glu Asp Gly Glu Asp Phe
Asn Leu Gly Asp Ala Leu Asp Ser Ser Asn 385 390
395 400 Ser Met Gln Thr Ile Gln Lys Thr Thr Thr Arg
Arg Ile Val Asp Gly 405 410
415 Lys Val Val Ser Glu Thr Asn Asp Thr Lys Val Leu Arg His
420 425 430 121485DNAHomo sapiens
12tccggggcgg gggcggggcc tcactctgcg atataactcg ggtcgcgcgg ctcgcgcagg
60ccgccaccgt cgtccgcaaa gcctgagtcc tgtcctttct ctctccccgg acagcatgag
120cttcaccact cgctccacct tctccaccaa ctaccggtcc ctgggctctg tccaggcgcc
180cagctacggc gcccggccgg tcagcagcgc ggccagcgtc tatgcaggcg ctgggggctc
240tggttcccgg atctccgtgt cccgctccac cagcttcagg ggcggcatgg ggtccggggg
300cctggccacc gggatagccg ggggtctggc aggaatggga ggcatccaga acgagaagga
360gaccatgcaa agcctgaacg accgcctggc ctcttacctg gacagagtga ggagcctgga
420gaccgagaac cggaggctgg agagcaaaat ccgggagcac ttggagaaga agggacccca
480ggtcagagac tggagccatt acttcaagat catcgaggac ctgagggctc agatcttcgc
540aaatactgtg gacaatgccc gcatcgttct gcagattgac aatgcccgtc ttgctgctga
600tgactttaga gtcaagtatg agacagagct ggccatgcgc cagtctgtgg agaacgacat
660ccatgggctc cgcaaggtca ttgatgacac caatatcaca cgactgcagc tggagacaga
720gatcgaggct ctcaaggagg agctgctctt catgaagaag aaccacgaag aggaagtaaa
780aggcctacaa gcccagattg ccagctctgg gttgaccgtg gaggtagatg cccccaaatc
840tcaggacctc gccaagatca tggcagacat ccgggcccaa tatgacgagc tggctcggaa
900gaaccgagag gagctagaca agtactggtc tcagcagatt gaggagagca ccacagtggt
960caccacacag tctgctgagg ttggagctgc tgagacgacg ctcacagagc tgagacgtac
1020agtccagtcc ttggagatcg acctggactc catgagaaat ctgaaggcca gcttggagaa
1080cagcctgagg gaggtggagg cccgctacgc cctacagatg gagcagctca acgggatcct
1140gctgcacctt gagtcagagc tggcacagac ccgggcagag ggacagcgcc aggcccagga
1200gtatgaggcc ctgctgaaca tcaaggtcaa gctggaggct gagatcgcca cctaccgccg
1260cctgctggaa gatggcgagg actttaatct tggtgatgcc ttggacagca gcaactccat
1320gcaaaccatc caaaagacca ccacccgccg gatagtggat ggcaaagtgg tgtctgagac
1380caatgacacc aaagttctga ggcattaagc cagcagaagc agggtaccct ttggggagca
1440ggaggccaat aaaaagttca gagttcaaaa aaaaaaaaaa aaaaa
148513430PRTHomo sapiens 13Met Ser Phe Thr Thr Arg Ser Thr Phe Ser Thr
Asn Tyr Arg Ser Leu 1 5 10
15 Gly Ser Val Gln Ala Pro Ser Tyr Gly Ala Arg Pro Val Ser Ser Ala
20 25 30 Ala Ser
Val Tyr Ala Gly Ala Gly Gly Ser Gly Ser Arg Ile Ser Val 35
40 45 Ser Arg Ser Thr Ser Phe Arg
Gly Gly Met Gly Ser Gly Gly Leu Ala 50 55
60 Thr Gly Ile Ala Gly Gly Leu Ala Gly Met Gly Gly
Ile Gln Asn Glu 65 70 75
80 Lys Glu Thr Met Gln Ser Leu Asn Asp Arg Leu Ala Ser Tyr Leu Asp
85 90 95 Arg Val Arg
Ser Leu Glu Thr Glu Asn Arg Arg Leu Glu Ser Lys Ile 100
105 110 Arg Glu His Leu Glu Lys Lys Gly
Pro Gln Val Arg Asp Trp Ser His 115 120
125 Tyr Phe Lys Ile Ile Glu Asp Leu Arg Ala Gln Ile Phe
Ala Asn Thr 130 135 140
Val Asp Asn Ala Arg Ile Val Leu Gln Ile Asp Asn Ala Arg Leu Ala 145
150 155 160 Ala Asp Asp Phe
Arg Val Lys Tyr Glu Thr Glu Leu Ala Met Arg Gln 165
170 175 Ser Val Glu Asn Asp Ile His Gly Leu
Arg Lys Val Ile Asp Asp Thr 180 185
190 Asn Ile Thr Arg Leu Gln Leu Glu Thr Glu Ile Glu Ala Leu
Lys Glu 195 200 205
Glu Leu Leu Phe Met Lys Lys Asn His Glu Glu Glu Val Lys Gly Leu 210
215 220 Gln Ala Gln Ile Ala
Ser Ser Gly Leu Thr Val Glu Val Asp Ala Pro 225 230
235 240 Lys Ser Gln Asp Leu Ala Lys Ile Met Ala
Asp Ile Arg Ala Gln Tyr 245 250
255 Asp Glu Leu Ala Arg Lys Asn Arg Glu Glu Leu Asp Lys Tyr Trp
Ser 260 265 270 Gln
Gln Ile Glu Glu Ser Thr Thr Val Val Thr Thr Gln Ser Ala Glu 275
280 285 Val Gly Ala Ala Glu Thr
Thr Leu Thr Glu Leu Arg Arg Thr Val Gln 290 295
300 Ser Leu Glu Ile Asp Leu Asp Ser Met Arg Asn
Leu Lys Ala Ser Leu 305 310 315
320 Glu Asn Ser Leu Arg Glu Val Glu Ala Arg Tyr Ala Leu Gln Met Glu
325 330 335 Gln Leu
Asn Gly Ile Leu Leu His Leu Glu Ser Glu Leu Ala Gln Thr 340
345 350 Arg Ala Glu Gly Gln Arg Gln
Ala Gln Glu Tyr Glu Ala Leu Leu Asn 355 360
365 Ile Lys Val Lys Leu Glu Ala Glu Ile Ala Thr Tyr
Arg Arg Leu Leu 370 375 380
Glu Asp Gly Glu Asp Phe Asn Leu Gly Asp Ala Leu Asp Ser Ser Asn 385
390 395 400 Ser Met Gln
Thr Ile Gln Lys Thr Thr Thr Arg Arg Ile Val Asp Gly 405
410 415 Lys Val Val Ser Glu Thr Asn Asp
Thr Lys Val Leu Arg His 420 425
430 141439DNAHomo sapiens 14gcagcctcga gggccaacaa cacctgctgt ccgtgtccat
gcccggttgg ccaccccgtt 60tctgggggca tgagcttcac cactcgctcc accttctcca
ccaactaccg gtccctgggc 120tctgtccagg cgcccagcta cggcgcccgg ccggtcagca
gcgcggccag cgtctatgca 180ggcgctgggg gctctggttc ccggatctcc gtgtcccgct
ccaccagctt caggggcggc 240atggggtccg ggggcctggc caccgggata gccgggggtc
tggcaggaat gggaggcatc 300cagaacgaga aggagaccat gcaaagcctg aacgaccgcc
tggcctctta cctggacaga 360gtgaggagcc tggagaccga gaaccggagg ctggagagca
aaatccggga gcacttggag 420aagaagggac cccaggtcag agactggagc cattacttca
agatcatcga ggacctgagg 480gctcagatct tcgcaaatac tgtggacaat gcccgcatcg
ttctgcagat tgacaatgcc 540cgtcttgctg ctgatgactt tagagtcaag tatgagacag
agctggccat gcgccagtct 600gtggagaacg acatccatgg gctccgcaag gtcattgatg
acaccaatat cacacgactg 660cagctggaga cagagatcga ggctctcaag gaggagctgc
tcttcatgaa gaagaaccac 720gaagaggaag taaaaggcct acaagcccag attgccagct
ctgggttgac cgtggaggta 780gatgccccca aatctcagga cctcgccaag atcatggcag
acatccgggc ccaatatgac 840gagctggctc ggaagaaccg agaggagcta gacaagtact
ggtctcagca gattgaggag 900agcaccacag tggtcaccac acagtctgct gaggttggag
ctgctgagac gacgctcaca 960gagctgagac gtacagtcca gtccttggag atcgacctgg
actccatgag aaatctgaag 1020gccagcttgg agaacagcct gagggaggtg gaggcccgct
acgccctaca gatggagcag 1080ctcaacggga tcctgctgca ccttgagtca gagctggcac
agacccgggc agagggacag 1140cgccaggccc aggagtatga ggccctgctg aacatcaagg
tcaagctgga ggctgagatc 1200gccacctacc gccgcctgct ggaagatggc gaggacttta
atcttggtga tgccttggac 1260agcagcaact ccatgcaaac catccaaaag accaccaccc
gccggatagt ggatggcaaa 1320gtggtgtctg agaccaatga caccaaagtt ctgaggcatt
aagccagcag aagcagggta 1380ccctttgggg agcaggaggc caataaaaag ttcagagttc
aaaaaaaaaa aaaaaaaaa 143915400PRTHomo sapiens 15Met Thr Ser Tyr Ser
Tyr Arg Gln Ser Ser Ala Thr Ser Ser Phe Gly 1 5
10 15 Gly Leu Gly Gly Gly Ser Val Arg Phe Gly
Pro Gly Val Ala Phe Arg 20 25
30 Ala Pro Ser Ile His Gly Gly Ser Gly Gly Arg Gly Val Ser Val
Ser 35 40 45 Ser
Ala Arg Phe Val Ser Ser Ser Ser Ser Gly Ala Tyr Gly Gly Gly 50
55 60 Tyr Gly Gly Val Leu Thr
Ala Ser Asp Gly Leu Leu Ala Gly Asn Glu 65 70
75 80 Lys Leu Thr Met Gln Asn Leu Asn Asp Arg Leu
Ala Ser Tyr Leu Asp 85 90
95 Lys Val Arg Ala Leu Glu Ala Ala Asn Gly Glu Leu Glu Val Lys Ile
100 105 110 Arg Asp
Trp Tyr Gln Lys Gln Gly Pro Gly Pro Ser Arg Asp Tyr Ser 115
120 125 His Tyr Tyr Thr Thr Ile Gln
Asp Leu Arg Asp Lys Ile Leu Gly Ala 130 135
140 Thr Ile Glu Asn Ser Arg Ile Val Leu Gln Ile Asp
Asn Ala Arg Leu 145 150 155
160 Ala Ala Asp Asp Phe Arg Thr Lys Phe Glu Thr Glu Gln Ala Leu Arg
165 170 175 Met Ser Val
Glu Ala Asp Ile Asn Gly Leu Arg Arg Val Leu Asp Glu 180
185 190 Leu Thr Leu Ala Arg Thr Asp Leu
Glu Met Gln Ile Glu Gly Leu Lys 195 200
205 Glu Glu Leu Ala Tyr Leu Lys Lys Asn His Glu Glu Glu
Ile Ser Thr 210 215 220
Leu Arg Gly Gln Val Gly Gly Gln Val Ser Val Glu Val Asp Ser Ala 225
230 235 240 Pro Gly Thr Asp
Leu Ala Lys Ile Leu Ser Asp Met Arg Ser Gln Tyr 245
250 255 Glu Val Met Ala Glu Gln Asn Arg Lys
Asp Ala Glu Ala Trp Phe Thr 260 265
270 Ser Arg Thr Glu Glu Leu Asn Arg Glu Val Ala Gly His Thr
Glu Gln 275 280 285
Leu Gln Met Ser Arg Ser Glu Val Thr Asp Leu Arg Arg Thr Leu Gln 290
295 300 Gly Leu Glu Ile Glu
Leu Gln Ser Gln Leu Ser Met Lys Ala Ala Leu 305 310
315 320 Glu Asp Thr Leu Ala Glu Thr Glu Ala Arg
Phe Gly Ala Gln Leu Ala 325 330
335 His Ile Gln Ala Leu Ile Ser Gly Ile Glu Ala Gln Leu Gly Asp
Val 340 345 350 Arg
Ala Asp Ser Glu Arg Gln Asn Gln Glu Tyr Gln Arg Leu Met Asp 355
360 365 Ile Lys Ser Arg Leu Glu
Gln Glu Ile Ala Thr Tyr Arg Ser Leu Leu 370 375
380 Glu Gly Gln Glu Asp His Tyr Asn Asn Leu Ser
Ala Ser Lys Val Leu 385 390 395
400 161490DNAHomo sapiens 16agatatccgc ccctgacacc attcctccct
tcccccctcc accggccgcg ggcataaaag 60gcgccaggtg agggcctcgc cgctcctccc
gcgaatcgca gcttctgaga ccagggttgc 120tccgtccgtg ctccgcctcg ccatgacttc
ctacagctat cgccagtcgt cggccacgtc 180gtccttcgga ggcctgggcg gcggctccgt
gcgttttggg ccgggggtcg cctttcgcgc 240gcccagcatt cacgggggct ccggcggccg
cggcgtatcc gtgtcctccg cccgctttgt 300gtcctcgtcc tcctcggggg cctacggcgg
cggctacggc ggcgtcctga ccgcgtccga 360cgggctgctg gcgggcaacg agaagctaac
catgcagaac ctcaacgacc gcctggcctc 420ctacctggac aaggtgcgcg ccctggaggc
ggccaacggc gagctagagg tgaagatccg 480cgactggtac cagaagcagg ggcctgggcc
ctcccgcgac tacagccact actacacgac 540catccaggac ctgcgggaca agattcttgg
tgccaccatt gagaactcca ggattgtcct 600gcagatcgac aatgcccgtc tggctgcaga
tgacttccga accaagtttg agacggaaca 660ggctctgcgc atgagcgtgg aggccgacat
caacggcctg cgcagggtgc tggatgagct 720gaccctggcc aggaccgacc tggagatgca
gatcgaaggc ctgaaggaag agctggccta 780cctgaagaag aaccatgagg aggaaatcag
tacgctgagg ggccaagtgg gaggccaggt 840cagtgtggag gtggattccg ctccgggcac
cgatctcgcc aagatcctga gtgacatgcg 900aagccaatat gaggtcatgg ccgagcagaa
ccggaaggat gctgaagcct ggttcaccag 960ccggactgaa gaattgaacc gggaggtcgc
tggccacacg gagcagctcc agatgagcag 1020gtccgaggtt actgacctgc ggcgcaccct
tcagggtctt gagattgagc tgcagtcaca 1080gctgagcatg aaagctgcct tggaagacac
actggcagaa acggaggcgc gctttggagc 1140ccagctggcg catatccagg cgctgatcag
cggtattgaa gcccagctgg gcgatgtgcg 1200agctgatagt gagcggcaga atcaggagta
ccagcggctc atggacatca agtcgcggct 1260ggagcaggag attgccacct accgcagcct
gctcgaggga caggaagatc actacaacaa 1320tttgtctgcc tccaaggtcc tctgaggcag
caggctctgg ggcttctgct gtcctttgga 1380gggtgtcttc tgggtagagg gatgggaagg
aagggaccct tacccccggc tcttctcctg 1440acctgccaat aaaaatttat ggtccaaggg
aaaaaaaaaa aaaaaaaaaa 149017378PRTHomo sapiens 17Met Asp Ser
Val Arg Ser Gly Ala Phe Gly His Leu Phe Arg Pro Asp 1 5
10 15 Asn Phe Ile Phe Gly Gln Ser Gly
Ala Gly Asn Asn Trp Ala Lys Gly 20 25
30 His Tyr Thr Glu Gly Ala Glu Leu Val Asp Ser Val Leu
Asp Val Val 35 40 45
Arg Lys Glu Cys Glu Asn Cys Asp Cys Leu Gln Gly Phe Gln Leu Thr 50
55 60 His Ser Leu Gly
Gly Gly Thr Gly Ser Gly Met Gly Thr Leu Leu Ile 65 70
75 80 Ser Lys Val Arg Glu Glu Tyr Pro Asp
Arg Ile Met Asn Thr Phe Ser 85 90
95 Val Val Pro Ser Pro Lys Val Ser Asp Thr Val Val Glu Pro
Tyr Asn 100 105 110
Ala Thr Leu Ser Ile His Gln Leu Val Glu Asn Thr Asp Glu Thr Tyr
115 120 125 Cys Ile Asp Asn
Glu Ala Leu Tyr Asp Ile Cys Phe Arg Thr Leu Lys 130
135 140 Leu Ala Thr Pro Thr Tyr Gly Asp
Leu Asn His Leu Val Ser Ala Thr 145 150
155 160 Met Ser Gly Val Thr Thr Ser Leu Arg Phe Pro Gly
Gln Leu Asn Ala 165 170
175 Asp Leu Arg Lys Leu Ala Val Asn Met Val Pro Phe Pro Arg Leu His
180 185 190 Phe Phe Met
Pro Gly Phe Ala Pro Leu Thr Ala Arg Gly Ser Gln Gln 195
200 205 Tyr Arg Ala Leu Thr Val Pro Glu
Leu Thr Gln Gln Met Phe Asp Ala 210 215
220 Lys Asn Met Met Ala Ala Cys Asp Pro Arg His Gly Arg
Tyr Leu Thr 225 230 235
240 Val Ala Thr Val Phe Arg Gly Arg Met Ser Met Lys Glu Val Asp Glu
245 250 255 Gln Met Leu Ala
Ile Gln Ser Lys Asn Ser Ser Tyr Phe Val Glu Trp 260
265 270 Ile Pro Asn Asn Val Lys Val Ala Val
Cys Asp Ile Pro Pro Arg Gly 275 280
285 Leu Lys Met Ser Ser Thr Phe Ile Gly Asn Ser Thr Ala Ile
Gln Glu 290 295 300
Leu Phe Lys Arg Ile Ser Glu Gln Phe Thr Ala Met Phe Arg Arg Lys 305
310 315 320 Ala Phe Leu His Trp
Tyr Thr Gly Glu Gly Met Asp Glu Met Glu Phe 325
330 335 Thr Glu Ala Glu Ser Asn Met Asn Asp Leu
Val Ser Glu Tyr Gln Gln 340 345
350 Tyr Gln Asp Ala Thr Ala Glu Glu Glu Gly Glu Met Tyr Glu Asp
Asp 355 360 365 Glu
Glu Glu Ser Glu Ala Gln Gly Pro Lys 370 375
181851DNAHomo sapiens 18agacactcac cccggactcc cttgaacagg gacagggagg
aaccccaggc agctagaccc 60cagcagcagc cacacgagca cactgtgggg cagggagggg
catctcttga gaacaaaaga 120tccatttctc gactttccaa actggagagc ttcttgagag
aaaagagaga gacaggtaca 180ggtccacgcc acccacacac agccctgtgc acacagaccg
gacacaggcg tccacagttc 240tgggaagtca tcagtgatga gcatggcatc gaccccagcg
gcaactacgt gggcgactcg 300gacttgcagc tggagcggat cagcgtctac tacaacgagg
cctcttctca caagtacgtg 360cctcgagcca ttctggtgga cctggaaccc ggaaccatgg
acagtgtccg ctcaggggcc 420tttggacatc tcttcaggcc tgacaatttc atctttggtc
agagtggggc cggcaacaac 480tgggccaagg gtcactacac ggagggggcg gagctggtgg
attcggtcct ggatgtggtg 540cggaaggagt gtgaaaactg cgactgcctg cagggcttcc
agctgaccca ctcgctgggg 600ggcggcacgg gctccggcat gggcacgttg ctcatcagca
aggtgcgtga ggagtatccc 660gaccgcatca tgaacacctt cagcgtcgtg ccctcaccca
aggtgtcaga cacggtggtg 720gagccctaca acgccacgct gtccatccac cagctggtgg
agaacacgga tgagacctac 780tgcatcgaca acgaggcgct ctacgacatc tgcttccgca
ccctcaagct ggccacgccc 840acctacgggg acctcaacca cctggtatcg gccaccatga
gcggagtcac cacctccttg 900cgcttcccgg gccagctcaa cgctgacctg cgcaagctgg
ccgtcaacat ggtgcccttc 960ccgcgcctgc acttcttcat gcccggcttc gcccccctca
cagcccgggg cagccagcag 1020taccgggccc tgaccgtgcc cgagctcacc cagcagatgt
tcgatgccaa gaacatgatg 1080gccgcctgcg acccgcgcca cggccgctac ctgacggtgg
ccaccgtgtt ccggggccgc 1140atgtccatga aggaggtgga cgagcagatg ctggccatcc
agagcaagaa cagcagctac 1200ttcgtggagt ggatccccaa caacgtgaag gtggccgtgt
gtgacatccc gccccgcggc 1260ctcaagatgt cctccacctt catcgggaac agcacggcca
tccaggagct gttcaagcgc 1320atctccgagc agttcacggc catgttccgg cgcaaggcct
tcctgcactg gtacacgggc 1380gagggcatgg acgagatgga gttcaccgag gccgagagca
acatgaacga cctggtgtcc 1440gagtaccagc agtaccagga cgccacggcc gaggaagagg
gcgagatgta cgaagacgac 1500gaggaggagt cggaggccca gggccccaag tgaagctgct
cgcagctgga gtgagaggca 1560ggtggcggcc ggggccgaag ccagcagtgt ctaaaccccc
ggagccatct tgctgccgac 1620accctgcttt cccctcgccc tagggctccc ttgccgccct
cctgcagtat ttatggcctc 1680gtcctcccca cctaggccac gtgtgagctg ctcctgtctc
tgtcttattg cagctccagg 1740cctgacgttt tacggttttg ttttttactg gtttgtgttt
atattttcgg ggatacttaa 1800taaatctatt gctgtcagat acccttaaaa aaaaaaaaaa
aaaaaaaaaa a 185119450PRTHomo sapiens 19Met Arg Glu Ile Val
His Ile Gln Ala Gly Gln Cys Gly Asn Gln Ile 1 5
10 15 Gly Ala Lys Phe Trp Glu Val Ile Ser Asp
Glu His Gly Ile Asp Pro 20 25
30 Ser Gly Asn Tyr Val Gly Asp Ser Asp Leu Gln Leu Glu Arg Ile
Ser 35 40 45 Val
Tyr Tyr Asn Glu Ala Ser Ser His Lys Tyr Val Pro Arg Ala Ile 50
55 60 Leu Val Asp Leu Glu Pro
Gly Thr Met Asp Ser Val Arg Ser Gly Ala 65 70
75 80 Phe Gly His Leu Phe Arg Pro Asp Asn Phe Ile
Phe Gly Gln Ser Gly 85 90
95 Ala Gly Asn Asn Trp Ala Lys Gly His Tyr Thr Glu Gly Ala Glu Leu
100 105 110 Val Asp
Ser Val Leu Asp Val Val Arg Lys Glu Cys Glu Asn Cys Asp 115
120 125 Cys Leu Gln Gly Phe Gln Leu
Thr His Ser Leu Gly Gly Gly Thr Gly 130 135
140 Ser Gly Met Gly Thr Leu Leu Ile Ser Lys Val Arg
Glu Glu Tyr Pro 145 150 155
160 Asp Arg Ile Met Asn Thr Phe Ser Val Val Pro Ser Pro Lys Val Ser
165 170 175 Asp Thr Val
Val Glu Pro Tyr Asn Ala Thr Leu Ser Ile His Gln Leu 180
185 190 Val Glu Asn Thr Asp Glu Thr Tyr
Cys Ile Asp Asn Glu Ala Leu Tyr 195 200
205 Asp Ile Cys Phe Arg Thr Leu Lys Leu Ala Thr Pro Thr
Tyr Gly Asp 210 215 220
Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val Thr Thr Ser Leu 225
230 235 240 Arg Phe Pro Gly
Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn 245
250 255 Met Val Pro Phe Pro Arg Leu His Phe
Phe Met Pro Gly Phe Ala Pro 260 265
270 Leu Thr Ala Arg Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val
Pro Glu 275 280 285
Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala Ala Cys Asp 290
295 300 Pro Arg His Gly Arg
Tyr Leu Thr Val Ala Thr Val Phe Arg Gly Arg 305 310
315 320 Met Ser Met Lys Glu Val Asp Glu Gln Met
Leu Ala Ile Gln Ser Lys 325 330
335 Asn Ser Ser Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Val
Ala 340 345 350 Val
Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ser Thr Phe Ile 355
360 365 Gly Asn Ser Thr Ala Ile
Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 370 375
380 Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu
His Trp Tyr Thr Gly 385 390 395
400 Glu Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn
405 410 415 Asp Leu
Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Glu 420
425 430 Glu Gly Glu Met Tyr Glu Asp
Asp Glu Glu Glu Ser Glu Ala Gln Gly 435 440
445 Pro Lys 450 201794DNAHomo sapiens
20gacatcagcc gatgcgaagg gcggggccgc ggctataaga gcgcgcggcc gcggtccccg
60accctcagca gccagcccgg cccgcccgcg cccgtccgca gccgcccgcc agacgcgccc
120agtatgaggg agatcgtgca catccaggcc ggccagtgcg gcaaccagat cggggccaag
180ttctgggaag tcatcagtga tgagcatggc atcgacccca gcggcaacta cgtgggcgac
240tcggacttgc agctggagcg gatcagcgtc tactacaacg aggcctcttc tcacaagtac
300gtgcctcgag ccattctggt ggacctggaa cccggaacca tggacagtgt ccgctcaggg
360gcctttggac atctcttcag gcctgacaat ttcatctttg gtcagagtgg ggccggcaac
420aactgggcca agggtcacta cacggagggg gcggagctgg tggattcggt cctggatgtg
480gtgcggaagg agtgtgaaaa ctgcgactgc ctgcagggct tccagctgac ccactcgctg
540gggggcggca cgggctccgg catgggcacg ttgctcatca gcaaggtgcg tgaggagtat
600cccgaccgca tcatgaacac cttcagcgtc gtgccctcac ccaaggtgtc agacacggtg
660gtggagccct acaacgccac gctgtccatc caccagctgg tggagaacac ggatgagacc
720tactgcatcg acaacgaggc gctctacgac atctgcttcc gcaccctcaa gctggccacg
780cccacctacg gggacctcaa ccacctggta tcggccacca tgagcggagt caccacctcc
840ttgcgcttcc cgggccagct caacgctgac ctgcgcaagc tggccgtcaa catggtgccc
900ttcccgcgcc tgcacttctt catgcccggc ttcgcccccc tcacagcccg gggcagccag
960cagtaccggg ccctgaccgt gcccgagctc acccagcaga tgttcgatgc caagaacatg
1020atggccgcct gcgacccgcg ccacggccgc tacctgacgg tggccaccgt gttccggggc
1080cgcatgtcca tgaaggaggt ggacgagcag atgctggcca tccagagcaa gaacagcagc
1140tacttcgtgg agtggatccc caacaacgtg aaggtggccg tgtgtgacat cccgccccgc
1200ggcctcaaga tgtcctccac cttcatcggg aacagcacgg ccatccagga gctgttcaag
1260cgcatctccg agcagttcac ggccatgttc cggcgcaagg ccttcctgca ctggtacacg
1320ggcgagggca tggacgagat ggagttcacc gaggccgaga gcaacatgaa cgacctggtg
1380tccgagtacc agcagtacca ggacgccacg gccgaggaag agggcgagat gtacgaagac
1440gacgaggagg agtcggaggc ccagggcccc aagtgaagct gctcgcagct ggagtgagag
1500gcaggtggcg gccggggccg aagccagcag tgtctaaacc cccggagcca tcttgctgcc
1560gacaccctgc tttcccctcg ccctagggct cccttgccgc cctcctgcag tatttatggc
1620ctcgtcctcc ccacctaggc cacgtgtgag ctgctcctgt ctctgtctta ttgcagctcc
1680aggcctgacg ttttacggtt ttgtttttta ctggtttgtg tttatatttt cggggatact
1740taataaatct attgctgtca gataccctta aaaaaaaaaa aaaaaaaaaa aaaa
179421163856DNAHomo sapiens 21gcggccaggg gcgggcggcc gcagagcagc accggccgtg
gctccggtag cagcaagttc 60gaaccccgct cccgctccgc ttcggttctc gctccttcgg
cccttgggcc tccaaacacc 120agtccccggc agctcgttgc gcattgcgct ctccccgcca
ccaggatgcc ggtaaccgag 180aaggatctag ctgaggacgc gccttggaag aagatccagc
agaacacgtt cacacgctgg 240tgcaacgagc acctcaagtg cgtgaacaaa cgcatcggca
acctgcagac cgacctgagc 300gacgggctgc ggctcatcgc gctgctcgag gtgctcagcc
agaagcgcat gtaccgcaag 360taccatcagc ggcccacctt tcgccagatg cagctcgaga
atgtgtccgt ggcgctcgag 420ttcctggacc gtgagagcat caagctcgtg tccatcggtg
agttctctgg ccgggcccag 480gcgcccactg tggtgccgac ccgcccccgc gcgtgcaccc
ctgcggaggg cgaggatttc 540ccgcagcgcg cccccacctc ggagataagg gggagtcgtc
cccaggggtg ggttataggg 600ggcctagacc ccctccccgg tgtcttcccc tgggatggga
cctgttgtga tcgctccccg 660ccatccgccc cagcagtgca cctttggctg gctaagggtt
gagggtttgg gctggggtca 720caggaggaga ggtggagttg ttgcatttct ctacacctgg
ggcgccccta tgggagctag 780gggactagaa accctcgttc gctgtccccg ggggcgggcc
ctagggtcag atgctccgcg 840gagtgctctc cctgctgcgc ccaggttggt gctctcagag
gcagctgaat gggcgttggc 900tcggaggccg ggccgtgaga cctgaggagg aaccgttctc
tgcgcctggg gcctccctgc 960ccaggtggag acagagacct ggtaccttcc cctgccgtcg
ctggaatggg tgtgggcccc 1020gaggttgcaa gggtaggcgc gggtgtgtgt cctcgctctc
tctgctccca gctcagctct 1080ggccgcgcgc cgcaggttga acccactcct tgctgccgaa
gttataattt agagatggtg 1140gtggtaacag taattgctgt cttgtaggga gcccaactag
cgtccactgt gtaccgtcag 1200ccttctaagt tatctccgtc cctacgcatc ctgccatctg
gggtgaggct agacccattt 1260tacagataag ggggtccgga gggttaattg acctgtccaa
ggtcagcaag tagggcccag 1320ctgagaactg aaggaagtgg gcaacagtta gaaggaggct
ttgttttcct ctcctctccc 1380aaacctacac cagggtcttc ctgaaaggag ggagggaatt
ggtgtctctt gctggactgg 1440gccttctggt ctggggagga agaataagga tgaagtctcc
cttgtggtct gagatagttg 1500gaggcttccc agagggccac aaggctactg atagtgtggg
ctgtgatggt aggggctgtg 1560atgtgtgtgt gcatgtgggc gtttgtgcag agaacgtgtg
tacacacata gcatgtgtgt 1620atagcatgtg catatgcaaa gagtttgcat gtacacggaa
tgtatgcaga gaatgtgtat 1680ccacctacac gtgtgtatgg gtgtgtgtat gtgtgtgtgt
gtatgtgggt gggtgggtgt 1740gggttggggc agaggagggt tctgggtctg gatctcttcc
taaggagaac cagggactgg 1800ccctggcctg tgatttgggt ctcttcctga ggaaaccagg
tcactatagt gaccctagtg 1860acaggaagaa agggagatgg gtgtggctgc caggactttc
tccagtggaa aagggattcc 1920ctctaggctg agcctcccct gggccttagg gcctcaccct
tcccttcccc cacacctgtc 1980ctggcaggta aggctgcttc ctgcttcctg ggcccagatg
gcagccgcac cacccagctg 2040atctccagca gccctccccc tccccaaggg tggcttccct
gcagaagaat ctgcatggca 2100cgctgttgtc ttctttctgg ggtccatctc ctgtactggg
gagggagaac ctcagaatct 2160cctggaattc tttaccattc agaaaccagc ctcccctctg
aagaatccca aggcccagct 2220gggctcaatt tggatctgtt ctttgtttta aaaatgtgta
tttatttaat taactgaata 2280aagaaactta aagtaaacca gaagtatcca aatacgacat
gaaatctcta aaacaacaac 2340aaaaccaaac caaaccgcag cactagcaaa tcacagactg
cctgatctac ccactgttta 2400cagaggcagc agctacttcc agcactgtct ctcatcagtg
cccggggctg tgggtctcat 2460tctagatttt gtctacattt ttttacatgg ttctcctgat
tccctgctcc ccctccccac 2520caccgccccg cctggagatg gagccttgct ctgtctccag
gctggagtac aatggtgcca 2580tctctgctca ctgcaacctc cacctcccgg gttcaagcga
ttcttctgcc tcagcctcct 2640gagtagctag aattacaggc acatgccacc acgcccggct
aatttttgta ttcttagtag 2700agatggggtt tcaccatgtt ggccaggctg gtctcgaact
cttgacctca tgatatgccc 2760gcctcggcct cccaagtgcg ggggttacag ccctgagcca
ccgcgcccag cccggtcctc 2820cttttatttt cgaatccact caggccctag ctactcccat
tgtcccgacg ttccagggtt 2880agttagcttc ccttcctctg tgctgggcct gtgggctgtt
ggcagcttct tcctgttcct 2940accacaactt gcattctatt tttttccttt ttaatgattt
cttggatcat attccccaga 3000gtgacattcc tgggttaaag ggtgtgacca catttatgac
ttgtatcatt ggctgcctaa 3060ttgctctccc gagagatctt gcaacaaaca ggttttccag
cctctggaga ccacagagag 3120ccctggcaag tgccaggact gctgtgggga taaagcagga
ggcttcttcc ctaagctctt 3180gaggctgttg tgggtaatgg tccttcatcc ttcaaggcaa
agttacctcc agcttggact 3240aaggttcata tattcactgc ttaggttgtg ttacattgtg
ctgacaatga cactagcttc 3300aatttggggg cacctactgg gtgttaagtg tgttctgttg
atcaccccat tgaattttca 3360tgctaatcat tgattgacag caactactgc cctatctcta
atgatctgct tctgcaagtc 3420acttagagag ttcagggctt aacactgtcc tgggcatgtg
ttgcttagaa aatggcgcct 3480gttaattaaa taaggtgctg tctaataatt atctcaaaag
taatgccagg gctggatgcc 3540gtggctcacg cctgtaatcc cagcacttta ggaggccaag
gtgggtggat cacctgaggt 3600caggagttcg agaccagcct ggacaacatg gtgaaaccct
agctctacta aaaatacaaa 3660aattagctgg gcatggtggt gcacacctgt agtcccagct
actcgggagg ctgaggcagg 3720agaattgctt gaacccggga ggtggaggtt gcagtgagcc
gaggtctttg tgtaactgca 3780ctccagcctg ggagagcgag actctgactc aaaaaaaaaa
aaaaaaaaaa aagtcatgcc 3840cgaatggttt gcacaccgaa gggacgttca aaattagggg
agaacagcct ggttgtttgt 3900ttctgtttgg ttgatcatac tcttgccatg gttagtatta
ttatctttat ttaaagatgg 3960gaaacaggag tgaagccact tgtggaggtg acccagctag
ctagtaaatg gtgtctgaaa 4020cccaggtctg cccagctgtt gaattggagc cttaactgac
ttgccttcca gtttcagaga 4080tgagtaaaat acagcttttc tctccacatc agagggtccc
tgcaacacta ggtttgcaag 4140tcttaggtgt tagggtggtg gctggatacc cacactctga
acctctgacc ttggacaaaa 4200tagggatgtc agggccttcc atgattggca ggatgaatcc
tctgggctgt gatgaaggtc 4260tcacaagttg agagtcagcc gggaattaag tgggatcagt
ttgcctcttg tgttttcctc 4320attgtgtttt ggttggttgg ttgagatttc ctactaccca
atggatgatg ttttattcca 4380tcgtcaggga aggtatcatt gaatgaatac agggttttgt
atgctttgga taagaccaga 4440cagttgtgga gtcattagaa ttgtgtacat gcctccagct
ctgagatagg tggtgtttca 4500acagctgcca gaggactctg gcttttctgc ctagaattca
ctgaaagaca accctggcta 4560ttgattcaca tttgtggttc attgtaaggt aggcccctag
gcgccatcca aaagttgaaa 4620atttccttac gtttcttgtt atgtgatggg cagttcatag
tgaggactca gtgtctttaa 4680ttccagctgt ttgccaggag ttggcagttt tatttacttg
tttttccaaa aacctttctg 4740acatggggca gtccagccag ctgggaggaa aaggggtctc
tcagcccaag aatgatgatc 4800aaggcctaga agtttgggtg gtgtgttttg ttttgggcct
ttagagaaag gaattgtttc 4860cttttcagag gatgtggtct aaccctaaag tttacttgac
tgacttaaac caggccagcg 4920ccagagcagg cagggtgcgt gttcccaaga cttcgggtca
ctaggcagct tccagggtgg 4980tgggtcactg gtccagtcag ctccttttcc ttcctctccc
ttttgtgcta ctactaccaa 5040aataatttcc aaataacctt aagttctgct ctttcttgca
tgtctagcag atgccagcat 5100gtcttttggg tagtacagag agtgcttaaa aagtagcaaa
gttggccgga cgtggtggct 5160catgcctgta atcccagcac cctgggaggc caaggtgggt
ggatcacctg aggtctggag 5220tttgagacca gcctgaccaa catggagaaa ccccatctct
actaaaaata caaaattaga 5280tggccgtggt ggtgcatgcc tgtaatccca gctacgtggg
aggctgaggc aggacaatag 5340cttgaatcca agggcagagg ctgtgttgag ctgagatcat
gccattgcac tccagcttgg 5400gcaacaggag caaaactcca tctcaaaaaa aagtagcaaa
gtagcatgct ttgtcagaat 5460tattaataac aagttgtggg ccatgtacaa ggtggcacat
tagcattcaa tgtcacttgt 5520gtagtagtta agagcaagga ttcttggttc aaatcccact
tgccactaag tagctattag 5580aaacttctgt gccttggttt ccttatcact aaaatgggga
taataactac cttcttaaaa 5640ggctgttata aagattaaac aagttaataa tttttaaagt
gcttggcaca gtttatggta 5700catagtaagt gctctgtgaa tgcctgttaa ttaaataagg
cactgtttaa taatctcaaa 5760agtcatgccg gaaaggtttg cacactgaaa gggcatttga
aatcagcgcg ctctggggag 5820aacagcttgg ttggctaagg ttgatcctac ttgctaaaat
acggctatgg actgcctaga 5880gggtgtcacc tccttgaaag gggctgcccc ctgctatgtt
atggctgcct ccagggccca 5940ttcacaccag ctttgtttcc aagctggaca gggagctcca
ggcgtctggt cattccagcc 6000tcccacccct ttcaggaatc tctgggccaa atcacttcca
gatggtggtt gggcctctgt 6060ggagttctcc cagcaacggc ggagccagca tgccagtcgg
cagccgcctt cgttcttgga 6120gagtctgagc taaaggaggg ctttgatttg gagccaaatt
gtgtctcttg ggtcctggtt 6180ttgtgctgtg aggcaggtac catggagtgg gctgctggct
tagttgagga tggctgccct 6240gctccttagg ggagcagata cccagggcct ggagccttta
ggccctgcct ccagtagctc 6300catggtcagg gtgccagtca ccttgcgttt tctttttctt
tttttttgag atggagtctt 6360gctctgtcgc ccaggttgga gtgcagtggc gtgatctcgg
ctcactgcaa cctctgtctc 6420ccggggtcaa gcaattctcc tgcctcagcc tcctgagtag
ctgggattac aggcgtgcgc 6480cactatgtct ggctaatttt tgtattttta gtagagatgg
ggtttcacct tgttggtcag 6540gctggtctcg aactcccaac ctcgtgatcc acctgcctcg
gcctcccaaa gtgctgggat 6600tacaggcgtg agccaccgga cccagccaac tttgctacat
cagtttccag gtagcatatc 6660ctaggcaaaa ctggatgtag cctagtgatt cagggcctcg
gtctgaagct agactgtctg 6720gattctaatc cgcactctgc ctgataccag ctgtgcaact
ctagtccact gctttaacct 6780ttctgtgcct gcttccctgt ctataaaatg caagagcaaa
atagttgcta tcttagagtt 6840gctgggagca ttatatttga tgaggttaag ttatagcaca
gtgttgtcat tatcactatg 6900aatattgtgc ttttggaccc aagtccagga ctttgtcttg
tcttctgtct attctctggc 6960cagtccagat atttttggaa tcctattgct gtcatctggt
gtgttagctg ttccctttct 7020ccaagttcag aacgtctgat gaagatgtct cccaagatcc
tttcttcctt tcctcattca 7080acaaatatat gaaagcccat ctctgaacca ggccctgtgc
tgggtgctag gacaacagga 7140atgagaggat catgtccttt gcttgcctca gatactgctc
agaggagaag agacaagcaa 7200gcagggagag ccatgcagag gagagctgct caaaccttca
ggcccatgct catcacctgg 7260ggactttgtt aaaaatgcag gtctgattga gtaggtgctg
gggtgtaggc tgggattctg 7320cgtttccagt cagcttcaga tcctgctgtc tgtgcaccgt
gctgtaagta gcaaggatct 7380aggtgccaag ccctctgaaa aggaggagca cctgccccta
ggctgggtat gggtaatcta 7440gaaggttccc tggaggaagg gacctttcag ctaagaccta
aagcgtgact agaattaggc 7500aggcaaacag acatttacac aggagcagac gagtgtgtca
gtttagaggt cttgatgctc 7560aggtcagagg ggcagtggag gggtgggcag ggctggttta
ccaagggctt tctgaaactg 7620gaggctgcct atggggtatg ctccttgagt ttgtttgttt
gttttttttt ttgagttgga 7680gtttcaatct tgtttcctag gctggagtgc agtacagtgg
catgatctcg gctcactgca 7740gcctccatct cccgggttca agagattctc ctgcctgagc
ctcccaagta gctggaatta 7800taggcatgtg cacacctggc taattttgta tttttagtag
atatggtgtt tcaccatgtt 7860ggtcaggctg gcctcgaact cctgacctca ggtgatccac
ccacctagcc tcccaaagtg 7920ctgggattac aggcgtgagc cacggcatcc agccccttgt
ttagtgtagg gtagtaaacc 7980cagccaaaag gggtcgttta tctcaggggt ctcacctgtt
gctccagtca ttcctattag 8040cagaaagttt tgtatgtgcc ccttcctcat atatatatat
atttatatat gtatttatat 8100atatttataa gttataaaca tactctactg tcaatttgta
tattaaatat tagtaaatct 8160tagtttcttt ttagatgaca aatccaaata taaaatctgt
ttttttcctg gctctaacgg 8220attatcttat gtccccttgg ggtggacata cctcttttgg
aggctcccgt gaaggtttgt 8280gtttctacat ttagtttttt tcttttttcc atattcttgt
tattctgctt ttaattttca 8340tctttgagta ttctaaatta aggagctgga tctgtaattg
taacaccttc ccccaacaat 8400aagtttaact aatgaaaata ttcaatggaa tgagccattt
taatctaaat ggggctattt 8460cctgctttta taatgattac agttgctttt catgacattc
tactagaagc catcttacat 8520tactgttgta aatctagtta ttcattaaac gggcacagta
atccctaaat tggctcaggt 8580tattgtataa taaacaacaa tactttcttc ttcaggagct
tgagaagtga tcttgtattt 8640ttaaggtgcc taactaactt ttcatgggaa actgagtcca
tgtactggga agaaagcttt 8700ttggggaaaa tgattagaaa accaaatggg tctctttatg
actgaagtga tgaaccagca 8760ggtgagagta ggtatagatg gtacagagga cggaattact
gggtatttta atcaggccca 8820cttagtatca caatttatta ttctattcta tttttattat
tattttttga gatggagttt 8880cgctcttgtc atccaggctg gagtgcagtg gcgctatctc
agctcactgc aacctccgcc 8940tcccgggttc aagagattct cctgcctcag cctcccaagt
agctgggatt acaggcatgc 9000gccatcacac ctggataatt tttttgcatt tttagtagag
atgaggtttc tccatgttgg 9060tcaggctggt ctcgaactcc cgatctcagg tgatccgccc
gctttggcct ctcaaagtgc 9120tgggattgca ggtgtgagcc atcgcgcctg gccagtgtca
ggatttattc tgtgggaggg 9180gaggaggaca aagaaaaata ctgagctatg tttgaagctc
ctgccctcta agagccttag 9240agcagctgac ttaaatgtgt tcctttgata aactgtagat
ggttgttgta actcttctgc 9300aaactgttta tttttaaaaa caatttgatg agattttact
tatgcccatt gtttgagtac 9360agcatttacc aaagaacaat tttggccaga tcccatgcag
tagaatgccc ttggccaaaa 9420ttttcttgta ctataagcaa agaagcagtt tggtttttca
cttaggcaag actgcctatc 9480agactgagtt attgtgacag agccgctgac tctctccctt
tccccattat caaaatctgg 9540cttttctaag cagcgcatgt aaaaagcttg gcaaggagga
cccttgtcct cctacatatt 9600attctttggc tcttcttggt accaagaata catacaaata
atgctggctg tgtactgaat 9660gttgaggtgt gcactgttga ggatattcat cctctaatat
aacatctagt atttctcaca 9720ccttccgtct gctgagcatt ggtctatctt acttatacta
cttctaatcc tcgtgaactc 9780tgcaaaacta gtggctttac atctatgaga aaagaaaaga
acttttatcg gaagaaggtg 9840agtcctttta aagtatcagg cctggaaaga cattaaatga
gacagcgaac acatcctgct 9900accctctttg agctatgtat tcattgactt tttttttttt
tttttttttt ttttgaggca 9960gagttttgct ttgtcaccag gctggagtgt agtggtgcaa
tcttggctca ctgcaacctc 10020tgcctccggg gttcaagtga ttctcatgcc acagcctcct
gagtagctgg gattacaggc 10080gcctgccacc ttgcctggct agttttggta tttttatttt
tatttattta ttttaagaca 10140gggtctcact ctgtcaccca ggctggagta cagtggcgcg
atcttggctc actgcaacct 10200ctgcctcccg ggttccagcg attctcctgc ctcaacctct
ccagtagctg ggattacagg 10260cgccttggca ccacagccag ttaatttttt gtatttttag
tagaaacggg gtttcagcat 10320gttggccagg ctggtctcga actcccaacc tcaggtaatc
cgcctgcttt ggcctcccaa 10380agtgctggga ttacgagtgt gagccattgt gccccgccta
tgtattcatt tcttaaaatt 10440ggttgctggc taggtgtggt ggtacatgcc tgtcctataa
tcacagcact ttggaaggcc 10500ggtgctggag gatctattga ggccaggagt ttaagaccag
cctgggtgag atcacatctc 10560tacaaaaaaa aaaaaaaaaa aaaaaattat ctggatgcag
tggcacaagc ctacatagtt 10620gtagctgctt gggaggctga gttgggagga tagcttgagc
ccaggagttt gagtctgcag 10680tgagctatga ttgcgtcact gcactctagc ctgggcgaca
gagtgagacc cgtttctaaa 10740acaaagaaat tgctattgtc acaattagtt ataaattaat
ctaataatgc tgcacgcagt 10800accataatcc acaccctata gcttaacgat ggatggccaa
ccactaatca atgctatttc 10860tgtacgccaa tgagaattcc tgacaaaaaa ctttgtatca
gccccactcc ctgtctgtcc 10920cctcttttgc ttttaaaaac ctgcttgtaa caaaggccaa
acagagctca tatccaaggt 10980tacttgggcc tgagtctttc aggcagctgt cttcactttg
gctcaagtaa actctttaat 11040agtttaaatt ttaagcctct gcctctttct tttaggttga
catctgtttc cattttacag 11100atgagaaaac tgaggctcag ctctgcctca ctttacaggt
caggcttaat ccctaatccc 11160tgcctgcatc atgctgtaaa ggacttttgt gtcaaaactg
agtttcacac tctgtaaagt 11220aaaatagata tattgtagtg agagggtgta gaagagactg
ttttctgctt ctgtggattt 11280tttttcttcc tgttttgctt tgctccaaac tttactcatt
tgcgcttgat tcatgtgaaa 11340ctgaaatttc cttctacaga acaaaacttt ttgggggcta
cttaccatat cttttcccac 11400accgtggagc tctgactggg accttttcca gtttttggag
acattgctcc agttctttcc 11460ctgcctttgg tttccagggg gcagtaatgt caccgcaggt
gtggacagta gggaccagct 11520aaaggttgct ttggaggagg tgggcagggc ttttgtttgt
gaggtctaga aaccagaggt 11580gaggaaggag gtgtccctgg aactccccct ggctgcaggg
ctcacagcac acaccatgac 11640accacagggg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg
tgtgtgtgtg tgtgtgttga 11700ggggagtgtt gttgagagcc aactatgcca ggagatcctt
ggtgacagcg gacataggca 11760cagctatgct ctgtcaggaa tgagttcacc cacacccttt
tcttctgcta ccttgtttaa 11820ctggtgggag ggtgtgctgg gttgtgtttg ctggtgagcc
cagcaactgc acccttcttt 11880ccaggcctag cacccagcct ttatcagtct catggccctg
gcacaagtgg gcagcctgct 11940tccaatccaa gcaggcagct ttccgctcat ctgcaggtag
cctcgtgctg tggcagcaca 12000aagttgtgtg agccagagct gaacttgtga tccccacggg
catctcctga ggcgcacctc 12060tcctgagaga gaaagctggt ccgtccagcc cattcagggc
tcagcctccc cagccgtcgc 12120agggctggct tgctgaaagg tctgggtgtt aacacagcac
tcctgttctc tctctctgaa 12180ggccctttat gctggcatga attccttttc tcatagagat
ctgaaagctc ttttgactaa 12240atgggtcacc tttctgagta ttttcataag gctgtcagcc
tttaccatgc cagacaagtt 12300ttctggaatt tcctttccag aaaaaaaaaa aaaaaaggct
actaaagagg ttggagttat 12360ttggaacaca gggtggaatt ctggcattcg aactataggg
aaacgggtgg ggatttgtgg 12420caggcactat gtaaatttgc cgcaagccca taaattcaga
ctttaagatg aaagatggca 12480agcagcagtc agctttcctt caacaggcag gaacggtgct
accttccgcc tgtgctgagt 12540gtgactgagg gagaggcagg cctcctaggg aggccggggc
aggaaaggtt tcttggtggc 12600taaaatagga tttctcagtt tcccccgtgt cccaagaaaa
taagttctta tcatgcttgt 12660accacacttc ttgtgcgtat caccctggtt tccctgcacc
tccttgaagt ggtttatcag 12720attccaggga cacaagaatg gtttggcatc tacagcctat
tgtgggagca ggggcccggc 12780ctggtgcttc ttgcccagga acaaactgat tgttcccttg
gtgtggggta aagcaggcca 12840gagtatggga ccaggccctg cctcccaggg gacctgaggt
gcaaggtctt tgagctgaga 12900ccctaaaagg cctttgtgag tctgtagtgc tatcagttga
gcagagttca gggttctgtt 12960tacaagattc cctctcagca gaggcaggga ggggtacctg
ctggaagacc aggaatgtgc 13020tgctgctggg atgggggccc tcggtggagc ttctagccat
ctggaggcag aacccagaat 13080gtgttctgag tgaggcgcct tggcagagtt ggcttgaaag
cacctaggca gtggcttgtc 13140acattcctta tctccaccaa aggaggcaag ctagcacctg
ggggatggct ctcccatcag 13200ggagtccttt acaggatgtg atccaggtgt cacattacac
ttcctgcagg tgtgcacctc 13260ttacctaatt gtctctccta tccctttttc tcagcactat
tgtctgacat ccatggggag 13320tcacacccaa agttgggcat gaggtcctct cctgggcacc
caacaccttg tttttttgtt 13380tttgtttttt ttggagatag agtcttgctc tgtcacccag
gctagagtgc agtggtgcca 13440tcacagctcg ctgcagcctc gacctccttg gctcaagcga
tcctcccacc tcagcctccc 13500acgtagtcag aattacaggc acacacacca acactgctgg
ctaattttgt attttttgta 13560gattcggttt gctatgttgc ccaggctggt cttgaactcc
tgggctcaag cgatctgcct 13620gcctcagcct cccaaagtgt ggggattaca ggcatgagcc
acctcacttg gccacactgc 13680cctcttactg agccgtattg gtgttctaaa tggccttctt
actctcccac gggtcatcag 13740tgctccaggg gcaggcgctg tgtctcttgt ttacctctgt
ggctctgacc ttggcactta 13800ataggaattt aataaataac ttgttaaata aacagtctct
agtataatag cttgagtatt 13860aagactggta cattgactta tttgcaattc agaaaatgca
aaacagtggt tctttgctgc 13920ctttagtgaa gtgggaatta tatgtagtag acaactgggt
ctggggtccc agtggaacac 13980ttcgtttttg gactgtgatg ctgaacttaa agaactcagc
agttcatgtt cattctctgg 14040acatctgtga tttgcttcaa caactgttag agaacaaggc
cttttccagg tgaagctcag 14100aaaatgaatt taataggaaa ttactgaaag tcacaatcat
agtaacagtt tcattagtta 14160cagtgaatat agagagagcc catacaaagt accaggcatt
gtgataaacg cttcttacta 14220atagctatac aaaacatcat tgcaattctg agaagtagtt
attgttgtaa ttcccgttat 14280gcagatgaga aaactgaggc acacccagat tggccagtga
gtgtgtggtt attactcaga 14340ttcttgtctg agattttaat cttcatattt tactgctttc
ccaaggaaag ccatcagctc 14400agcaagtctt tgaaatttgc ttcttttttt ttttttgaga
cagagtcttg ctgtgtctcc 14460caggctggag tacagtggcg caatcttggc tcactgcaac
ctccgcctcc tgggttcaag 14520cgattctctt gcctcagcct cccgagtagc tgggaatata
gttgcatgcc accacacctg 14580gctattttgt atttttagta gagacggggt ttcaccatgt
tggccagcct ggtcctgaac 14640tcctgatctc gagatccacc tgcctcggcc tcctaaagtg
ctgggatcag gcttgagcca 14700ccgaactcgg cctttttttt tttttttttt gaaatgatgt
ctccttttgt tgcccaaact 14760gcagtcttgg ctcactgcaa cttctgcctc ctgggttcaa
gtgattctcc tgcctcagcc 14820tcccgagtag ctgggactac aggcacgtgc caccatgccc
agctaatttt tgtattttta 14880tagagacagg ctaagcttgt cttgaactcc tgacctcaag
tgatccacct acctggccct 14940cccaaagtgc tgggattaca ggagtgagcc cctgtgccca
gcctgaaatt caattctaat 15000aaatttttat tggagcatta aaaagttaca tctgtagttg
ttactctttg caaaaaattg 15060caagaacaca gaaaaatata aagaaaaaaa tcacctgtga
agaattttaa tgaatctttt 15120tctactttta ggggattttg cttacagctg ccttttaatc
agaataggga agaaagagat 15180tcctttctca ggaaaaaagt gactgtggac tggaaatgct
ttgtgaaata attttggtca 15240tactgatggt tataacaaga ttcgtcttca attgagttat
tgctgagctt tgtccaacat 15300taaaatgaaa ggtctcattt gagtctcatt gtggtttgca
agtctccctt ggtctagaaa 15360tatgtttggt caaccacggc atggaggtgt tccagccact
ttctgtctct taaaagtttt 15420taggacctac ttttattggg actgccaggg tctcttaata
atagttatta tacttggtaa 15480ctattgtgac cttgtctcat aggcagccca gcatagaaac
tcatttagct tttagttgct 15540cagctccatt agctgtttaa acatgtttca gatgtgagcc
tgacaatgta cttgggcagc 15600ttggttcacc cttgactgcc tgggaacttt gagaagtctg
aaaattatat gtagccctaa 15660ggtcttcatg gtattgtttt tttggaggca ccatttccca
atagccctga ggacaccagg 15720cccatgaagc catcctgtct cagccaggag gcagaggaga
tggaatggaa accacttctg 15780gatacagatc cagccacttc cggagtgctt cagagcatgg
gtcagataga ccttgctgct 15840ttctagctgg cagacttggg gaaggttgtt tgacctctct
gagtttgtgt cccagactat 15900agcagtaccc ccttactggc gttatcgaag ataaaatgat
ataatcctga taaatcactt 15960gacccagtcc ttggaggtgg tggtgggggc tggggtaagt
gccccatgaa tggtggtcat 16020catgctcccc accaacctcc tttctctctt ctcctttccc
gtctttcaca cccctaattc 16080ctggacctgg gggtggtctc tccagactag atgaagaagc
aatctaatta tctaggaagg 16140tgaaaggtgg ttgggaatac tcccagaaat aggccaaaga
taccgcctcc tacctaacag 16200actcttttta gaagaagagg caacctgggt ttttggataa
ctgttgagta ggaaccatca 16260tgagtggcat ttctgcattt ctggtcttct ggccaagcct
cctttttttt tttttttttt 16320ttttttttta accttgagac agtcttgctt tgttgccagg
ctggattgca atggtgcagt 16380cttggctcac tgcaacctcc atctcccagg ttcaagcgat
tctcctgcct cagcctcctg 16440agtagctggt actacaggtg ccgccactat gcccagctaa
tttttgtatt tttagtaggg 16500acggggtttc atcatattgg ccaggatggt ctcaatctct
tgacctcata ctctgcccgc 16560ctcggcctcc caaagtgcca gaattacaag cgtgagccac
tgagcccagc cttccttttt 16620tttttttttt tttaagtagc tccattgccc tccctcaccc
tttcttttgt ctcctgtaat 16680gtccttccct tccatttctt ttttttcttt tttcttttct
tctttctttc tttctttttt 16740ttttttttga gataggatct cattctgtgg caaaggctgg
agtgtagtgg cacattcacg 16800gctcattgca gcctcgacct ccaggactca ggtgatcctc
acatctcagc ctcccgagta 16860gctgggacca caggcacaca ccaccacacc cggctaattt
ttgcattttt tgtagaggta 16920gtgttttgcc atgtttccca ggctggtctt gagctcctgg
gctcaagtga tactccctcc 16980tcagcctccc aaattgctga gattacaggc ataagcctct
gcacctggcc ttccctctca 17040tttttttttc tttcctggtt ttgcctgtcc cagaccaccc
tcttggaaag atgctctccc 17100agcagcggca gtaaggtcct ggtcttgtgt ttgctcctgg
gcctgagtct tggctttgct 17160gctttgtagc tagctggctg acaccaggga gctgcttccc
tccaggagcc tgtcgtccat 17220atgctgaatg tgatccttaa atgctctgtc ttacaggggc
cagacattgt ggctcatgca 17280cttcaggggg ctgaggcgtg cagatcactt gaggccagga
gtttgagacc agcctggcca 17340acatggcgaa accctgtctc tactaaaaat acaaaaatta
gccggaggtg gtagtgtgtg 17400cctttaattc cagctacttg gaaggctgag gcaggaaaat
cgctagaacc tgggaggcgg 17460aggttgcagt gagccgagat catgccactg cactccagcc
tgatcaacag agcgagattg 17520tctcaaacaa acaaacaaaa aatgttctgc cttacagagt
tcttaggtat aaaagagaag 17580gtgcctctaa agctcttggc accgtgcctg gcttatagta
agtgcttggt aaacgtcagc 17640tgctgctgtt gtggtgttag tatcagcatt gttgctgtga
gaccctgcac ttcccactta 17700gccttggaaa aataagtctt cacgttaatg ccatgggcta
ccgcttctct tttcagggct 17760tcttggagga gggtggagat ggagagacag gtgggggact
gccagggtta catcctccat 17820gaggctgagg ctgtgctgac tgccttgtgt gctttcaacc
tggagtaaag ggtggctgtg 17880ccagctgctc ccatccccca ggagtctgac tcgtccctgc
cttggccctg ggcagcactt 17940tccctcctag ctctttggca tctggggtca tggtggggct
gcctgccatc tgtcaaaatt 18000tttgctgccc tgggtgtggt ggtaaacccc cgcactatcc
aacttggtgt catggagctg 18060gcgacaatat ttttacagtg gttagtgctt ggaaactgga
cttctgggtt atgccctgta 18120caaacagcat caaagtcgct gggctagggt gacagaggag
gctgccaaca gggaattctg 18180tggctcctgg gacaggaatg gatatgggag gttgggggcc
agtattttcg gttctcttga 18240ggagttggcg agtattagtc tttgccctga tggatagaag
gaatctgtct gtgtcttgca 18300tgaaccgtgt acttccccca gttactcctt ggacaccagc
tgcctgctgt tcataattgg 18360gccagatttc taatactgca gcgctaccaa atgtcagttt
taggccatct ctggtgtagc 18420cagggaacgc ccaacacctt tcccaaaggt agaatttgtg
tgggttttac ttcactgagt 18480gactaatgca gatctttatg ttttaatgat gggaagaaat
tcgtcagcct gggtactttt 18540tccatgtgat ggggcaaaaa tttaaaacac ttgcacaacg
gcttttgttt ctccagctac 18600taaaggtgac tgtcatttag gcattatcag tatgatcagc
tgatgttaac ccactcccct 18660tctggagacc cgtttctgtt tctgggaaag gtgtaggaca
tgctggattt ggcaagattg 18720caggtcccag gcagatgtcc ggacttagac tctggctctt
tttttttttt ccagacaggg 18780tctccctctg tcacccagtc tggagtgcag tggcgcgatc
tcggctcacc acaacctccg 18840cctcccaggt tcaagggatt ctcctgcctc agccccctga
gtagctggga ttacaggcgt 18900gcaccactat gcccagctaa ttcttttttt ttttttgaga
tagaggctca ctgtcaccca 18960ggttggagtg cggtggcccg gtccgcctgc ctcagcctcc
caaagtgtta ggattacagg 19020tgtgagccac cgtgcctggc ctcagctaac ttttgtattt
ttagtatcaa cgaggtttca 19080ccatgttggc caggctggct ttgaattcct ggcctcaatt
gatctgccca cctcggcctc 19140ccaaagtgct gggattacag gcatgagcca ccgcgcctgg
cccagaccct ggctcttact 19200cctaggtcta cctctaccat cactggggcc ctcgcctgaa
ccttttgccc catctataaa 19260atgggagaac tagactaggt ctgtgtcccc caagcttcaa
tcatttgtaa aggaaccacc 19320tttactattt tgccatatcc cacggctgtc tctatttcat
ttttcactta atattatttt 19380cccctgcagt tgactcactt gtaaaacaaa tgtatttgaa
aaggagactt tgtgtcacta 19440taataacgga aaaacagcgt cactaggtaa atggaaggta
accataaata aaccccaaac 19500agttattaaa ttccagccag cactgttgcc tgttcacaac
atgaggcata ctctcttttg 19560gttaaaaagg gaaattagca agagatggag aggtgttgaa
ggtaacctag cactacattg 19620agccttttcc ttgacctgct caggaggatt gagaaagaac
taggagaact gggaagagaa 19680taacgtcttt ttgtgatgca aagtgcctga gtgtgaccaa
gagctcagag tagtaatgta 19740tagatgcttt gtttggatac ttatgcagcc attaccatgt
gccaggggtg tagaggggct 19800aggagtatag aggggattgg gacttgttca ctgacttctg
gttgcttgtg gtctagtagt 19860ggggaggtgg tcatagaata ttgaatacaa acgaagatcg
aacaggctgc aggggtttaa 19920taggaaaatc acaggactaa attctgtcat gtgtacatgg
ggtctacaaa taagagttgt 19980ttagaatttt ttttaattta aatttcccat gaaatataaa
tctatttcat tccagaatga 20040ttctagagaa gctctaaata cattaaagtt gtgttggctg
ggtgcagtgg ctcatgcctg 20100taatcccagc actttgggag gctgaggctg gagaatcact
tgtggccagg agtttgagac 20160cagcctgggc aacatgggag accttatctc taccaaaaaa
aatttttttt tcttttcttt 20220tttttttttt tgagacaaag tttcgctctt gttgcccagg
ctagagtgca atggcatgat 20280ctcagctcac tgcaacctcc gcctccctgg ttcaagcaat
tctcctgcct cagcctccca 20340agtagctggg attacaggca tgtaccacca cacccagcta
attttgtatt ttttttagtg 20400gaggtgggat ttcaccatgt cgatcaggct ggtcttgaac
tcctgacctc aggtgatcca 20460cccatctcag tctcacaaag tgttgggatt acaggcgata
gccactgcac ctggccaaaa 20520acattttaat aaattagctg ggtatggtgg tatgtgcctg
taatcctagc tacttgggag 20580gctggggcag gaggatccct tgagcccagg aattccaagc
tgcagtgaac tataatcagg 20640tcactgcact gaagccggag tgacagagtg agaccttgtc
tcttaaaata aatttgtgtc 20700attgtttgtt gtttttatgg tgttatgaca atgatccatc
ttaacccttt atgtagtggt 20760aactaacttt ctcttttcct aaaagctgat ttgagtttta
ggttctcttg gagtctgtga 20820caattgtaaa tagataagat ataacaaaat ggcctgaaat
actcttgcaa cactcatatt 20880tcccccctca gattagcatg ttctatactc tctgcaaagc
aagatataca ccagaattag 20940gcctctaaaa agcctcatac tgctaatctc tgggaatgaa
tggtgttctt tgggataatg 21000ggatatgaag ctcagtctga tttttctgtt ctgctggtag
cttagggccc cctttcttct 21060gttgggtttt ttgggagaag ggaagttgtg attaagaatg
agaattcttt tttttttttt 21120ttgtctcaag agtcttgctc tgtcgcccag gctggagtgc
aatggctcga tctcggctca 21180ctgcagtctt cacctcctgg tgtcaagcga ttctcctgcc
ttagcctcca agtagctggg 21240aatacaggca cctgccacca tgcctggcta attttttgta
tttttagtaa agatggggtt 21300tcaccatgtt ggccaggctg gtctcgaact actgacccca
tgatcccaac ccccccgacc 21360tccccggcct cccaaagtgc tgggattata ggggggagcc
actgcgtcca gccaagaatg 21420agaatttggg agtcaggcac ctctgggatt gaatctggaa
ttgactgagt gtacatgctt 21480tctctgaggc ctccgtcctc actgctctca tctataaact
gggaataatc atagtttcta 21540tctgaaacag tgggtgtgaa gatttaacga gctaaattgt
aaagtgcctg agacatggga 21600agaagtcagg atgtgctaat gggtaatctt acacttcccc
aatggaaagg gccaggttta 21660tattactcta ggctggtagt aagcgaggca aaggagatat
caggtttcag ctttgttaga 21720acatgctaat ggcaccagga cactcagaag agatacagag
tttgagacaa atggcaccat 21780gagccctgag acattgtgta tggggtgaat cggatagcaa
gaatagactt caaggaggga 21840agtagggcag ttagaatcct ttcagctgca aggaactgaa
aactggctca catagaagga 21900aaatgattgg ctcatgtcag caagcctaga tgcagagcaa
gttatgggtt tcagggatcc 21960agcatctaaa tgatgtcatc aagaacccaa gttttttggg
tctctgctct gttggtttct 22020ttcatcctaa agctggttct cctgtggttt accatagtag
agttcctgtg agaactccac 22080tctgaccaat caggccttcc cagagccagg gatggatgga
gtcgcttctt ttgaggccca 22140tgggtcctat ctggagggga tggatccaga ctcctatcag
gaatctagga ggggccgggc 22200acggtggctc atgcctgtaa tcccagcact tcataatgcc
aaggtggaca gatcacttga 22260ggccaggagt tccagatcag cctggccagt atggtgaaac
cccatctcta ctaaaaatac 22320aaaaattagc taggcgtggt agcaggcgcc tgttgtccca
gctactcggg tggctgaggt 22380gggaggatca cttgagcctg ggcacagagg ttgcggtgag
gttgtggtga gctgtggttg 22440cgctgctgcc ctccagcctg ggcaacagag tgagaccctg
tctcaaaaac aacaacaaca 22500aaatcttatg taccccataa atatatacac ctactgtgta
tccacaaaag ttaaaaatta 22560gaaaaggcaa attgcagaga tttccatatg ctatgatacc
gtttatatga agttttacat 22620atgtcataaa aatacagata acctttaggg gaatgatcat
taccaaactt ttggataacg 22680gtttctgggg atgggcagag agggctatac agtcatgaag
aggtgtatag gggctttcaa 22740ctctttgtag tgttttattt cttcagtccc atggtggtta
tatgattctt cactcccctt 22800tttttgtgtg gaatattttt cttataaaaa gtgtgtcttt
tatttattta tttatctttt 22860tcacatggag tctcactctg tcgcccaggc tggagtgcag
tgttgcgatc tcggctcact 22920gcaagctccg cctcccgggt tcgcgccatt ctcctgcctc
agcctcccga gtagctggga 22980ctacaggcgc ccgccaccac gcctggctaa ttttttgtat
ttttagcaga gacggggttt 23040cactgtgtta gccaggatgg tctcaatctg ctgaccttgt
gatctgcctg cctcggcctc 23100ccaaagtgct aggggattac agacgtgagc caccgtgccc
tgcctttttt tttttttttt 23160ttttttttta aaggcagagt cttgccctgt tggccaggct
gcagtgcagt ggcctgataa 23220tggctcactg cagcttccac ctcccaggct caagcaatcc
tcccacctca gcctcctgag 23280tagctgggac tacaggtatg tgccaccaag cctggctaat
ttttccattt ttaaaggttt 23340tgccatgttg cccaggctgg tctcgaaccc ctgggttcaa
gccatcctcc caccttggcc 23400tcccaaattg ctgggactat agacgtgaac cactgcaccc
ccatccaaaa gtgtcatttt 23460aatgctgaca tactgcatta ctaagcttga ccaggggaag
agaaaaaaaa ataccttgtg 23520tttattattt tgtttgtttg tttgtttgag acagggtctt
gctctttctc ccaggctaga 23580gtgcagtggc atgaacatgg ctcactgcag cctccacttc
ccagggtcaa gccatcctcc 23640cacttcagcc tcccaagtag ctgggattac aggtgtgtgc
caccacacct gactaatttt 23700tctttttttc tttttttgta tttttggtag agacagggtt
gcccaggctg gtcttgaact 23760cctgagctca agcaatcctc tcttcagcct cccaaagtgc
tgggattaca agtatgagcc 23820actgtgcccg gcctgtttgt ttgttttaaa gacaagtttg
ggcccagttt ataagaaaag 23880aaaacagacc atccttaggg tgtcaggatg atattttgac
aaaggcattc atgcttagca 23940ggatttctct ccccctaccc ccaccccaag tgttgaaacg
gctgagctaa ttaccttaga 24000atgtaaggct tcctctgttg cttgtgaacg tggcagactt
gggattctca gagacagagg 24060gcttcagaag cttgcctctg ggagcgtcca gtcaatagct
ttttgtctga gcagaaggag 24120atattgctca aggtaccatc tcaagggact gctgaatcag
ttgcattgtc tctaaaagta 24180ggtaaaagtc tagagtaggg ctggttcaac agtggaatga
gtgttaagag agagttgcat 24240tctaagaaca cctttacact gtggccaaat tcaagcaggt
ccattttgtg gtttggtggt 24300ccccatctag tgggatgtgg tctggtatcc caggcacctg
catatatgag ctcagatggg 24360tttaattttt gaaaaactgc tttattggct gggtgtggta
gctcatgcct gtaatcccaa 24420cattttggga ggccaaggca ggaggatctc ttgagcctgg
gaattcagga ccagcctggg 24480caacattgag agatccccat ctctactccc ttccccgcca
aaaaaaagct aggtgtagtg 24540acatgcacct gtggtcccag ctactcagga ggctgaggtg
ggaggattgc ttgagcccgg 24600gaagtcaaga ctgcagtgag ctgagattgc atgactgcac
tccagcctgg gcaaaagagt 24660gagacattgt ctcaatctcc ccacccctgc caagaaaacc
caaaaaatat tgaggtataa 24720ttgttataca atgaagaaca cattttgatt agcttataca
cacactcctg tgtacacatg 24780tacactcaca catcaggaaa ccatcaccat aatcaagaca
gcgaacctcc ctatccagcc 24840ccagaagttt ccttgtgcct ctttgtaatt cttgcctttt
atctctccat gtcttccaca 24900cccatgctca agcattcact gatctgcttt ctgtcattat
cagtcagttt tcatctttta 24960gccttttata taaatggaat catatagtat gctgttttgt
ttttttttga gacaagagtc 25020tcactctgtt acccaggctg gagtgcagtg gtgcgacctc
ggctcactac aacctccatc 25080tccccagatt taagtgattc tcctgcccta gcttcccgag
tagcagggat tacaggcaca 25140tgctatcatg cctagctaat ttttgtattt ttagtaaaga
tggggattca ccatgttggc 25200caggctggtc ccgaactcct gacctcaggt gatcacccgc
cttggcctcc caaagtgcta 25260ggatcacagg catgagccac tacgccctgc cagtatgtac
tctttttgtc tggcttcttc 25320tagcatagtt attctgaaat tcatccttgt tgcatgtgtc
aatagtccta ttccttttta 25380ttgctgagta gtagtccatt gtatggatat actacatttt
gtttatacat ccttctgttg 25440ataacatttg ggtggtttct tatttattta tttatttttg
agacggagtc tcactctgtt 25500gaacaggctg gagtgcagtg gtgtgatctt ggctcactgc
aacctccacc tcccgggttc 25560aagcaattct cctgcctcag ccttctgagt agctgggatt
acaggcattt gccaccacac 25620ctggctaatt tttgtatttt tagtagagac ggggtttcac
catgttggtc atgctggtct 25680cgaactcctg accttaggcg atccgctcac ctctgcctcc
caaagtgcag ggattatagg 25740tgtgagccac cacgcctggc cgggtggttt ctaaataaag
ctatcatgaa catcttttac 25800tactctttgt atggatgtat atttctattt ttctgagtgg
aatgttagga tcatacatca 25860taggtgtacg tttaactgtt caagaaactg ccaaactgtt
tcccaaagtg gttgtattgt 25920tttacatttc cacgagcagt gtttgagagc tccagttctt
gcacatccta gccacaaaaa 25980ggttctgttt tttaaagaca attttttttt ttttttgaga
gtttcgccct agtcgcccag 26040gctggagtgc agtggtaagc gaatccctgc tacaggccag
agactgttct cagttggttt 26100ttacaccaag tatcgcactt cattctaaca ctccaccatt
ttacaaatga ggaaaccgag 26160gcactgagag gtttagtaac ttgtggcaca gccaggaagc
agtagagaaa gactttgaat 26220ataaatgtat ccattaggat gtatatggtt ccaagtcatg
ggaaacctac ctaatcctgg 26280tttatccaaa aagggagctc attggctctc gtaactgaaa
agtcaagggg taggcaggca 26340gttggacctg gaagtctcca gggcatcaga gagccttggc
tctgcttctc tgattctgtt 26400gtctctccac agacgggtgg gtgtagcagt cccaggcccg
cagccacacc ccacacctcc 26460cagaggaaga aggcgggccc tgatcccagc agtcccagga
aagccctgag gttcactgtg 26520attggaccag cctatgtcac ctgctcacat ctcagcccac
cactggcaag ggtgtttgac 26580tcttgggaat gactcttggg actggcttgt cctagatcac
atgttctacc tgaaattggg 26640gacattgcag aggattggtg gagtggacct caaggaggtg
tttcacgtgg cttcctgtgt 26700cactaggttg ccatttattc tttagaaagc ccctttgttt
gatgaaaccc tggtgtcaca 26760ggctgtgtga cttagggtaa tccccttgtc cacatctgtg
aagtgagatt acctcttcac 26820ctcacaggca gatcaaacag gaaaacaaaa acaaaaccaa
acccaaaata cacgtaaatt 26880gcagagtgct tgaggtttct tttaagctgt ctatgtaatt
aaaagctgtt acttagactt 26940ggatatgaaa taaaatctga cttcaaattt aagtggtgta
atttccatgc ctcttaaaat 27000atcaggtaac ttcatttgtg agcctcagtc tgtagacttg
agggatttcc atctgaagag 27060ggggcagaat ggtggtttag ggaacgcaac atgtacccca
cccccaactt ttttaagagg 27120aagagttgaa agaaataatg aatgtgtgag aaataagggg
tttgattgcc ttccagggtc 27180catgttgaag gagaggaaaa tgtagctcaa ccacagtgac
tctccccaat taaaaactaa 27240aaaaagatcc gtggttatag ggcttggact tcggacaagc
cagcagcctc agtcattgtg 27300agtgtgattc cagattggaa ggttctgcta ggaggaaagt
ggaagttttg agaattccta 27360gttggacaga atgcctcttg atcacggcct tagctaaagg
agaccactct ttgctggatg 27420gatcagtcag ctacgtgtga agtttggctc agtacaacat
tctcggcctg gggcggcagc 27480atgggaaaga tttttattgg aattaacttt ctacagagat
gtactttcaa atgagaccat 27540ccttctctca ctggtgagct cacccgggct cttattccac
aaagcttaat tgttttggac 27600ccatacattt aaactcctta attaattgac tcaagactta
ggacagattt gcttttcttt 27660ataatgactc catggctgta aatgctgctg attcagatga
aagaggaccc tagagcacag 27720aatgagaagg acgtggactc aggatacctg tttctttatt
ctgactgtgc tcttcgtcag 27780ctctggggct ttggacccca gttttgtaac cacctaacga
gttcaccttg cctgctgcct 27840agacggagct gatttatcaa gacagaggaa ttgcaatgga
gaaagagtaa gtcacccaga 27900gccagctgtg tgggaggcta gaattttatt gttactgaaa
tcagtctccc gagcatttgg 27960gatcagagtt tttaaagata attcggcagg taggggctca
ggaagtgggg agtgctgatt 28020ggtcaagttg gagatggagt cacagggggt cgaagtgacg
ttttcttgct gtcttctgtt 28080cctgggtggg atggcagaac tggttgagcc agattaccgc
tctgggaggt gtcagctgat 28140ccatggagtg cagggtctgc aaactatctc aagcactgat
gttaagtttt acagtagtga 28200tgttatctcc agaagcaatt tgtggaggtt cagactcttg
cagtttctga cccctaaacc 28260ttaatttcta atcttgtagc taatttgtta gtcctacaaa
ggcagactgc tcccaaggca 28320agaagagggt ctttttggga aagggctatt agcagttttt
tttcagagtg aaaccataaa 28380ctaaattcat tcccaaggtt agtttggcct atgcccagga
atgaacaagg acagcctaaa 28440ggttagaagc aagatggagt cggttaggtc tgacctcttt
cactgtctat aatttttgca 28500aaggcagttt cagtttctca cctgtaaacg ttgaagactg
agccagaatc agggtcatca 28560aatagcaccc cggctatact ttcttctctt catgacaaac
attgctggtc agttgatatg 28620atgttctttc ccactgggcc cagacttgac attagagtct
tttttttttt tttttttttt 28680tttttgagac agtctcgctc tatcaccctg gctggagtgc
agtggcacca tctcagctca 28740ctgcaacctc cgtctccaga gttcaagcaa ttctcctgcc
tcagcctctc aggtagctgg 28800gattacagga gtgcaccacc acacccagca gatttttgta
tttttagtag agacggggtt 28860tcgccatgtt ggccaggctt gtctggaact cctgacctca
ggccatccgc tcgctttggc 28920ctcccaaagt gctaggatta taggcgtaag ccaccacgcc
tggccgacat cagagtcatt 28980ttagcctgca atgcaagttg tcctcagtgg gctgctagca
ttggcttcaa ccttcatatc 29040agccagctaa agccccttgt aatgaatggg gaggttcctt
cacccttgcc tcccgctgcc 29100tcctcttgac cactcatttt ttttcttgta gttcaggaac
caattcagat gatttccctc 29160gtgaagtcct ctcgaaagcc cccaggtaga attattcatt
ttttcccttg cattcccaca 29220gcactgtgca cacaaattag aatccttgta aaatggccat
gattctgttt atgaccctgg 29280ccctccacca gaccagcctc tctgccctct ggctttttta
gatcactggc atggtttctg 29340cctactccag gtgccagtat tattttgtga atgttttttt
tcttcatatc tactcatctt 29400tatactactt tactcgtaaa aggaaactag agaacatgat
cttaaatgaa aaccacgatc 29460acttgccaga aagaacaggt aactaggctt tgaaaaaata
agttagagga gatagcataa 29520gaaaaaatta aaaaataaat aaaatcaatg aaaacaacgt
gttactaaat tcttgaaaag 29580ttttttgaag actttgagcc tgaggcctgt tcttattgtt
tgtttgtttg tttgtttgtt 29640tgtttttatg acagagtttc gctcttgttg cccaggctag
agtgcaatgg catgatctcg 29700gctcattgca gcatttgcct cctgtgttca agcgattctc
ctgcctcagc ctcccgagta 29760gctgggatta caggtgcccg ccaccatgcc cagctaattt
ttgtatttta gtagagatgg 29820gtttttgcca tgttggccag gctggtctcg aactcctgac
ctcaggtgat ccacctgcct 29880tggcctccca aagtgtgggg attacaggcg tgagccacca
tgctcggcct gttcttattg 29940ttaaaaagag agatttgtgt gaaagctgct gacgtctttt
tggcaccaag tcaagactga 30000gttagttctt gtcagaatct gattgtttgt gaattgatgg
cttttttttt tttcctgagt 30060tgggggtctc gctctgttgc ccaggctgga gtacgaccac
tataacctca aattgctggg 30120ctcaagcaat ccttccgcct cagctgccca agtagctggg
actactaggc atgctccacc 30180atgcccagtt aattaatttt tttttttttt tgagagacag
ggtctcacta tgttccccag 30240gctggtctca aattcctggc ctcaagtgat ctcctgcctc
agcctcccaa agctctggga 30300ttacaggagc gagccactgt gcctggccgg attttaaagt
tctgcccatg cacctcctta 30360gctctggcag ttactacttg caggcatctc ctttgtctgc
cctgcccctt gttaggaaag 30420gctgtgctga ctgtcagctg gcacccagtg catagaagag
atagttctct gtagatgatg 30480ttgaacaatg tggtactata atcccaacct gttgtatctt
tgtttactct caaaagcaac 30540aattgggctg ggcatggtgg ctcatgcctg taatcgcagc
actttgggag gctaaggtgg 30600gagggttgct tgaagttagt tccttttttt tttttttttt
aaaaaaaaga caagatctcg 30660ctctgtcacc ccggctggaa tgcagtggca tgatcatagc
tcactgcagc cttgaccacg 30720tgggctcaag gaatgaacca ttgtgccagg agttcaacac
cagcctggat aacatagcga 30780gaccctgtct ctacaggaaa aaaaaaaaaa aagaagaatt
gcataagtat catcagaact 30840gttgaatgga aaatcagact ttgtgggttt ggtttgttaa
ttacttctcg ttggattaga 30900atttgatagg taaaaaaaaa aaaaaaggtg tagaaaagtg
attccagtct tgagcaaatt 30960tttaatggaa aacggtgtct tggttctctg ttcactacaa
cttgtatcta agggaaagcc 31020tagtgatgca gacatttcat ttcgtgatgg gaaaactgat
gcccagaggt tcacagctga 31080ccaggggcta gtctgactgg ggggatctag gtcaccaccc
cccttgcctt gttttcccag 31140ctagtgcatt tcctactaga cttgactcta ctgtaattca
agttgctgag tagcaaacaa 31200gaactacaat gactagaagg aacagaacta gcttttttgt
gctctgaaag tggaaactta 31260ttgagggttc ttttcctccc agagaatgca gaagtgccct
gatttgcttt tggaaggaca 31320ccattcactt tattgcctct tttcattgtt gcccagaata
tcaccatgat ttattcatgg 31380gtggtgggga gggtagcact agtgtatgct cccagcaaag
aggaacatct cacgttgtga 31440agagatgcgc aaaactaagc cagggcaggg tgtggtggct
catgcctgta atcccagcac 31500tttgggaagc tgaggtgggc agatcacctg aggtcaagag
ttgaagacca ccctggccaa 31560catggtgaaa ctctgtctgt actaaaaata caaaaattag
ctgggtctga ttgcaggtgc 31620ctctaattgc agctacttgg gaggctgagg caggagaatt
tcttgaacct gggaggcaga 31680ggttgcagtg agctgagact gtgccgttgt actctagcct
gggcaacaag agccatctca 31740aaaaaagaag caagccagat ctttggggtg ctgtgacggc
aaatccccca gcgctggcct 31800ctcaggttct cttgcgggat tagtgtttgt tgaataataa
gcaatacacc ctgacccagc 31860gagccaaagc aaacaggaca gtaactgaaa ctgcagggga
gtgtgagtaa acagttacct 31920tctaccctca tggagctggc ctctggccag caacatgata
gctgtttgca tcttactctt 31980atggagccat tggccctctc attaaggtgg gggcagcttc
tggtccatgc ctgcaagtcc 32040tcatgggagt gggtacctga cagggtgtaa agggtaggtc
tgaggacatg gtttcttttt 32100tttattgttg ttgagatgga atcctgctct tgtcacacag
tctggagtgc agtggcctga 32160tctcggctca ctgcaacctc cgtctcactg gttcaagcga
ttctcctgcc taagcctcct 32220gagtagctgg gactataggc gcatcctgcc atgcctggct
aagttttgta tttttagtag 32280agacggggtt tcaccacgtt ggccaggctg gtctcgaact
cctgacctca ggtgatccac 32340ccacctcagc ctcccaaagt gctgggatta caggcgtgag
ccaccgtccc cagccaacat 32400ggtttcttta aaatatactc cccgctccat cccattcatg
tgtgggagtt gagctgcatc 32460tgggtttttc ttttctcttt ttctgtaaat ctttattgta
ttttttttgg atcatagaat 32520ggatacatgt ttcttaaagt ttgatcatta tagaaactta
attagactat tatttgagtg 32580ctaaccatag tgagtgagtg cttactgtgt gctaggtggc
tttttatgcc tcatgtcact 32640tacatgaggt ctgaggaacg gtgttaatcc cgttttgcag
ctgaggaaac tgaggctaca 32700tttacggtca cctagctggc aagcaagtgg ctgagcctgg
agcagcagca gatctgggga 32760actccacaaa ccagatttct gtgtggtatc cctgtggaca
caaggattta acttgattct 32820ttttgctttc agtatcactt tatgatatta caatgagctt
gcagtattta ttttcagaag 32880aaaagccaga ttattcccat ttatgagaga agcagccagg
tgggcaggga tttccagcgc 32940tgaaccagcc agtgtgtgca ttgtctcttc ccgctgagcg
gccctggtgt gctgggttag 33000tctgtgagcc acaggaaatg ttgtcagggc ctctgggctt
ttggatgtca gcaggccttc 33060agtggtgagg aggttgtggc tggactcaga ggactccttg
cttttgctga acgaccctcc 33120ccaccaacca ccaccaccac caccagtggg actagcccat
gagctgtaag ccaacctttt 33180ccttcctaac ttaattttcc aaagaatagt aacttaccca
ccaccactgc agtcactggg 33240ccgggaagac aagcactctt gccttgaatc catgccttga
gccagtagcc ttgacccagg 33300gtaaagcagt tatgtgcttg ggtcacctgg gtcatgtttt
tgaaattgcc tcaagcctac 33360cttacaaatc cttcctggaa ccctgcttgg cttttctttg
tgggcttccc ttaggaggga 33420agcttcccga gcagcttgtc ttgactgtag ccagctgggt
ggtcccagcc acagaattta 33480actgtcaaac agcaccagaa gggttcctca tccagctgtc
ttgccccaag tgccctcttt 33540gctttctttt tagagagttc tgagactcat tagagagttt
agagatttta gcattcttga 33600agttctttct gtggtcagtt tggtgaacca cttcatttct
aaagtttctc agttgacccc 33660attcttcccc agctttgcat tctccatgaa gccacctgtg
tttggtgtgt atgggttttc 33720tgcaacctag gttgaacaag tcctctagaa tcctgaacaa
ttggtgattc atgctggcct 33780ggtttttcta attggcctgg aaatgtggct gtagtggaca
caagtggact tggcctcctc 33840tttgatgcgg gtaaacttta gatttgcatt agctctgttt
gattagagga tcttactggt 33900ttttgttgtt atttatttac cttttaggag ctttagtctc
tgtaggtttt tttttttttt 33960tttttaaagt ccgggtctta ctctgtcacc caggctaggg
tgcagtggca tgatcacagc 34020tcactgcagc ccccaccttc ctgggctcag gtgatcctgc
caccttagtt tcctgagtag 34080ctgggactac aggcatgtgc caccatgccc agcaaattta
tttctacttt ttgaaaacag 34140ggtctcactt tgtcacccag gccagaatgc agtagcacga
tcatggctca ctgcagtctc 34200aacctcccag gcttaaggga ttctcccacc tcagcctccc
aagtagctgg gaggctactt 34260ggcatgcatc acaaggccca gctaatttgt gttttttctt
gtagaggcgg ggttttgcca 34320tgttgcccag gctggtctcg aactcctggg gtcaagttat
actctctcct ttgcctccag 34380ccatgagccg ttcgttgcgc ctgggctagt cattatagat
ttatcccttc tttcatctca 34440tgctacaaaa gcagttcttg tatttttacc cgacttgtga
ttttctactg ggaatgtttg 34500tttgtgatgg ttagcagggt gctgagaggg aattaatccc
aggaggccca atattgggcc 34560atgtcgtgct gttgagcaca gtcatttgac acctataact
tctcatcaat tcttctgata 34620gactgaggag gaattgggaa atttcctaga gttttgtctg
cattattggg ttgttttgag 34680aacataaacc ttaaactcta gctatgtaaa ctggataagt
cattttggta atttggcatt 34740cctttttttt tttttttttt tttttgagac agagtttcac
tctgttgccc gggggaatga 34800tctctgctca ctgcaacctc tgcctcccag gttcaagcaa
ttcttctgcc tcagcctccc 34860aagtagttgg gactacaggc acactccacc gtgtccggct
aatttttgta tttttaatag 34920agacaggatt tcatcatgtt gaccaggctg gtaatttggc
attcttttga gtacaagtga 34980gagaaactca cttgagctgg cttaagtgaa aaaattcttt
gtcaggagag ttttgtgaat 35040ttctgtttag tggcaagttg tagaaaccac ttgaaactgc
ttaaaggcaa aagagggagc 35100cacttgtccc agtaactgag acatcccaga gccgactgcc
cccaagcatt acttggtccc 35160aagtttcaaa cgggtcttca gggtttgatc tctctcctca
tctccagtct gcttcattca 35220ttttggctct atgtggtggc agaagggctt ctggcatctc
tggaccttta tgcctcccag 35280gtccaaaccc agccagaaag gagagtgaga gtgctgagtg
caaaactctc ctatagctcc 35340tatacaagtc caggatttgc tattagactc cttgaattat
gtgcccagct ctgagccaat 35400ggctgtgctt aggaggctcc tgtctcatgc acccacccca
gtactgggca tcagaaacaa 35460ccagtgatcc ctataatgaa ccacgggttc acagacttaa
gtgtaatcct gcagcagggc 35520ctcaggaaga cttgaaaccc aaaatcagaa agccatggtt
tcttgtcttc ctggtgtctg 35580ttttgtccct tccctctgta gaggagtcct gctatcactg
caggcaacgg ggctgccctg 35640cagctcctgc tgtttacatt tcactcggtg tagccatagg
cagagacctc agggagaacc 35700tgattcggct tggattgagt caggttccac cccagtccag
tcagttgtgg actgagaggt 35760gatgaggctg ggccctttaa gacaaatctg ggtgggtgga
gtctgtgctt aatgaagttg 35820tgatgttagc tgatggccca gaagggactg gtaggtgcct
ctcattgtct ggttgggaag 35880cattctctta agtccaagat gatgataaat agtattaggc
caggtgccgt gtcatgcctc 35940tatacccagc actttgagag gccaaggtgg gaggatcgct
tgagcccaga agttcaaagc 36000cagagtgggc aacataaaga gaccctgtct ctacaaaaaa
caaacaaaca aacaaaccaa 36060aaaaacccca caacaattag ccaggcatga tggcgcacac
cagtagtccc agctactcag 36120gaggctgagg tgggaggatt gcttgagcct ggcgggtcga
ggttgcagca agctgtgatc 36180acacctctgc gctccagcct gggtgacaga gtgagaccct
gtctcaaaaa gtaaaaaatt 36240caaataaata aacaaataat atcaagggcc tctctcccaa
gctaggaaga tatcagctga 36300agctctagcc cagctacgtg gatggctgct tcctgcctgg
aagcgatgcc cagatcagca 36360ccttgggacc cccctgaact tgcctctgct ccagtgtggg
cccttccttc ctgcagagga 36420gacagcactg tctgagaggc atgaatgaga atttcctcct
tctaggccca agtcagcatg 36480actcgaggat ggctttgact ggaaaaactg aatcaaagag
tgtgctacag ccaaggattt 36540ccccaaacac taatcagtgc tgattacttc cagggtattg
cctttggctc tgtggagttt 36600tgtccactgt ggctgcaatg tctggcttct gctgcccaga
agatgagaaa tgagtttgta 36660gggatgagcc tgggtgaagg gatgtgcccc ctcaccatcc
tgacctctat taggtgtaaa 36720agaccctgat tgccaaattc ataggtcatg ggttggctct
gcctccagca ttaacacttg 36780ggggtggagt tggggaatca tagtattact tgcataaatg
gaatcctaaa agtttgttgg 36840gacagtttca taaaaatcct caccatgatc agtttgaaaa
tgacgttccc ttcacatgtt 36900tgtcttctga actgagttgc aatgctgagt atgagtttga
gagtcccaag accatctaaa 36960gcaagcctgt ccaacccaca gactgcaggc tgtaggcagc
ccaggacagc tctgaatgcg 37020ccccaacaca aattcgtaaa ctttcttaaa acattatgag
atcctttcgc atttgttttt 37080taaagctcat cagctatcat tagtgttagt gtatcttatg
tggccaagac aattcttctt 37140cttccagtgt ggcccaggga agccaagaga ttggacaccc
ccgatttaaa ggaagtaact 37200caattttgtg aacctgaaac ttgatcttgg atgaaccaaa
tgaaatttta tgattctctt 37260aagctcacga aagttcaata actgtgctgt gtaaaataga
ggtaaaagac ttgagttgga 37320ccaggaatgg ttgctcatgc ctgtaatccc agcactctgg
gaggctgagg cgggtgcatc 37380acttgaagtc aggagttcaa gaccagcccg gccaacatgg
tgaaaccctg tttctactaa 37440aaatataaaa attagccggg cgtggtagtg tacgcctgta
gtcttagctt cttgggaggc 37500tgaggcagga taatcccttg aacccaggag gtggaggttg
cagtgagcaa gatcatacca 37560ctgcactaca gcctgggcta cagagcgaga ctccgtctcc
aaaaaaaaaa aaaaaaaaaa 37620aaaaagactt gagttggttc taatagaata ccttggagaa
cctcaagatg ccttctggtc 37680cagccaggtt tacagattgg aagatattct gttaatcaga
atctcagaga gggacaggcc 37740ctgatcaagg taacacagtg agttgtggta gctgggctgg
gctagaacct gggcctcctt 37800ggttccaggt cacagggacc aagggatttg gcttgtctta
gtcctacttg taactacaat 37860actgccttct gctaggaaga ataagagctt gcaggctaga
ggaatttata ggaattttct 37920ttctttaaaa aaatcccccc aaaaccagct ttactgagat
ataactcaca caccataaaa 37980ttcacccttt taaagtatgc aatttttagt atattcacag
aattatgcaa ctatcatcac 38040tataatttta gaattgtttt tttttttttg gagacggagt
cttactcttg cccaggctgg 38100agtgcagtgg tgcagtcttg gctcactgca acctccatct
cccaggttca agcgattctc 38160cttcctcagc cttccgagta gctgggatta taggtgcatg
ccaccacacc caactaattt 38220ttgtattttt agtagacatg gggtttcacc attttggtca
ggctggtctc aaactccgcc 38280tgccttggcc tcccaaagtg ttgggattac aggtgtgagc
cactgtgcct ggccaatttt 38340agaatatttt tattgcctca gaagaacccc tgtatccatt
agcagtcact ctccctttcc 38400cttccccaac caggcccaat aaaccactaa tctactctgt
ctctatggat ctgtccattc 38460agaacatttc atatggtaaa atcatacacg tgttctggtg
ttactgactt ctttcactta 38520gcagaatgtt ttcaaggttc agccatgtta tgtctgtact
ttattctttt ttacggccaa 38580gtgttggaat gtgtaggatt tgaattttca aataaagctt
taaagttttc agatttattt 38640ttactttgcc tggtgtgttt tttcctggaa agccaacttc
tacatttgga gattaaaaga 38700caaactttct caaactccct gtacctaagt ggttgctgct
tttcttaaat gttttgacac 38760caaagagaaa aattggtttc tggaagaaag tgtgttttct
tttattgcca agaaaattag 38820tgcatgttaa ttaatataga tgctcaggac ccagagttgt
aatgaacttt tttcttatat 38880ttattttcta gatgtttgac ttattttaac agttttcatt
ttagcaataa tgtttccttc 38940ccactcccaa atttattgga aaccctcaat caaccctatt
tatttattta ttttagagat 39000gggatctcac tatgttgtcc aggctggtct ggaaaccctc
actcttatag atagtatgaa 39060agaagattat agccaactct tatataacct tccccagagc
ctccaattgt taatgttttg 39120ccatatttgc ttgctctatc acttgctcta aagatgcata
tcacacactt tttttttttt 39180taatttattt ttgagacaga gtctggctct gtcgcccagg
ctgtagtgca gtggcatgat 39240cttggcttac tgcatcctct gcctcctggg ttcaagcgat
tctcctgcct tagtctcctg 39300agtagctggg attacaggca cgggccacca tgcccagcta
atttttgtat ttttagtaga 39360gatggggttg gccaagctgg tcgtgaacta ttgacctcaa
gtgatcctcc tgcctcagcc 39420tcccaaagtg ctaggattac aggagtgagc caccatgcct
ggccacatgc gtgtttttta 39480ttgaatcatt tgaaagtact cagctcgtat catgaccctt
cacccccaca tactccaaca 39540agcatctcta agaaaaagga cattctccta accacagtgt
ctctgcattc ccaggacatt 39600cttctaacca cagcgtcact gcatacccaa gaggttagca
ccgatacagt aataacatct 39660tgtgtaaaac ttcccaaaat gctcccaagt gtcctttatg
acagtttaaa aaaaaatggc 39720attttttggg atccaggaac caattaacga ttactcaatt
gaatttggtt tcaaagtcac 39780atacctcaac ttttccttta atcaagaaca gcccccctgc
cttttacaca tttttttgtc 39840tttcgtgacc gtgtcatttt tgaagaaatc aggcccgttg
tcttgtagaa ctggtgtttc 39900tcaagtgtgc ttgggagggt cttggtaaaa tgcacattct
gattctggag aacagggtgg 39960agcctgggaa tctgcatttc cagccagcat cccggtgatg
ccagtgcagc tggtcttcgg 40020ctgtagaatg ttccacattc taggtctgtc tgtttccttg
tgattaaatt caagttgaat 40080atttttggct agggcacttc ctgaggtcat aggtacttcc
cactgcctca cagcacaggc 40140tcacaatctc agtttgtcct gttacttcgt ggtgctaagt
gtggtcacct gcttcaagtg 40200gtgtccgcct gctctctgtt gaaacaatac ctttctccta
gtataatgat taggtaacct 40260gtgattgtaa ttggtaagta atctttgaga ctacatgaat
atcctgttcc ccagcagttt 40320tcactcattg gtgaactgtt ttgggaaaaa taatagcatc
ttacagttat aataccctgc 40380tggtaacaca tggctcttac ataatcagca gttaattgtt
tgtatgtgtg ttaattttta 40440tttttaaaat gtaactagtg actggtaact ctcatttgta
ttttaaacat tggcttttac 40500agcttctcag tacatttcac tctgtgtatg tttttggtag
agcatttgtt gtcctgtata 40560atggtttagg aaatcctata ggccaaatga agggctggag
actcacctgt gttcccacca 40620ctgtgtttca ctgtgtattg ccagagaaaa tacagttaaa
tttgaatttc agatagacaa 40680tgaataactt tttagtataa gtatgttcca agtgtggcag
acagctctca caagttacaa 40740gtcgttgcgt aggacatacc tatgctaaac gatttgatgt
ttatctaaat taatatgtaa 40800ctgatatctt gtatttttat ttgtacgatc ttccaagccc
acgtcccacc gccttctcgg 40860ggatggccac catttgtgtt tgctgcctgg tggtgtttgc
agctgcgaga agggccttgg 40920aggaggagca aagtgtagtg gtatctccgt gctgtggcct
tgggcactgg ggtgggggtt 40980agatgagtaa ttagctgaat atgacctcac ccatgaagaa
tgtgcccttg ctaggtatta 41040gcagaggttt aggctccagg gagccattgt cagaagcttg
tcagtgatgt catcagctgg 41100aagggccagc tttcaggcct caggaaaaag cttgaaagtc
agggctccag ttttggtaat 41160aaatgggaat ggagtttcac aggtagggtg tggaggaatt
tattgtgaca ggaagcctga 41220tggagcctct tgcctgtgtg cagcccccag ccaggtttct
gagttctgat gaactaccag 41280aaacttccac cacggcctgt gattacactg ttggcccaat
gccctggaaa aattggcttg 41340ctctcgggga acactccagg agctgcaaag ggggtgtcag
gactgttgtg cagctcccct 41400taaattgggg aggaggggtg gctgatgtgg aaactgttca
ttagactgct cagggtagtg 41460tgagaaaacg tgtaatctgt gggcatctac ccctagctgc
ccctctgatc tcacccacta 41520ctgtgggagg accccgtgga tgggggcaga ggagggtctt
ctggatttag acactcacaa 41580aacttccttt taccttgttc attggaagaa atagaaaatg
cctttttttt tttttttttc 41640tttttttttg agacagagtc tcgctctgtt gacaggctgg
agtgcagtgg catgatcttg 41700gctcaccgca acctctgcct cccgggttct aacaattctc
ctgcctcagc ctctggagta 41760gctgggacta cagccacgtg ccaccacacc cagctaattt
ttgtattttt agtacagacg 41820gggtttcacc atgttggcca ggacggtctt gagctcttga
cctcgttatc cacccgcctc 41880ggcctcccaa agtgctggga ttacaggcgt gagccaccat
gcctggtctc tttttcattt 41940ttaaagggta atttgctgtg caggagtggg ctctcagacc
agaagtgggg acctgaatga 42000aatcaaggac tgagtatggt aactacagcc atttaatttt
atttgaagtc tcccgtaaaa 42060tgttctggaa aaaacagggg ttccagggct gggtgggcag
tttcaatcat ggactggatt 42120ttgtggttca gatttctctg ggcctgttgg aggttcccct
taagcaatta cccaaggcag 42180ttctgcccag ctgaagtact gattacctgc acactatacc
agtgaggact catgggtgag 42240cagatgggag gcactgagct tgattctgaa accctggcct
ccatcccacc tgacattcaa 42300tgtcagatta gaatttggaa gaccctaagt ctccagattg
gtgcactggg tagctcctga 42360aatggggtgg ctgagacagg tcctctgtgc ccccttccac
agcttcctct ggggcccttc 42420tgctcactgg catgtgcttc tgggcaaata ggcctctccc
agcatttgtt ttggctctgt 42480gaaatggggt aatatttgtt cctattgcgg gtgaagcgct
gctgttggga tgctcaggta 42540actcactccg tgggtagctg atattgcctg ggcaagtggc
attttagagg aaatctgtgc 42600catcaaaaga gttggacctg atcacacttt tgcttttgaa
tatgctttgt cccagcctgg 42660ccattcgtca cttgggaccc cctgagtctc tctgacccca
ctgtaaaatg gatatgccat 42720ggagttgtcc caggaatcaa gggcaggtcc tctccagtga
gtgatgggct tgcctctcac 42780ttctctaaca cccttctgct tccttgtgta agatttcact
attagtggct attctctttt 42840acagaagaaa aagggagacg catgcctctt ccagttcact
gttcaccatt gcagcatatt 42900tattccaagg gactggccga atcatccctt tctttgttag
aatgtggttt tgttgccttg 42960agacaagtgg cccgcatgtc tgcactgaag gaggctttgc
gcaatagcct tgggcacctc 43020cggttctgca agcatgtaca gtacttgctc tcctttccct
ttctttgtat actttttctg 43080gtctgctacg tgtccatctg catgtggata aagggtcgtc
gtcttgagta gtgattttgc 43140tgtgatgtga ttcctgtgag gtctagttgc acacagtgat
tccgaaggta gacccagctg 43200gaaagctttt aaattgctga tactccagcc ccactcccca
agagatgctg attttgtttt 43260gttttgggga gggcagtttt tttgggtttt ttttttaagc
tttttgatgt gtagccaggg 43320ttgagactga agtgattttt gtgagtaacg gagaagtgtt
aaggcttgag aagttggaag 43380agccatgctt gagataggac caaggtcata tccccggcat
tagcacagag caaccctgac 43440ctgttggaga gttgggctgg atggatgcgg tcaggggaga
gactcgcttt attttattta 43500tttagagata cagtttcact cttgtcaccc aggctggagt
gtaatggcac gatctcggct 43560cactgcaacc tctgcctcct gggttcaagt gattctcgtg
cctcagcctc ctgagtggct 43620gggactccag gcacgcgccg ccacaccctg ctagtttttg
tgtttttact agagacaggg 43680tttcaccatt gttggccagg ctggtcttga actcctgacc
tcaggtgatc cgcccacctc 43740ggcctaccaa agtgctggga ttatgggtgt gagccactgt
gcccagcctc gactcgcttt 43800attatatcca cacttggaat acaattcgga ttgattgtag
tggggcattt tataattagg 43860aaaaattaat caggaaaaat cactccatgt agattagtac
caccatatga ggggacaaga 43920atttcttcag attaggaact tcttccaaca ggactgacag
ggtccaaaac tactcttgga 43980tccagcttta agatggaccc agcccactgt tgagtcccct
ctgaggtctt ctctctgtgg 44040atggatttga ttgttaacaa tggctgagtc atgtggcacc
cagcccggtg agtaagacag 44100ctgagtaaga ggggaaacag ggcctttggt cagaaaaacc
agactgactt cagtcttatc 44160tgtttagaga agccccagaa gctgcaaaaa ttgcagcttc
cagactttag tgtgccgtgg 44220tcatgacatc ggtgtggatg gcaggttgtc atctgagcag
tcagggtggc agcacacagc 44280ttgcgggctg gctgatggcc gaggtgtgtg aactgacctg
ccccaagtga cttcagtgct 44340gggcacagca taggagcagt actaatgata tggacagtat
gctcagagga cgttagggag 44400cacagctttg tgtaaagggc atgccctgcc ctgtccggat
ttaaagcagc tatagcactg 44460aaaccccatg gtcaccctcg catttctaca cttctgcctg
tgccaagtct agtttgtgtg 44520cctcctccat tttgtgtgta catgggggta tttttttctg
ctaggcaact gctatttatg 44580cctctcagta ctgtacttag tgtgtaccat tcctgcaagg
tatagacatt gtcagcccat 44640tttacagatg aggaaaatgg agtttttgag agggtgagat
cattcagtgg cagaatggaa 44700tgttaaccca ggtagtctaa cctctctgct gtagatctga
tgtccatttg aactttagac 44760ttcccatctg tgtctacagt ctagccctta aaaaatgtga
taaacaggtt tttaggtaag 44820tctgttaatt tcagaaagac attattatta ttttttagaa
agttagagct tatgttaggg 44880ctcagtctat cctcctgcct cagctgcctg aatagctggg
actgcaggca catgccacca 44940tgcctggtta atttctgtgg tatacatcat tgattactga
gaagtcacag tccgttgtta 45000aataactgag ctattcatag ccaaatcatt tttaaaaaca
caaatataag caaaaacaaa 45060acatttattt atttatttat tgagacggag tctcgctgtc
acccgggctg gagtgcagtg 45120gcgctatctc agctcactgc aacctctgcc tcctgggttc
aagtgattct tctgcttcag 45180cctccccagt agctgggact acagacaccc actaccatgc
ccggctaatt ttttttttat 45240ttttagtaga gacagggttt cactgtgtta gtcaggatgg
tctttatctc ctgaccttgt 45300gatctgcccg cctcggcctc ccaaagtgct gggattacag
acgtgagcca ctgtacctgg 45360cccaaacatg tggttttttt aaatgaaagt gtgttcattt
tacaaacagt gcattcttac 45420taattttaca ggccctgtgc tagggacatg gcctcgtctt
ccgctatctt agagtgaaga 45480agtaaagaca gagaaagtgt tcacaagttg ctgcacaagt
ctcattgcag tgcctcccag 45540aggcgcgaag agcaacacct ttcacctggg ctgtcctaga
aggcccgtgg cagggtgggg 45600ttggtgaaca ctggggctta agggggtgaa ttcagaagac
aaaggacctt ctgggcaaag 45660aagggcccag tagtgggaag tgcaggagtg tgagagtgcc
tggaattgcc cactcactgg 45720ctctggagct tggtgctgag tgcttgggaa gtgttgggag
gatcagttat attgctggct 45780gggttctaaa gaacctccaa agtttacata aaagttacct
ttgatttgac tgttctaccc 45840tccagtcacg tggctaaatt aattaaatca aatttaaaat
taagctcagc cataccaagt 45900atatccagtg ttcaataggt acatgtggct tgtggctgat
gcactggaca gtgtacatat 45960aaaacatttc catcgttgca gaaacttcta ttgaacagca
gttgtattag tccgttctca 46020acactgctgt gaagaaatac ctgagactgg gtaatttata
aaggaaagag gtttaattga 46080ttcccagttc cacagggctg gggaagtctc gggaaactta
caatcatggc agaaggggaa 46140gcaaacatgt ccttcttcac atggaggccg cagcaaggag
aagtgcagag agaagagggg 46200gaaaagcccc ttataaaacc atcagatctt gtgagaacag
cagcatgggg gtaaccattc 46260ccctgattca attacctccc accaggtccc tccaatgacc
tgtggggatt atgggaacta 46320caatttaaga tgagatttgg gtggggacat agccaagcca
catcagtgtt gttacacacc 46380acagtggtgc tgtggtgtgt aggtgggaaa actatggcat
gggggccata tctggtcctc 46440tgcctatttt tataaagttt tattggaaca taggccacac
tcatttattt atgtactgtc 46500tatggatgct ttcacactgc aacaatagat ccaaatagtt
gcaaagagac tgtgtggccc 46560acaaaaccta aatatttact atccaggcca ggcatggtgg
ctcatgcctg taattccagc 46620actttgggag gttgaggtgg gcagatccct tgaggtcagg
agttcaagac catcctagcc 46680aacatggtga aatcctgtct ctaccaaaaa tacaaaaatt
agctaggctt ggtggtgctt 46740gcctgtaatc ccagctactt gggtgtcgag acacgagaat
tgcttgaacc cagaaggcag 46800aggttgcagt gagctgggat catgccactg tactccagcc
tgggtgacag agtgagattc 46860tgtctctcaa aaaaaaaaaa cttactcttt ggccctttat
ggaaagtttg ctgacctctt 46920ctgtagatgg tagggtacgg tagaaggtgt tcaagccagg
agtaacatga atgattgtat 46980ttatggccta agaggataac tcgtggtggt gggcgggcca
tatttgtgga gagacccatt 47040ttcagtgact tccaagagtc tgcgtgagag atgactgagg
tcttgccctg gcaggaatgg 47100ttccattaat ctgtgtctca tttgacaaat gaggaactac
aaatgggaac agtttaagat 47160gagatttggg tggggacaca gccaaaccac atcagtggtg
ctaatagaca gtggtgctgt 47220ggtgtgtagt agggaaaact atggcctgtg ggccaaattt
tgaagtcctt ttactttttg 47280gttctaaaaa ttattaattg tagccagagt tgttaactta
atatgtcttg gaccccttgg 47340gctctctgaa gactgtactc tttctttcca cttaataata
tacatggaat tgcaaaggaa 47400accaatgata ttgaaataga tatcagaaat aaaattttta
gatatagcaa taaatgcaca 47460tctgtattaa aatgtgtaat aacaagatct aacagtgagt
ctaagaacta ctataattat 47520catgtagcaa tggcataaag gatagtttgt gctatctaaa
acagtcaatg acaggagaaa 47580atctgatttc tttggtgata aaacgacagg tgctgctaat
acacctgtgt tttatggtct 47640tcgtttgtaa tgaaaagaaa tgccattaat aaattttatt
tatttattta tttatttatt 47700tatttatttt tttttttttt gaggtggagt ctcactctgt
cgcccaggct gaagtgcagt 47760ggcatgatct cggctcacta ctacctcctc ctcctgggtt
caagggattc ttctgcctca 47820ggctcctgag tagctgggat tacaggcgcc caccaccatg
ccaagctaat ttttgtattt 47880ttaatagagg tgggggtttc accatgttga ccaggctagt
ctcgaactcc tgaccttgtg 47940atctgcctac ctcgggctcc caaagtcctg ggattacagg
tgtgagccac cgcacccggc 48000cagatgctgg gatgtttttt aagaccttag accctaagcc
tatcatatca aatacaatga 48060aacacaccca cttttcacac tttaaaaaaa gtgtgttggt
gtttattgct gtaaaatagt 48120ttgaaacttt ttaaaaaaag ttttggtctt gctcatactt
gtgttttaaa aaagtatttg 48180gctatgacta actcagttat gtatttattt atttattttt
gagacggagt ctcgctttgt 48240tgcccaggct ggagtgcagt ggcatgacct cggctcactg
cagtcgccgc ctcctgggtt 48300caagcctcag cctctcgagt agctagaatt acaggcgtgc
tccaccatac ccagctaatt 48360tttgtatttt tagtagagat ggggttttac catattggtc
aggatagtct tgatctcctg 48420acctcctgat ctgcctgcct cggcctccca aagtgctggg
attacaggcg tgagccacca 48480cgccctgtga ctaactcagt tatttaacaa ttgactgtaa
tttctcagca atcagtgtat 48540acttggaaat tcttgggatg tgagaaaact aacctataac
tcattttctt ttttctttga 48600ggtgaggtct ctctttgtta cccaggctgg cgtgcagtgg
catgaacagg gctcactgca 48660gccttgacct cctgggctca atcctcccac ctcagtctcc
tgagtagctg ggactactgg 48720cacgtgccac catgcctggt taatttttgt attttctgta
gaaatggggt ctcactgtgt 48780tgcccaggct gatcctgaac tcctgagctc aagcaatcca
cccactttgg cctcccaaca 48840taccgggatt acaggcatga atgagccacc atgcctggcc
tgcaacttct ataaatagca 48900aagttagtaa ttagtgaaga tgatggtttg caagcactga
attatacttc tattaatttc 48960atttcctttc aattttctaa tgttttgtgc ccaatctgtc
ctgtctgcct ctacctagct 49020ttagaagtgt tttgttggtt cctgagatgg agctgtgcct
gaagggtatg aggttaccct 49080ctgggttcag cggggagatt tgggaagagt tttgatttgt
aggccagtaa aggggcctga 49140cattagatga tggctgctgg gctagggaac aacttagagg
cagctaacag gattcaggga 49200gagtggattt ggtgggagag agtagtctag gatgaatcca
attgggtttt tatgagtagt 49260ttggtagttg gttgactggg tgggtggtcc cttggtaatt
atttgttgat tagtggttgt 49320tgggttaggt tggttacact tacattatag tcgatggaat
ctcagatttg gatctaatac 49380cacatgtaag tcgagtggat ttttttttga gacagagttt
tgctcttgtt gctcaggctg 49440gagtgcagtg gaacagtctc agctcaccac aacctccgcc
tcccaggttc aagcgattct 49500cctacctcag cctcccgagt agctgggatt acaggcatgc
gccaccacgc cgggctaatt 49560ttgtattttt aagagttggg ggtttcacca tattggtcag
gctggtctcg aactcccgac 49620ctcaggtgat ccgcctgcct tggcctccta aagtgctggc
attacagggg tgagccactg 49680tgcctggcca gttgagtgga tttttttagc actcaagctt
cgtggctcat tgctattatt 49740gtgcatgtga gcgttttatc tttcagtagc attagggatg
ctacttggat gtgttttagt 49800tattacagaa atagttttta ctaactttta ctaagttatc
tttcctctcc tgtgtaggaa 49860gtttagagtg aagcggcagt tggctggagg ttctgaaggt
ttcccccttt cacataattt 49920gatgttccag ttgcccacat caggacgact ccctctcttt
ctactgatgt aagcagtggg 49980ccaaattatg gggctccatc cctgcatctt cctacttgtc
taaatcttcg tcacagacaa 50040catattgctc taaaggaaac ctagaaagga ggagaagctg
gttttcgccc aaattcctca 50100aaatcatcgc ctgttgttta agaattacag tttgcactgg
aacaataaga tgttccttaa 50160tgtggttttt aagtgagttg gttgtcgcct gaatttcata
aacactggct aaggattgtg 50220caaaagggtg tgcttccctt tagcatcctt aattagggac
agcgttttga aaactgcttt 50280ttattgtcct ttatctgcaa aacttcttga atccaaatag
cgagattctc atttcttaat 50340cactgccaca gaaagttgta gattagagaa agctccaatt
ccttatttcc tgtcttcctt 50400tctttctgtg tgtttattgc ctgtgtctca tcctcactcc
tgccagtttt atagaatgta 50460acctcccagc ctctgggaat gtttgggaga cttgttcata
gaggatctga agagcagttt 50520aaagtggact tacccaaact atcttctgga gaacattagt
ctctttggag ataaaatttt 50580taaacatccg ctagtccaat agtgttggca aattccctgt
gacactgtag ccctctcttt 50640gagattgtca atgtacgttg gcatgttaaa ggctctgaga
agtcctgcag cagttaaaaa 50700attgtttagt ctagtgtgcc cccagttgtt tggccactga
aacccccttt tctggaaaaa 50760ccagctaaca tctggtagtc ttttctaaga ggtggtactg
aagatgatac tcatgttaca 50820catttaaaaa ttctaacatg tgtttttcat gtgtttataa
aatgcaacta atgtatcaaa 50880cctgtgattt ccaggacata attacttaag ctaaggaaaa
aagaaaacat gagtgaagga 50940aaaactttag taaataggcc aggtggtaag aggagagagc
cttgtctgtg agtgtggtct 51000agggggatgc tggacctagc ttttcagagc taggttcagg
cagagctgct ctgagatgta 51060gacactgcag ctggggttct tgttgagccg ggaagcagct
tctgactaag gtgcagactg 51120tttagatgag ctggtcataa agagccctga ctgtggactg
cgtctccagc cacggcagca 51180gctggtggat ggggtgatgc cttggatatt tatcgtgtgt
ttcttgcctg gcctgccctt 51240ggacagtgcg cctcaggaat gttagaatgt gttccccctt
tagcagcaaa gccgatctgc 51300tgtgtacttg ttctgtttat cttactgcca cgaccgttta
tcacgggcca gagttcaggg 51360gcacactgat aaatctcttt taggaggatg atgtaaccct
cagcattttc cccctacttg 51420gttctgagtt tttaaagctt ttgtaacacc atcatgtcct
tgtttgggca tcttcctgtg 51480tactcccgtt tgggtctcca gggtgaaata gccaacagtg
gattctggag tcatggcctg 51540ggttcaaatt cctgctctgc tgcttatcaa ctctgacttt
gggtttaatt gacctattca 51600ttatttttct taatctggaa aatggagcca acagcagttc
ctcataaagc agctgtaagg 51660attcaggggg gtaactgcac agggccaagc cctcaggttt
cacctctcac tgggaggtcg 51720gacctctgca taatggacaa gctctcctag ggtgcaagtg
aacgggggcg caagggagtt 51780aggaaggtgg gtgttttttg tttttgtttt ttggtggctt
gaaaaacatg cccaaggctg 51840ggtgtggtgg ctcatgcctg taattccagc actttggaag
gcagaggcgg gagcattgtt 51900tgagcccggg agtttgagat cagcctgggc aacatggtga
gaccctgtct ctcttttttt 51960tttttttttt ttgagatgga gtctcgctct gttgcccaga
ctggagtgca gtggcgcaat 52020ctcagctcac tgcaaccttc acccccaggt tcaagtgatt
ctcctgcctc agcctcccaa 52080gtagctggga ttacaggcgt gtgccattgt gcccagctaa
tttttgtgct tttagtagag 52140atggggtttt gtcatgttgg ccaggctggt ctcgaactcc
tgatcacagg tgacccatcc 52200accttggcct cccaaagtgc taggattata ggcgtgagct
actgtgcctg gctgacccaa 52260aaaattagct gggcgtggtg gcacacaccc ctgtagtccc
agctacttgt gaggctgggg 52320caggaggatt gcttgaggcc agcctgggca acagagcaag
accttgtctc aaaaaaaaaa 52380aaaaaaaaaa aaaaaaaaaa gaaagaaaga aaagaaaaga
aaagaaaaga aaaacatgcc 52440caaaggcaac caaatgactc catcttttgc aatgtaatct
tcaacatcga ctcctctggc 52500aagctgtttg gaaatggcaa agtccatctc ctgaggctgg
gagattgctt gtccaggacg 52560ggtgtgtctg gtgaggaatg gaaggcattt ggatggccac
tgagaaagct gagccaagga 52620gcatcagaaa gacaatcagg caaacccaca gagtctccag
gtattccttt gctgataggt 52680aacattgcac tagcgattta aacaaacagg tgaaaggcca
ttgccctacc accccacctc 52740acctctattc cttgctgctc tttccagaag caactgcatg
gtctgggaac agttttttgt 52800cttgtcaaga gacagtctgt acatagatga attcaattat
attacttctg tagtaccctg 52860tactcaaatt tgaacctgtc atacacattg cttttatcat
ttcataatac ctgttgattt 52920tcccacgtta gtacctatag atcctgacaa gcaattttgt
taagatgaag agttcttcat 52980atgtattgta ctatgtttct ttttttgatg atgtatgtca
agatttatta taaaagtaac 53040agatgggtag ggcatggtgg ctcattcctg tgatcccagc
actttgggag accgagatgg 53100gaggattgct tgagcccggg agtttaagac aagcctggga
aacctggcga aatcctgtct 53160ctacaaaaat tacgaaaatt agccaggcat ggtggtgact
gtcccagcta cttgggaccc 53220aaatgtccca gatactcagg aagctgagtc gggagcctga
tcctcagagg tcgaggttgc 53280agtgagccgt gattgcacca ctgcactcca gcctaggtga
cagagtgaga ccctgtctcc 53340ccctggcctc caaaaaaaaa aaaaaaagta acatatgtag
tttaaatttt aaaaattaaa 53400tttttggggg ggctgggtgt ggtggctcat gcctgtaatc
ccagcacttt gggaggccaa 53460ggtgggcaga tcacctgaga tcaggagttc aagaccagcc
tggccaacat ggtgaaaccc 53520tgtctctaga aaaacacaaa aattagctgg gcatgatggg
gggcgcctgt aatcccagct 53580acttgggagg ctgaggtggg agaatcgctt gaacctggga
ggcggaggtt gcagtaagcc 53640gaaatcatgc cactgcactc cagcctgggt gacagagcga
gactccatta aaaaataaaa 53700ataaaaaatc aagcaatgca gaataaataa caacaataaa
atgaaagccc atcttccacc 53760atcagcttct tagttttctt cctagaagga gccagtgagg
acagtttggt gtttatgctt 53820ccagatcttt ctgttcagat gcagtcatga cttctgaaaa
acaggattgt acaattcata 53880cttttctaca aattatcccc ttcccttaat acatcataga
agcctattca tattggaaca 53940aacaaacatt tcttattctt ttcacagcac cctgttttcc
tcttgcttga atgtaaagtt 54000tatttaacca cttactgtca gggaggcatt tgttttcagt
tctccctccc tccccccacc 54060agttgtcttg taatgaactg ctttaatggc taaagatcac
tttaatatca aaacctcccc 54120cacctcccat tagaaaaaga aatcatgtta gggaacttca
aattgaattt acggaccttg 54180tgtttaattt tctatcagca gtggccccag cctggcccct
gcagactgcc ccggaatctg 54240tgggaggagt tggggtggcc tgcagactag agcacactgc
cagttcattc agcagctcac 54300cgagcaagaa acatcttgat tctatcagcc ttaatgctgt
gtcccattag ggacccagct 54360cttgtggtca ttagcagatg gaatgctcat ctgtgctaga
aggcggaatt ctagggcatt 54420cggctctgag cagtcttgaa ccagaattga atggcttgaa
tccttttcac aatgccaacg 54480gggaggcacc cttagctccc aaacttgtgt gtgttataat
actatggtag taataacagt 54540ggttgtagta gcccccgtga atttgatggg acagtcgtca
ggcagtgctg cttgcttgct 54600ttactccatc gtatcaccgc agcctgatga ggcgagggag
ttacgactct cattttgcag 54660gtgaggacac tgagcacagg gaatcgaccc actcatggtc
acacagcttg ccaagtcgct 54720gtgcttggga ggtgaaccag gcttctctga cgccccagca
ggacgtctga acttctagct 54780gccccatcac taactgactt aatgcccctg actcctgggt
gacttggcca ccagttactt 54840cagccagcga cctgcccttt ctttgagtgg gttccaccca
tccctgcacc atgcctttta 54900ctttggatgt tggtggcatg gaattccacc cgtaagaagg
aggtcggtcc ctgggctgag 54960agagtttgca gagagctctg ttgggattgg gtgggacgtg
tgtttggagg cctcctcaca 55020taattgtggg ctgaaaggtc cagatttggg gatataaagt
tgagccgtca gctgagctaa 55080agacagggca cagggaggag ccatccagaa agtgtcagtg
taggtaaagc aggcagagtt 55140ccccctatct gtcctctgag ggcctccttt cttgtggttt
cctccctttt ctgtggtgat 55200ggtcagagcc agcggttata aattatttgg aattttcctc
agcttggttc ctactcaaga 55260ctttaaatta ggagttttgt tcccttttat gacttcacaa
tctttgggca ggctgccatc 55320tctacagcag gctaatatga gttgtaactt gaggtgagtt
acaggggaaa aatggaagct 55380gatttctccc cttttaaacc aaggaagcca ccttgatctg
actttgtaac aaagctcaac 55440ttttgtaagt ttgcaattaa aggataaata cctatcctat
ttattattat tattaacttt 55500ttattataaa aggggaaaaa actcccagga aacatagcct
aatatgaggg acaaaaagcc 55560aaaaggtttt ttttttcttc ctttaaaagg tcctcaatgt
cttgccctgt ggagacacca 55620gttttcatta taataacgcc attatctctt tgtagagtca
tttcaagcca atttaacttt 55680ctcatttaaa agtataattg gtattcagca cagagctggg
agctcagtag gcagttagaa 55740aatatgtgta tattttttga gacgaagttt cactcttgtc
acctaggctg gagtgcagtg 55800gtgcgatctt ggcttactgc aacctccacc tcccgggttc
aagcaattct cctgcctcag 55860cctcccaaat agctggaact acaggcactc accaccacgc
ccaactaatt ttcgtatttt 55920tagtagagat ggggtttcac catggctggt ctcaaactcc
tgagtttcgc caggctggtt 55980tcaaactcct gatttcaggt gatctacctg ccttggcctc
ctaaagtgct ggcattatag 56040gcatgagcca cagcacctgg ctggcagtta ggaaatattt
attgaatatg agaaaagaaa 56100aatagagcaa attgaatctt caagtagtat gtgagtaact
ctaattcctg ttttctggaa 56160aacacacagg ctgataggtt tgggtaaata agagcagagc
tgcatcttct ctcaagttcc 56220ctgattccct caaggagtta cctgagaata gctctgtgcc
aagcagtgcg gcatgcatag 56280gggacctctt gaatggaggg acagtccatt atcattagaa
tccccagttc cagccaggtg 56340cagtggctca tgcctgtaat cccagcactt tgagaggcca
atgtgggcag attgcttgag 56400ttcaggagtt caagactagc ctgggcaaca tggcaaaacc
ttgtctcccc ccgccacaca 56460cacaccacac agacacacag acacacacac actggctagg
cgtggtggca ggtgtctgta 56520gtcccagcta cttagaaagc tgaggtagga ggattgcttg
agacttggag gtcgatactg 56580cagtgagctg tgatcgtgcc actgcactcc agcttgggtg
acagagcaag accccggacc 56640ctgtctcaaa aaaaaaattc cccagttctc agggtgtggt
agaggccgag tcagtcatgg 56700ctgagacaag gggactgtgc tctgtgtgct tctgtgccct
gtgtttatat ggttcatacg 56760ctgcctgtcc accatgtttt tcccgagagc ctcggcagcg
caggcatcat gggaatgact 56820gagtcaggtg gaaattcaga ggccctgccc tggtgggcag
agaagcctgg cttacctccc 56880aagcacagca tgtgtgtgga tcacttctgt gcactgtctc
ctcatctcca aaatgggagt 56940cataactgaa ctcacctcat caagttgtta tgagatgatg
tagattcagc gaagtagcaa 57000gagtaggagt ttgggctttg ataacagaga gaagtgagtt
tccatctaga ttctccccct 57060gtgtcacttt tggcagttgg cttcacctct gtgggcctct
gttatgtcat ctgtaaaatg 57120ggattaaccc taaaagccac cctcacaggg tcattgtgag
gattgcacaa ggtgatgcaa 57180gtggcacagg gtctggccca ggagaggggg ctggaagaga
gcgagctgcc attgtatttt 57240ggttgctgtg gatctaagga gaagagatgt ttaggagtct
ttccctggca tggttcctcc 57300tgccttcacc catcactctt ttcctcgagg gattccctgt
ggggtgcaca gccccagggt 57360gggccagact gagctcacag gagcatgggc tgtgtttcag
gtgaggtggc ctcaccacat 57420gacaaactga gctggagtca aagggtcacg aggacctcca
ttcacagcca gcatttatta 57480tttcagctgg aaatgtttgc cgagcagttg tagctggaag
ctgtgagcga gacacagact 57540gccatcaggc tgaggcctcc agagctcatg ctgggcttta
acctgagcct cttgggggct 57600gggctctgag ctcctccact tctgctcatg cccaggcgtc
cttgggggcc ttgaactgtc 57660agttgtccag gagaactgtg tggcagcaac agaatgagtt
tgtatagcaa cctgttgctt 57720tgaggtttaa aacttagttt agaacgcaat tgctttgacc
attttggagt gtctatactt 57780tttttcttct tctttaagtt ttcttttttc tttttttctt
tttttttttt ttgagacaga 57840gttttgctct tgttgcccag tggcaacaag agtgcaatgg
cgaaatctcg gctcaccaca 57900acctctacct cctgggttca agctattctc ctgcctcggc
cttctgagta gctgggatta 57960caggcgcccg ccaccatgcc tgaccaattt ttgtattttt
agtagagacg ggtttcaccg 58020tgttcaccag gctggtctcg aactcctgac ctcaggtgat
tcatctgcct tggcctccca 58080aaatgctggg attacaggca taagccatca agccctgctt
ttttgtttcc cttcttcgac 58140ctttctaaca agaggttgga atcctcgttt tgacttttaa
aggatttccc agtgctagaa 58200agtggtaaga tagttactgt atcctaggcc ctttagcaga
cctgtctcat tgatcattta 58260tttagtccag tgtggctttg ttgttggata ttaagtaatt
ctcaaaattt taccttttca 58320aaagtggcat tgaaaataaa ggcattgggt gatgaaaatg
gaacttttaa atacagtgat 58380tcctgttaac cagaaatagg gtgtttggga taatttatga
agcagtacac catcatagat 58440actatgagct gaaagttcac caaactctct atcccaaaat
aacaataagg tatttatgaa 58500gtgattcgtt ccaactattt gaggcaaaaa ttgtccagca
agtgagagag aacagaagga 58560atagttggca aaatagggaa tttgaagtct gaggttatgc
ataaggaatg tgttatgggc 58620ctatagtaga aatctcaaat cagggattag ggaatgttta
ctcagttctg ttgcagagaa 58680atcctggcca cgactccccc atgccatgcc cagggcaggc
attgctaatc ttcactgcct 58740ccattctcca tgccctgttc acggaagaca tttctaatgc
attttagcag tctttttttt 58800ttttgctgaa tccagatgtg gcctcagaat ccttctcaac
acagtgtact agcaccactt 58860ggtgctcctg atctactgta tcatctcttg aaaaactact
aacatgaaaa gacctgccaa 58920gtcaacttta tattaactga acccttgaca cagtgatgga
taaaaattaa ttcaaacagc 58980ttctttgtga tctttgagta gttcatgagc aagaaagaga
attggaaatc cagccaactt 59040cggccccctt gtctacttgt attttactgt ggtttatgtt
ttctcttacc aattgagata 59100ggcccatgag acttctggtc ttccaaagcc cagaacatcc
ccacattata gtttaaccac 59160tgtaacaaag aggttttttt tgtttgtttt tttgtttttt
ttttgttttt tttttgggac 59220agaatctcgc tctgtcgccc aggctggagt gcagtggcat
gatcttggct cactgcaagc 59280tccgcctccc aggttcacgc cattctcctg cctcagcctc
ctgagtagct ggggttacag 59340gcgcccacca tcacgcccgg ctaatttttt gcatttttta
atagagacgg ggtgtctgga 59400tctctgacct cgtgatccgc ccacctccgc ctcccaaagt
gctgggatta caggcgtgag 59460ccaccacgcc tggccagagg ttttcttaaa aacaataaca
acaaaaacag ttgtggaaag 59520catgtagagt gtgggttttt tcggtcttca ggttggcagg
gcatctgata ctgggaccca 59580ggttccttcc ctcaccttgc tgtgcctctc ctagtgcagg
ccaaagccag gtgactgcgc 59640tgtctgggct cctggctggc aatcggggaa agagtgcatg
gagcaggcat gcccactgtt 59700caggtcctga agccgtggct catttcatat catttgttgc
ttatttgaaa gacaggcaca 59760gcactgactt ccaggggagg ctgactgacc atctaggtgg
aagttgcatg cctgggaggg 59820agaaggggac aaaggccaca gataggcatc agttatcagg
gccttaagtc tgccttgttg 59880gcatgcagcc ttttattgga tcaaggccct ggagaaaagc
cctgagcagg aggagataag 59940ccagcttggt ccccttcatc ctacccaggg gcctctgggg
tacctgagcc aaagtgcaca 60000gttcattggc tgtgtggatg gaagggatat gggacttgaa
aatgggacac tggtcctggg 60060cagctgaccg acatggtcct ccttaacctg ctgtctgggg
agatgggttg catctggcta 60120ggttttgact gaggaactga ggagagctgt cagctgtccc
cgctttggtt cagaatgccc 60180ttttgtttgg acagctgaag cctacaattc agccatggtt
tgtttgggct cagaaaacag 60240gcaaggatgg agagaaactg caaagctgac ctgggctgtc
agtgggcacc aggtcctgct 60300ggcctggggt ctggatgcag gagatctgag ctcttcaatg
tggggtggtc ttgcagcagc 60360tcttcacagg ctgctgctgc tgctgctgta ggctcaccca
agcagccaag acggacagga 60420tctattctag ttttgtgcag agttggatat agaagaggca
ttagagggag aggggatggg 60480gaaggagttc caggccaggt gagcatgggg cacagtaaac
tgggatgtta aggaggggcc 60540agtttgtgac cagcctgggc aacatggcgg aaccctgtct
ctataaaaaa ttaaattagc 60600caggtgggtg gcatgtgcct gtagtcctag ctacccagga
ggctgaggtg gaaggatcgc 60660ttgagcccag gaggcggatg ttgcagtgag cagagattgt
accattgtat tctagcctgg 60720atgaccgaga ccctgtcttt aaaaaaaaaa aaaaaggagg
ggccagaccc ctgacccata 60780tgtgctgctc ttttctttca gggaggtctg ataaaatatc
agtagttcaa ttcttttttt 60840tttttttttt ttttttctga gatggagtct tgctctgttg
cccaggctgg agtgcaatgg 60900agtgatttcg gctcactgag acctccgtct cccaggttca
agtgattctt gtgcctcagc 60960ctcccaagta gctgggatta caaggtgccc accgccatgc
ctggctgatt tttgtatttt 61020tagtagcgac agggtttcac catattgtcc aggctggtct
cgaactcgtg acctcaggag 61080gtcctcctgc ctcagcctcc caaagtgctg ggattatagg
cgtgagccac catgcccggc 61140ccatagttca gttctttagg tggttcttgg tgctgcatat
gagatctctg caagaaggac 61200acgtctgagc cgggtggttt agaagaccag catggcccaa
gaccctcaga gcaacaccaa 61260gaaccaccta aaattctttc tcagacgtgt ccttcttgca
gagatctcac gtgccccagg 61320ttcgctgcag cgttaggggt cagcctccct ttggagcagg
agagcagggg ccttggaggt 61380ggcagtcatg gccctcctaa ttaattgctt ggctcagaga
agtgacaaat tgaacatttc 61440aaccacctgt taattcacaa ggtacttctt ttcatttctt
gctgcttgca caaaacactt 61500ggagtatggc ttgtggatgt ctggccctag ggaagagtgt
ttggcacata gcaggtactt 61560aagtattagg aaaatgagga tggaggggag ggagggaaca
ttattaagcg gccaactgtg 61620agacaggcat tgtgcttgac tctttctttc tttttttttt
tttttttgag acagagtctc 61680tttctgtcac ccaggctgga gtgcagtggt gtgatctcgg
atcactgcaa ccgcgcctcc 61740tgggttcaag tgattttcgt gcctcagcct cccaagtagc
tgggattaca ggcgcctgcc 61800attatgccct gctaatttta tttttagtgg agacagggtt
tcaccatgtt ggccaggctg 61860gtctcgaact cctgacctca gtgatctgcc tgcctcggcc
tcccaaagtg ccaggattac 61920aggcgtgagc cactgtgccc ggccgacact tggcattctc
taacctacct actccttata 61980acagccctgg gaagtagttg accatggcca tttctatttg
gtagatgagg aaaaataagg 62040ttcagagatg gattgttcaa accgatgtat ctagtcaagc
tactggttcc cgagcctgtg 62100tttgcaaccc ctctaccatg tagcctctcc gggtggtaga
gatgaggggg cagagtgcac 62160agtgcatggc atcctgttcc ccagatggcc aagtcttagt
gcgagtgtgt gtggccttgg 62220taacttgtgt caagcacaca ccccatctct ctctctctct
cttttttttt ttttttttga 62280aacggagtct cactcggtca cccaggctgg agtgcagtgg
tgctatcttg gctcactgca 62340acctctgcct cctgggttca ggcgattctc ttgcctcagc
ctcccgagta gctgggacta 62400caggcacatg ccaccacgcc cagcaaattt ttagaagaga
ctgggtttca ccatgttggc 62460caggatggtc ttgaactcct gacctcgtga tctgccctcc
ttggcctccc aaagtgctag 62520gattacaggc tctcttgctc tctctctctc ttgttttttt
ttttttgaga cagagtctta 62580ctttgttgcc cagcttggag tgcagtggcg tgatcatggt
tcactgcagc ctcgatctcc 62640tggctcaagc aatcctcctg cctcagcctc tcaagtacta
gttggtacta atgggcatgc 62700accactacac ctgactaatt ttttttatta tttgtaggga
cagggtgtcc ctatgttgcc 62760caggctctgg tcttgaactc ctgggctcga gctatcctcc
tgtctcagct tcccatagtg 62820ctgggattac agagatgaac cgcctggcct acacacccct
atctctcctc gattcttttt 62880tttttttttt tttttttgag acagagtctc cctctgtctc
ccaggctgga gtgcagtggg 62940gtgatcttgg ctcactgtag cctatggctc ccaggttcaa
gcgattcttg tgcttcagcc 63000acccaagtag ctgggattac aggcacacac caccatgccc
agctaatttt tgtattttga 63060gtagagacag ggtttcaccg tgttagccag gctggcctcg
aactcctgac cccaagtgat 63120cctcctgcct cggcctccca aagtgttgag attataggtg
tgagccacca tgcctggcct 63180ctccttgatt cttacagtca ctttgttggc tgtttctgac
tcagcagcta cctgcattgt 63240ggccaaagga tgacctattc cttctcagga gggcaaaaat
gtggaatagt gtctgtccat 63300gcctctcctc atgggctacc acctctgcca ccgtggttaa
tcagtaacaa ccaggagaga 63360agctgctgga actgacctct gggaactccc tggatggttt
ggtgcaggaa tgtagtaggc 63420atacacgtgg ttgcgtggat ctgggccctc ctgatgtgag
tagagaggta aaaggccacc 63480atctccttga cctctgggga actcatccac aaagaagatg
tttccaagat gcttctgaag 63540attgcctaaa aatagccggt ttccaccccc gtgaatgcat
ccattctaga atgctccttc 63600accaggacca gagaactgat ttacagaagt gacatgaaaa
cattccatcc cagaatttgc 63660agtagctcaa attaagtttc tagctattaa aaagaaaaga
aaacaaaact aaacaaaaca 63720cacccaccct gctcacttag aagcaacact gagtaatttt
aagtagttcg agaaaatgta 63780tgtggtttga gggtcagggt tgtccagagc caagaccagt
tatgtgggaa ttgttattgg 63840ctggatttgg ggaggagaaa cccatggccc aattccaacc
cactgaaatc taagcagatt 63900ctaggtggtt aggcggacct ggtaggcgtt ggtttatttt
attcccgaaa aaggccctgg 63960agcaagtctt cacatggaat cctgctgaaa ggcttccggc
tcatctggcc ttttcctcct 64020cttaaggttc tgctccatgt tttaccctcg gcgtaaacat
tgcagagcac gttcagatct 64080gaaaagtgtc tcatctacgt gatggtcaga cgttgttgac
cctgtgatgc tgtgtaacat 64140ttcattttcg aggcttgggg agtctcctat ttcatgtgga
tgggaacctg gaggtctttg 64200ggcaagtcgc catcttttta ttgttccaag agtttggtga
agcgtttgaa ccttcacctg 64260tcaaaatcag ttttggaatg agaactgctc tctctctagt
ccttataata gcagaaggaa 64320ggtatcattt atcccaatga gaccataaag ggggctttcc
cgtgtggaca cccaccttga 64380attcaattgg aaacagaaat tctgggcatt gtattttttg
taaatttggc tcagacttca 64440actggatcat atttccccca aaatcttttc gaaaaagact
tgtgtctcat tcctttagac 64500tagcatgtgt aagctgggta aaaatagagc aagccgattt
catgttaatg atttcatgtt 64560aggtttgtga atcaaatctg caagtctgct tttgaaaagc
atttaacata taacttggga 64620aagtttgagt tttgcagact aatgcctgtg gccggatgag
acttcatagc tccatccaat 64680ccctcctggt gcaagagatc aatgccttga gggtgcctgg
ccaccaccat taccctgaca 64740gtatacccac tatttattta tttatttatt tatttattta
cttatttatt gtttaccctt 64800ttgaagattg ctcttctccc tttaacttaa aggaattggc
atggaaactt gtttgatctg 64860gaatttctga taatcagtag gtagtaactc cgtaatcaat
agcacttcaa aacaacaacc 64920aaataacagg ataactaatc caaaaaattc agtcatggtc
aaggacttcc agctcaggaa 64980atgtctggtc ccgtggggtg gattccttgg ataaccaagt
tccgtgcagg gcctggagtt 65040ttatgcagac cattgctcct tgattgacca caggacctca
aaaggagggc tggcttcatg 65100accacatgac ccgtgtgctc agaagggccc tgtacttggt
ttattgctct gctgttgctg 65160tcttgaagtt cttaattttt tttttttttt tggcactggg
gagttgcagt ttcaaacaac 65220acttattcat tgtctcacag tttctgtggg ccaggagtcc
agccatggct taagaccagg 65280tcctctgctc cgggtctcac gagactacaa ggaaggtgcc
atctagggtg tgttttcatc 65340tgaatgccta actaaggaaa aatccacttc attcaggttc
attcaggttt ttaaaagaat 65400ccatttctgt gtgattgtcc cactgacagg tcccagcttt
ttactagctg ttgcttggag 65460gctaacctca ggttttacag gctacgctca tatctctgcc
atgaggcctt ctgcataggc 65520aattcataac acaggtgcct gtttcctcac agccagcaag
agaatctgtc tcctgtctgc 65580taaagtggag tttcatgcat cgtaatatgg tcatgggagt
aatagcccgt cacctctgcc 65640atttttctgt tggttagaat aaaggcacag gttttcccca
cactcaggaa gaacccatga 65700tataaaggct ttcagtaaag gagacgacaa acagaatatg
gaatgatcag aattactctt 65760atgacccaga ccaagaacat cagcattacc tacgaattta
ttggaaattc aaattctcct 65820gtttcacccc aggcctgtta aatcagaaac tttaaaagcg
agcccagcat tctgtggttt 65880aacagatcct tcaggtgatt ctgacacctg ctgaattttg
agaaccactg gtctagaggc 65940aggcaggtct tgctccccta ggagttaagt ttgatgtatc
ttctggtaat actgagaaat 66000gagctgggaa atggttccaa aatcagatta tcctccccag
gattaacaag actcatactt 66060gcaaaagaga gtgaagaaga gaaactaaaa aaagcaagag
gctgtgtgtg aagctagatt 66120caaacagtta aagacagcaa cacatggcaa aggatgggaa
tttgaggaag tgggtagtga 66180aagcaattct tgagctaaat tacaagaaaa cacggtgaat
ttgtatctgt ttcctatatt 66240tagggggctg gcttaaacgt tagtgataca tttggggagt
agaaaatgga tgttggtgtg 66300aagttcttaa gttttggaca aggaaccctg tattttcatt
tttctctgag ccccatgaat 66360tatgtagaca gtcctgcttc gaagttatta tttatacaat
tcattataga gaaagtcctt 66420gggaacctta actttgagtg aggattgctt gagttagttt
ttcttaccag ccactccatg 66480atactctttg ttttttccag gttagatgat cgagttttat
tatgactgaa tctgcacctg 66540caaaattaat tctgattaat taatttaata attaaattct
gatgatttct ctctgatggt 66600ttgggtgtgg gctcttaaag agggtctttt tttgcaagag
gatataacaa taatcaggtt 66660aattaaaaaa ataaggctct caccctttca tttttgagtg
gcatgccatg caccccttat 66720cagcatgtga gtatgctttt catgtggtcg tggttgggtt
tcattaagtg taatttggca 66780tgtgttcaac cagcattcag gtggctcttg gtgggtggct
ggggagacac caagatgcag 66840atagctcagt cactcctcaa caagcggctt agttctggaa
tgaggtggga ggccaaggaa 66900ctcacacata aatgctggtg ggagtgaagt gccaccagct
gtagaatctg gtgtcagaat 66960gatgagccag gagttatccc acaggaggat gggtgaaggt
cttcccatca aagggataga 67020gaacatgtga agaggtccag gggctcaggg caagatgtag
tccaggaaca aggagtcttt 67080gagcctgcag tatggtgggt ggaagtggca agagtggaaa
gcggattgga tggggtttat 67140gtaggttctg aggtgctgtg tatgtttaag gagctgattg
tgtgcagcgg gaaccctggt 67200gaatttggaa gcacagaggc acctgacgag aaagatggtt
ctggggttat gtgaacagtg 67260attcggcttc aaggctatca aagacaaaaa tgtttattgg
gagggtatag aaaagggttt 67320gccaaaagag ttaggtaggg atagaattga cacattgtgg
aaactatacc cagagtttaa 67380gaggtggagt ccaggatagt gcccatgttt gtagcttggg
gtcctggtag aatgggagct 67440ggctatggag tatctttgtt ggagagtggg tatagggaaa
cggagagaga gagaaagttg 67500cagggggtgc gggagatgga tagctgcaga gaaggcaagg
gcagggaaag tggaaacaaa 67560tggcagtgag actcctggaa ggtgctggcc aggggcatgg
catggcatgt tctgttaagc 67620aaggaaagga ctagaaaggg gccatgattt tggctgggca
cttatcctcc tcacaacagg 67680acgcatttgt gtcatggctt actcttaaga atgactgacg
tgtcagaata gcaaatatga 67740aaatgattga taacacctag cattggtgag atttgcaggg
ataactagct ggcctcttaa 67800atctatagat aggaatgtaa acagaaacaa actttttata
gggaaaagat atctaggaca 67860taatgattaa tgaaaagaaa aaaattccta cctatcgaaa
aacgtgaatt caggcagcaa 67920acacacatgc atgtatacac atacacacgt gcacacacgc
atacacacac aatctggtag 67980gctgtatact accagtttag caggttgtta cctctgggat
gcagtcactc ctttttgttg 68040tgtatatttg tgaaatgatt tctttcaatt tttgagacag
ggtctcactc tgttgcccag 68100gctggagtgc agtggcgtga cgtcagctct ctgcaacttt
cacttcccgg gctcaagcga 68160tcctccaacc tcagtctcct gagtagctgg gactacagga
gtgagccacc atgctcggct 68220aatttttttt ttttttttgg gtagagaggg agttttgcca
tgttgcccag gctggtcttg 68280aactcctaag ctcaaagcaa tcctcctgcc tcggcctccc
aaaagtgctg gggttacagg 68340agtgtgccac tgcacctggc cattattatg gaaaatttta
ggcgtataca aaagtagaga 68400cagtggtgtc ttacatgctc atgaacccat gatccagtga
catccgttaa tggcattttg 68460gaatcatatt tcatctgttt ttgtcctcaa atgttttgaa
gcaaatttca gcattacatc 68520atttcactct taaatatctc agtatggttc tctaatagtt
gaagactcca tttacattta 68580tataaggagc ataatttaca cttgtgtaac ccaaaggaat
gaccaagcct gtgcttctct 68640ccccagatag caaagccatt gtggatggga acctgaagct
catcttgggt ctggtgtgga 68700cgctgatcct ccactactcc atctccatgc ccgtgtggga
ggatgaaggg gatgatgatg 68760ccaagaagca gacgccaaag cagaggctgc tggggtggat
tcagaacaag atcccctact 68820tgcccatcac caactttaac cagaactggc aagacggcaa
agccctggga gccctggtag 68880acagctgtgc tccaggtaag tggccagggc tgcctaaacc
atctgtccag gatgggggtg 68940tgtgggtccc aaacattctg gttttcaacg ggaatgctat
ctttgctttg attagcgtat 69000ttctccaggt cttagcccat tataagccca ttataaggaa
actaaaactg gctctgtgta 69060cccttccaag ggcagatttt ctaggtatat ccatagacat
gtttgagcat caagttgagt 69120cttttatcca aattccaatg aaggagttgg tgcttagaag
caagacttgg gtttaggttc 69180cagactccaa aatcctgtgt cttcccacat tggtgctcag
tttctcattg gatttggaga 69240aacatttggt cctattaggt ggcttggcat gaaaatctga
aaacttccat ggagtggaaa 69300gtacccattt ttattaacca ctggtttgac tatatatggc
attctccacc cttttctttc 69360tgtgttgctg tgaaatagca tttggtcagg atccagttgg
agccttttcc acccttgatg 69420ggctgctcat ttcttagtgg ttgagtgtat atgaaggttg
taattattcc cactggaggg 69480tttagattga tgggtagagt ttgctggtac acactcagta
gaaagaccag agtcagagtt 69540tacacacacc ccctaaagtt gattttaata aaaaaaaaag
gtattaatca tattttccat 69600ttactgtgta ttctgtattt actgggcaca ttagtattta
gttagttagt ggttcttgac 69660atactcaaag cagaactagt gtcagttggg taggggaggg
ctgaaggcct cattcttact 69720tgagagccta taagttggtg tcatccagga aaaattcaaa
gtgcagcatt aattgatttc 69780ctaatatcct cttctttact tccatttaag gacacatttt
aggatacctc tttccaattt 69840aaacctggga gtttttactc tagtccttta cctcatgtgc
ttacaaaggc ttttaagata 69900attctaggtt tgtgcctttg agcaagtgga tttttgaatc
acacaggatg ctattctaga 69960ctttttagat atatccagga atagagtaaa aaataaaatc
cctcctgcat aaaggcacca 70020ggctttttcc aagctttgtt tattttttaa caccacttct
tcaaggaatg gataatcccc 70080atcttcatgc aagaacatag cacccggagg agaagtctca
gtaatggagg atagtttaca 70140ccctggcaca ctcatacctg tgatactttt tgcctattaa
atatatgatt tgctcagatt 70200ttaggaaaaa atcattctct gaactaaaag aaaaaatggg
gttagtttag gcacatggtt 70260tcctttaatc tctttggtca gctaatgcta aaagaatctt
ttgtgttctg ttaacaggtc 70320tgtgcccaga ctgggaatcc tgggacccgc agaagcctgt
ggataatgca cgagaagcca 70380tgcagcaggc agatgactgg ctgggtgtcc cacaggtatg
cacaagtgtg ccaggtcctg 70440tgaggctgcc cccacccact agcttgttct gtggatgcct
tcccgggtca ggcagcccga 70500ccttcttggc attgagactt cagagagcat tgcctgtgat
gctctctcat cttcctcagt 70560ttacccataa taatagtagg ttctcattga ctcaggtgct
tatagatctt agtgtgttgg 70620tttaatgtag atcatccaga aattttcatg tcactcttct
ttgtcacaca ctggcaaatt 70680ttctagtatt tcttctctaa atattttgaa gactaccttt
aaaccccaga ctacaaatat 70740ggaccctaac tattaggttg agccataaga aattgatagt
atttgaccat ttttcaatct 70800acattttaaa aggtaatttt aatccaatag cttaagaaaa
gtcacaggac ttaaaatttt 70860tttttttttt tgagatggag tctcgctttg tcgcccaggc
tggagtgcag tggtgtgatc 70920tccactcact gcaacctctg cctcccgggt tcaagcaatt
ctcctgcctc agcctcctga 70980gtagctggga ttataggtgc gcaccaccac acctggctaa
tttttgtatt tttagtagag 71040acagggtttt accatgttgg tcaggctagt ctcgaactcc
tgacctcgtg atctgcccgc 71100ctcagcctcc caaagtgctg ggattacagg cgtgagccac
tgtgcctggc cgacttaaaa 71160cttttaaaaa catgtaagcc aggataatcc accattaatg
gaaactgtgg aagaatctct 71220atcacccata atcctatcac aggaatataa caagagaact
cagaaatcaa ataagtcttg 71280gataccatct acagtagtca cattgcttag ttgaagtctg
atcttcctag ctgggaggaa 71340aaccagtgtt ttctttccag aaactccctc taacagttag
gcaccatgag tcccgtgtcc 71400aaaggctagc cagggaagat tgcaggtagc cagtgccatg
ggactgatgg cgtcactata 71460ggctgcattg aggtctgagt tcagtgtatt ttgtaacagg
gtcccttgga aggtagaaca 71520acatgcctgt ttctttggtt tggttttgga gtcatgtctc
tcctacatgg ctcattggtt 71580tcttggctcg tccaccctca ggaagtggtg tggtgtgttt
ttcatctccg cttaaaccta 71640aaccgtctcc tttttacgtt cacgtgatgt tggcatgggt
gaagttgttg aaggagctgc 71700tgggaagaaa tgccaaatcg acacacatcc tactttttat
ggaatgtatt gaaggcgact 71760gttcaaaccc aagtagctct tttgttcctg caggctaatg
gtcagaatgt tttctggtgc 71820tttttatcac atggggaggg aagttggaca catctgttgt
tcattgcaca tggttaacct 71880ggtccatgag acagagcctc tgttcatctg aggaagtgtg
atttacctcc ttagcaccat 71940tactggaggc agggaggact ctgcaagctg tttagggctg
ggtcagatga tggtactgaa 72000actgaggtgg tggcaccttc agggaagtca cctgtccagg
atgggtctag tcttgctcct 72060aagctgaata tcaagagaag ttcacccatt ccctattttt
tttttttttt tttgagatgg 72120agtcttgctc tgtcacatag gctggagtgc agtggcacga
tctcagctca ctgcaacctc 72180cgcctcctag gtacaagcga ttctcctgtc tcagcctccc
gagtagctgg gactgcaggt 72240gtatgccacc atgcctggct aattttgtat ttttagtaga
aatggggttt caccatgttg 72300gccaggcttg tcttgaactc ctgacctcgt gatccaccca
cctcggcctc ccaaagtgct 72360gggattacag gtgtgagcta ctgcgtctgg cctttttttt
ttttttaaag agacagcgtc 72420ttactcctct gttacccagg ctggagtgca gtggcatgat
ctcggttcac tgaaacctcc 72480acctgctggg ttcaagccat cctcctgcct cagcctccct
agtagctggg attacaggtg 72540tctgccacca cactgggcta atttttgtat ttttagtaga
gactgggttt taccatgttg 72600gccaggcttg tctcgaactc ctgacctcaa gtgatttctc
ttgtcttggc ctcctaaagt 72660gatgggatta cagtcatgag ctaccacgcc tggcttccct
atttttttaa tggctcctaa 72720tatattgaga tcacatatct aatatttaca tgttatttct
tttttattta ccttttttaa 72780ttagtagagt taatacagat acagaccatg agtatacaag
caaaggaaaa agctggttaa 72840cctgtgcact tttttgtaac atgctctaat cccatgtgtg
cttgtttctt cattttcctg 72900ccttgctata gcttatcctt ttatcatttt tgaaattttg
accagaggag taaatggact 72960tttggggaat ggggaggaca atgaactttt ggaagttaca
tgcagaattt tttggagagg 73020ggcccctagc tttcaaaggg gtctgcaatt tctcaaaaat
ggttaaaaac actgatattg 73080gtgtgttggt ttaaagtaat ttcacttaat tgagaagctg
actcagtttc ttaatatttg 73140tagtgcttgg tttaagaggc atttgcaaac acttcaatag
ttgcaaagtg atgtgttctg 73200ggtgttcatc caccatgtca ttatcctagg tcatcactcc
tgaagaaatc attcacccgg 73260atgtggacga gcactcagtt atgacttacc tgtcccagtt
ccccaaagcc aagctcaagc 73320cgggggctcc tctcaaaccc aaactcaacc cgaagaaagc
cagggcctat ggcagaggtg 73380agtgctggtc ctctggtgtt gtattggaga catgtcctct
ggtgttggag atgatttcat 73440ggcttcaaga gtgatgttct tagaatcaaa aatagatagg
tgtaatcctc aaagagaccc 73500caagcctcct ttgtaacaca ttttatgact gttttattct
gccttgtttt tctaaggctt 73560taagaaatgt ttctgcttag atggaaaggg caagtttgct
gcttggtgat tttagtgcag 73620tagcccattg ctcccatttt tcagaagagg aatcgcgggg
tagggagtcg ggggagtttg 73680gtcttgcccc agatcaccac agtcagtgat gggggtgggc
catctggctg ctgattcatt 73740tctccttctg ttacactaag cctgcctcag atttccagcc
ggagtgggag ctattgttaa 73800cccctggcag atacttcctt gctaagacat cctgtttatg
actgcgaggc agctgcggaa 73860caccgttttg ctcagaacat tatagtgggt agaagccatt
tcaaggcatt tggtgttgtg 73920attggcacct gacttcaagc acactagctt tgtgaagaga
acagttacat ggctgcaaag 73980tgtggtttct ggtgaagatc aacatggcca gatacaactt
aatgcctttt ctatggggga 74040ggggaaggag tgcattttat ttctcatttt tcataattaa
gaaaatatcg gccgggtgtg 74100atggttcatg cctataatct cagcactttg agaggccgag
gcgggcagat cacctgaggt 74160caggagttgg agaccagcct ggccaacatg gtgaaaccct
gtctctacaa aaaatacaaa 74220aattagccag gcatggtggc gggtgcctgt aatcccagct
attcaggagg ctgaggcagg 74280agaatcgctt gaacccagga ggcagaggtt gcatcgagcc
gagatcttgc cactgcactc 74340cagcctgggt gacagagtgc gtgagcctcc gtctcaaaaa
aaaaaaacga gaaagaaaat 74400gttatcccag tgggataata gttatacaca cagtattctg
tatatcttct cccagaattg 74460acagttgtta ccattctagc ttaatagttt tctcttgccc
tttgtgtgtg tttgcatatg 74520tgttcatgtg tatgattgct gaattatttg aaaataagtt
gcaagcatgg tgacagttct 74580gtcctcagta catcactaag cttctcctaa gaataggata
tcctctagca taaccacagt 74640attcattgcc acatgtaaga aaattaacaa tagtttcata
taatctaata ttcagtttgt 74700tgtagaattt ctctattgtc ctaagattat cttttatagt
tgttgctgtt ttacaaacta 74760agatctgatt aaggttcact tactacattt gtttgttatt
tctctttaga ctcttttcat 74820gctaaataat ttccccaaac tttttttttt ttttttttaa
atgacactga ctttctgaat 74880agttaagggc atgtgtcttg taggatgttc cttccctaca
aatgttccct ttgaataaag 74940tattttcctg cttggtatca gcttagtctt tttttttttt
tttttttttg agagtcttgc 75000tctgtcgccc aggctggagt gcagtggcac gatctcagct
cactgcaacc tctgcctcct 75060gggttcaagc gatcctcctg cctcagcctc ccgagtagct
gggattacag gcatccacca 75120ccatgcctgg ctaatttttg tatttttagt agagatgggg
tttcaccatg ttggccaggc 75180tggtctccaa ctcctggcct caggtgatct gcccggctcg
gcctcccaat ccgcttattc 75240ttaagacgac acatggctag ggcagtgatg ctgaccacgt
gctgttctca cctcagtggt 75300cgagtcttct catctgactt tttgggcatg atttagaccg
gcagatagtt ctggaacaaa 75360ccccttacca tttgaggttc cgtttgcagt gggttgtgag
gtgtgtgaga catcacttgt 75420gttatgtagg gactagggac ttcaaagccc tcctcccatt
cacagtcact tgaaggctgg 75480catgtcctca ctttctttaa aagtgctttc tttggccggg
cttggtggct cacacctgta 75540atcctagcac tttggaggct gaggcaggca gatcacaagg
tcagaagatt gagaccatcc 75600tggctaacaa ggtgaaaccc catctctact aaaaatacaa
aaattagctt ggcgtggtgg 75660tacaagcctg tagtcccagc tactcgggag gctgaggcag
gagaattgct tgaacctggg 75720aggcggaggt tgcagtgagc cgagatcgcg ccactgcact
ccagcctggg tgacagaacg 75780agactctgtc tcaaaaaaaa aaaaaaaaaa gtgctttctt
taaggcatac cacaggtggt 75840ggctggaatg aggaatctct gactttaaag gttatgcttc
cttaatgaca aaacagttgc 75900aaacaaccaa ttaaatcctt tgtcaaccag attggtcaaa
tggactgaat ctaatcaagg 75960catagtgtat gtttgtaata accttatcac tggccatccg
gcttccctgt tgttaatgtg 76020agacggtttc ctttcacggt gctattttct agaaaatgat
cacttgttat ggttcaggaa 76080tgtggctggt cattgccatt tccttcatct gcctcttagc
aagtgtggtg cacttgtaga 76140ggaaacacac ccttttaaaa aaaaattttt ttttatatgt
gtgctttttg cattttttta 76200attgtgggaa aatatccata acataaaatt cactatttta
accattttta agtgtggcat 76260taagtgtatt cacgttgttg tgcaaccgcc actgctatcc
atctccagaa ctttttcaac 76320ttcccaaact gaaactccat actcattaaa caatagcgcc
ccattctccc ctctcctctg 76380ctcctggtaa cctttattct actccctgtc tctatgaatt
tgcttattct agggacctcc 76440tagaagtgaa atcatatgct gtctgttagg tacctcctag
aagtggaatc atacgctgtc 76500tgttaggtac ctcctagaag tagaatcata tgctgtcttt
ttttctctgg cttacttcat 76560ttgtcatatg ttttcagggt tcaccatgtt gtagcatgtg
ttagaatttc attccttttt 76620aaggctgaat aatattcctt tgtacgtgta tatcacattt
tgcttataca ttcgtctgct 76680gatagacatt tgggttgtta cattcttttg gctattgtga
ataatgctgc tatgaaaaca 76740tgggtgtaca agtgctgttt gagaccctgc tttcaattct
tttagggata tacccagaag 76800tggaattggt ggatcatatg gtaattctat atgcagctta
tttttcagga ggaagtggcc 76860tcactctgct ttttaaagta ggagacaaaa tggtcatatt
aggtgacagg gtcacaaggc 76920cacatgggtg gggctgtgag atatgtccct gtcatgtggt
tagatgaaag ccggggtcag 76980ttttggtctt ctctgtgtga ccacattgct tcatttctgc
cacctgagcc caggaagaga 77040gaccgtttca tcttctagtt tctaaaagat ttgaaagtgt
tgttttattt tttatttcct 77100gattgtttaa tagatgccag ttgccagcca gttagcattt
gttgatccat tcactgagtc 77160ccaccttgct tagttctagt gggttgaaag gagagagggc
tggggtgagg tggacctcca 77220gccacaaaca gatctttgtg gtgggcttcc ttgcagggtt
agctatgtga aaagcattcg 77280tccatgagct aatcagaaat ctttgtaaaa atctagttct
ctatgaagca tttactgtag 77340agcaatcctt aagcaccctt ctatctgagt aatcagaggg
gtaccagttg tctcctttca 77400tggtaagcaa agctccgcag aagtttacag agttggggtg
tggttcaact ttctaaccag 77460ccatggttag ccacgggtga ccaacccaag cccagacctt
tgacaagctg cagagtacgt 77520tgtttcttag gctgctggag tcacacgaag tggaactttt
agtattttag gtgcatgttt 77580atttacttac ttatttttgt tgttgtcgtt ttcagataga
gtctcactct ctctctctgt 77640gtgtggagtg tcgtgatgcc atcacggcta actgcagcct
tgaccttctg ggctcaagtg 77700attctccctc ctcagcttcc ctagtagttc ggaccacagg
tgtgcaccac catgtccagc 77760tttttttttt tttaatattt tagtttgaga ccagcctggc
catgttgccc aggctggtct 77820caaaatcctg agctcaagca atccccctgc cttggccccc
tcaaagtgct gggattacag 77880gcatgagcca ccatgcttgg ctattaggtg tatgtttaaa
tccatttgct tatatcagtt 77940acataacctg agtgttatgt aaatcttaag caaaagaaaa
atatatgaaa taaaaattga 78000aactcacttc ccaactgcca atctcattcc tgccttcaaa
gtttcaggta tttatttcta 78060gccttttttc tatgctgagt taaactgtgt atcttctttg
ctttgcattt cttactgagc 78120agtgtgggaa ggctaccttt taaaatttat ttgtagttct
ttataatttt tacctttctt 78180tttaggcaga aagattatct tattatataa cagtctacgg
ccattttttc ttaaactaaa 78240ttattgggaa atgaatagaa atccagagta tagtaacaaa
tgacctagtg tctttaacag 78300attggtagct aggaaaagga agtggtggag agacagccgg
agattaaatg agacttaaga 78360gacttagcaa ccatttgtaa tatgtgacct tatttggatc
ctattcaaac taatggttaa 78420aaaaattcat gatagctggg catggtggct cacgcctgta
atcccagtac tttgggaggc 78480tgaggtgggt ggatcacgag gtcaggagat cgagaccatc
ctggccaacg tggtgaaacc 78540ccctttacca aaaatacaaa aattagctgg gcatggcggc
atgtgcctgt agtcccagct 78600acttgggagg ctgaggcagg aaaatcgctt gaacctggga
ggtggaggtt gcagtgaacc 78660gagatggcgc cactgcactc caggctggcg acagagctag
actctgtctc aaacaaacaa 78720acaaacaaat aaaaattcat gataaagcag cagctcaagg
tgctgtaaga aattcatgat 78780atttataaga taattgaaaa tttgaacact gaatatttga
cattaaggaa ttattttttt 78840ttatatggta tcgatattgt gggtactttg caagtatctt
ttaaggatac atagtgattg 78900tggataaaaa atctgaggtc taggatttgt gtcaaaataa
tacaggaagg ggaggtggcg 78960ggagtgaagg tgaaacaaga ccagctgtga gttgatagtt
gttgaagctg ggtacaggag 79020gtccactgtg cagtgctctc tacatctgtg tttgtaattc
tttttttttt ttgagacgga 79080gtctcactct gtcgcccagg ctggagtgca gtggcatgat
ctcggcccac tgcaacctct 79140gctgcccggg ttcaagcgtt ctcctgcctc agcctgccaa
gtagctggga ttacaggcgc 79200ccaccaccac acccggctaa ttttgtagtt ttagtagaga
tggggtttca ccatcttggc 79260caggctggtc ttgaactcct gacctcgtga tccacctgcc
tcggcctccc gaagtgttgg 79320gattacaggt gtgagccact gcgcccagcc ttttttttga
gacagagttt cgctcttgtt 79380gcccaggctg gagtgcaatg gcacgatctc ggctcactgc
aacctctgcc tcctggattc 79440aagtaattct cctgcctcag cctcccaagt agctgggatt
acaggcatgc accaccacac 79500cccgccaatt ttgtattttt agtagagaca aggttacacc
atgttggtca ggctggtctt 79560gaactgctga ccttgggtga tctgcccacc ttggcctcga
aagtgctgag attacaggtg 79620tgaaccacgg cgcccagcct tttttttttt tttttttttt
tgctgaagtt tcacttctgt 79680ttcacaggtt ggagtgcaat ggtatgatct tggctcgctg
caacccccgc ctctgcctcc 79740tgggttcaag ggattctcct gcctcagcct cccgagtagc
tgagattata ggcatctacc 79800atcacacctg gctaattttt gtatttttag tagagacgga
gtttcaccat gttggccagg 79860ctggtctcga actcctgacc tcaggtaatc cacctgcctt
ggcctcccaa attgctggaa 79920ttacaggtgt gagccactgt gtccagccta gtttggaatt
cttcataata aaaagctttt 79980taaaaaggta atatttggac ttctgctcct gggaagatgg
aataggactt ttcctaattc 80040tttcttctaa ctacaactaa aacccctggg ctatacataa
ggaaaacaca gggagcctct 80100gaaaaaggat gaggcagacc aaccagggat cttgggactc
gaggaatgac acagtactga 80160gttccttggg tttactttgc tttatatatc ccagacttgg
agccaaagaa agaagctgac 80220aacctgaaaa tgccagtggg cacaaacaca gaaagtgcca
acaaaagctc ccctgtccag 80280ccagaagacc aggaaagggc agcccagtga ggcagaaaac
ttaaagagtc actgctctac 80340tccaggtcca caccatagaa aaaactatgc agccccacac
ttacacccgc agaggtgaat 80400ggggagccta ggctttgaca acagtctagc aataaggaag
ccactctccg gggccatgga 80460ggagcagtaa tgaggcactc ctacttcctc cagccagaac
tcccaccttc acgcaccagt 80520aatgagcccc ccaatcttga gcatcagtcg aggttgaatg
gagagcctag acttcttccc 80580ccactgttag taacaaggtg tgtacccttc cctcccctgc
cacagtggta tcataaaatg 80640ccagctacaa cagaacattt acagaagacc cagagtctca
ttacatgata ccccaaatat 80700ccagtttcaa aaaaaaaaag aaatcacttg tcataccaag
aaccaggaag atctcaaact 80760gaatgaaaaa gacagttgat gccaacactg aggtgataga
gatgttagaa tcctatgaca 80820aaaattttaa agcagccatt aaaaaaggct tcagtagcca
ggcgtggtgg ctcactttgg 80880gaggcttgta atcccaggac tttgggaggc cgaggcgggc
agatcacctg aggtcaggaa 80940ttcgatacca gcctgaccaa ccttatgaaa cccagtctct
actaaaaata caaaaaatta 81000gccaggtgag gtggtgggca cctgtaatcc cagctactcg
ggaggctgag gcaggagaat 81060cgcttgaaac tgggaggtgg aggttgcagt gagctgaggt
catgccgttg ccctccagcc 81120tgggcaagaa gagtgagact ccatctcaaa aaaaaaaaaa
aaggcttcgg taggcagtta 81180agaacaatca tgaaaaaaat gaaaaaatta aaaatctcaa
caaagaaata caatgtccca 81240gcaaaataat aataaaaatt taggagataa aaagaaccaa
atggacattt tagaattgga 81300aattgcagta actgaaataa aaacttattg gataagcgca
atagcagggt ggaaggacag 81360agaaaagaat ccttcaactg gacaacaatt ggttgttttg
ttctgaggtg gagttttgct 81420cttgtcaccc aggctagagt acagtggagt gatcttggct
tactgcaacc tctgcctcct 81480gggttcaagc tattctcctg cctcagcctc cctagtagct
gggcttacag gtgcccacca 81540ccacttctgg ctaatttttt tatttttagt agagacgtag
tttcaccctg ttggcctggc 81600tggtcttgaa ctcctgacct taggtgatcc acctcggtaa
tccaccttag gtgatccaaa 81660gtgctgggat tacaggtgtg agccactgga cccggcctct
gtaagctttt ttctgtgttt 81720aaaacttttc atttttgtac ttttaaaact tttttttttt
tttaaacaca cacattagtc 81780tagacttaca cagggtcagg atcatcatta tcactatctt
ccacctccaa atcctgtccc 81840actgtcccac tggtaggtcg tcaagagcag taatgtgtgg
aaccgccgtc tcctataata 81900acaatgcctt cttctagaat atttcctgaa ggacttgctt
gaggctgctt tacagttaac 81960ttaattttta aatagaagat gcccactcta aaatataatg
ataaaaagta tagcatatta 82020aatacataaa ccagtagcat tgtcatttat catcaagtat
tatgtattga acataattgt 82080ctgtgctata tatgtttcta tggccggtag cccagtgggt
ttgtttatac cagcatcatc 82140acaaatacat gagtaatgcg atgcgttact gtgacgtcag
taggcaacag gaattttttg 82200gctctattta taatcttacg ggaccatcat tgtatgtgtg
gactattttt gactgaaact 82260tcattattta gcaaatgact atattagcaa ataaaattga
gctgtatata atgaagaagt 82320atgcattata accaagtggg gtttattgca gggatgcaag
gcctcgttca ctattagaaa 82380atcagtcaac agcctggctc ggtggctcac gcctgtaatc
ccagcacttt gggaggccga 82440ggtgggcgat gggcggatca tgaggtcagg agatcaagac
catcctggct aacacggtga 82500aaccctgtct ctactaaaaa tacaaaaaat tagctgggcg
tggtggtggg tgcctgtagt 82560cccagctact cgggaggctg aggcaggaga atggcatgaa
cccgggaggc agagcttgca 82620gtgagccaag attgtgccac cgcactgtag cctgggcgac
agagcgagac tccgtctcaa 82680aaaaaaaaaa aaaaagtcaa atagtaaaga taccacctct
cctcaaattg tcattcaggt 82740ttgatgcaat tgctgtcaaa atcccagcaa gagtttttgc
agatagcaag attattattt 82800taaaacctat atgaaaaggc aaaggaatta aagtagcaaa
aacaattttg agaaagaagt 82860acaacatgga ggaatcagcc ttcctgattt caagacttgc
tgtatagcta cagaagtcca 82920gattttgtag tattggtcaa aggatagaca ttatagatca
gtgaaacaga attgcagccc 82980cacacaaata tgcacaactg attattgaca aaggtgcaaa
gataagtcat tgggggaaaa 83040aaccttttcg gcacatggtg gcagagaaat tgaacatccc
taggcaaaac aaaacaaaag 83100caaaccccaa accaaaaaac aaaaaaccca tataactata
aaactttgag aaaaaaacat 83160agaagagaat ctttgagatc tagagctagg caaatagttc
tcagatttga caccaaaaac 83220atgatccatt aaaaaaaaat aagttggatt tcatcaaaat
taaaaacttt ttaatgtttt 83280aagaaggatg gtctgtctca aagactcaac atggtacatg
gtggttggcc tttatgtgct 83340gttgagggtt ttcctgcatt gaagggtgca ctcctgggtc
acctactgtc ctgcaagaca 83400agctgtctta gccctcacac tataaaagcc acccggacac
cgtctcaaac agaactcaaa 83460atgttgctga gactgggatc tgggggctgg attttacttt
tacaaacaat ttaaaacttt 83520ttacagttaa gaggatgaat atacaggcta aagactggga
gaaaaaattt gcaaaccata 83580tgtccaacag aacactagta tctagaacat gtagaaagaa
ctctcaagtc ttagtcgtta 83640aaaaacagac aaacatttaa ccaaacaacc caataagaaa
atgggcaaaa gacataaaca 83700gtttctgctg aagagaacgt ccatatgaca aaaaaacaca
tcgaaatttg ttcagtatca 83760ttaaccatga gaaaaatgcg aattaatcct agtacacact
atcagaacgg ctaaaataaa 83820aaatattaat actgataaca ctaaatgcag aacggatgga
gagaaactga atctggatca 83880ctcactcata cattgctggt gggaatgtaa aatggtgtag
ctactttgga acactgtttg 83940gtagtttctt aataaagaaa taggctgggc acagtgactc
ccttctgtaa tcccagcact 84000ttgggaggct gaggctggag gatcacttga gcccaggagt
ttgagaccag cctgggcaac 84060atagggagat tgcatctcta caaataattt ttaaaaatta
tacaggtgtg gtggtatgca 84120cctgtggtcc cagctactca ggagattgag gcaggaggat
tgcctgagcc tgggaggtcg 84180aggttgcagt gagccgtaat tgtgccactg tgctccagcc
tgggctacag agtgagactt 84240ggtctcaaaa caaaaacaaa aacaaaacct caaaaaacag
tacatgcaac taccatatgg 84300cccaacaatt gcactccttg gcatttatcc cagaggaatg
aaaacttact gtatatgaga 84360gccactgttt ttccttctat agtctcacag ctaaagaaaa
aaaacttttc tcatcttctc 84420tactactcct ctcagtattt cgcttccggt caccaaaatc
tatggatttc tgtcccccat 84480actgacaagt tctccaattt tatgtggaca acaagtaggt
gtcctataat caattccctt 84540caattctgac actatctacc tgaagttagt gcagacgcca
ttaagggctc ggtccctcaa 84600aactgcccct gacttcagag gccagtcaga agtggtgggt
cctcaggtaa cccacagctt 84660ctgtccaggt ttgctacaaa tcagaaggtc ccattacccc
ttcctcatgt tatgttattt 84720gctagagtgg ctcacagaac tcagggaaac acttaccttt
agcagttgtg tagtgaagga 84780tatgatagag gatacagatg atgccccaga tgaagaggtg
cacggggcaa agtttagagg 84840cgttttgaac acaggagcgt ctgtccccat gaagttgggg
tgggccatcc tcttggcaca 84900tggatgtgtt caccaaccca gaagctctct aaactccata
cttcagggat gtggaggcta 84960agtcacgtag gcgtgattga cattaactga gactacagtt
cctctccctt ccctgtagga 85020tggggagtgg ggccgaaagt tctaagcttc tgatcatgac
ttggtctttc tgttgattag 85080ccacatcttg aaagctatcc gggagcccac taagagttgc
ctgattagaa cagaagatgc 85140tcttgtcacc aaggacattc caaggggttt aggaactctg
gaaccagggg cagagaccta 85200tatatataat ttcttactat tttatactta tgttcacaca
cacacacaca cacacacaca 85260cccctatgca cagatgttta cagcagcttt attggtaaga
gacaactaga aacaacccag 85320atgttcttca gtgggcgaat ggttaaactg tggtacatct
ataccatgga atattagcta 85380ctcagcaata aaaaggaaaa aaaccattga cagaagcaac
aacctgggtg aacctgtaga 85440caattatatg tagtgaaaaa ggccactcct aaaaggttac
atagttatga ttccattgat 85500gtgacgttac cgaaataata aaattacagt gtggagaacg
ggttagtggt tatcagggct 85560aaggagagtg tgggtgtggt tatgcaaggg cagcaggagg
gctccctgtg ctaaagggaa 85620tgttctctat tttgattgta tcaacgtcaa taccctggtt
gtgagattga gtcatagctt 85680tttaccgtgt taccactggg gaaactattt tgagatggag
tcatgctctg ccgcctagga 85740tgcgatctgg gctcactgca acctccacct ccctggttca
agcaattctc ctgcctcagc 85800ctcccaagta gctgggatta caggcatgtg ccaccacgtt
gtatttttag tagagacagg 85860gtttcaccat gttggccagg ctggtcttga acgcctgact
tcaggtgatc cacctgcctc 85920agcctcccaa agtgctggga ttacaggcat gagccaccgc
tcccagcaag ggcattgttt 85980cttacaccta caggtaaaat ctgtctcgat gaatttgctc
gatcatctta aaataaaaag 86040gttaattaaa aaaatgattg aatataattt ttaaaaatgt
caggcaatac aataaatgct 86100gtttaatgag aaataagctt cgctcctccc tgctgtgttg
cttccatcaa ggcaagctct 86160gctactactt attaaccaca ttatttccac aattttatat
agactcctga ctgaggttct 86220ctgaatatca aaattggata ttacttcaat aacatgggca
aaattaaggc tttcgacctg 86280cctgattttc cttgtcaagg cagtttgtcc ccatttccca
catgggatct gcagggctgg 86340gtcccatctc tcagttccct gaaagagatg cagtgggcga
tggctcatga cacaccctcg 86400cctggcttct aacatgtctg tgtaaacctg tggcaggaat
cgagcccact ggaaacatgg 86460tgaagcagcc agccaagttc actgtggaca ccatcagcgc
cgggcaagga gacgtgatgg 86520tgtttgttga ggacccagaa gggaacaaag aggaggtatg
ttggaggatg ctgcctctcc 86580tttccagcac ctcatggagc ttttggggct tgtaatgcgg
ccagggactg tgcctccatt 86640ttcatttcag ctcacaacca aaagtgtttt ttaccaaaag
gatactgagg cttatagctg 86700ttaaagtaac ctgcccaaga ggtgagcctt gaaatcaaat
ttaaattgat tgccagggac 86760acagtgttta atgaaataaa ggatactttg gatttagcaa
aggtgccttg tcagttgagg 86820tttatgtatg tatttattta tttatttatt tatttattga
gacagagttt cactcctgtt 86880gcccgggttg gagtgcagtg gcacaatctt ggctcacggc
aacattcacc tactgggttc 86940aggcgattct cctgcctcag cccggctaat ttttgtaacc
caagtaactg ggattacagg 87000gacctgccac cacgcctggc taatttttgt atttttagta
gagacagggt ttcaccacat 87060tggccaggct ggtcttgaac tcctgacctc aggtgatcca
cctgcctctg cctcccaaac 87120tgctgggatt acaggtgtga gccaccgtgc ccagcctcag
ttgaggtttt atatactgat 87180ggccagaata ataagagtct tgccctgctc tcttcccaca
ttggccattc tttggttcct 87240ccctcagagc ctttgcacat gctgttcttt ctgtcactta
ttttcgtagg accatatttt 87300attcttggca tttagcataa tttgcaattc taagtttaca
gatggatggt ccatttcccc 87360caccggggca gggattgtat ctgacttgct catgttttat
ttttagtacc taacactggg 87420ccctgcattt cataagcttt caatgaacta ttgagtggat
aaaggtttaa gtttcttgct 87480tcatattctc tcttacctag agagtgccag cctgacactg
gacactggag agtcctgact 87540ctgttatgcc tctgtgctgc atggttttgt ttctgtgact
tcaagcagtt tctctctagg 87600ggcgttgtgc aagagggaca ggagctcgcc agcaccttca
gtgtttccga cctggcagct 87660cctgcagaac ccctgctgac acagcatgct ccttactcac
acccggcacc ttttctaact 87720gttgcccacc ttccctccta ggcacaagtg acccctgaca
gtgacaagaa caagacatac 87780tctgtggagt atctgcccaa ggtcaccggg ctacacaaag
taagatgaag cagcatggct 87840gtggcttggg ctgctctggg gctaggagaa gaaagatagc
ccaggaagaa gagtgttttt 87900cttaagtgaa tttctgattt tcctttctga ttatagaagg
atctatgctc atgatagaaa 87960attggaatca ctaggattcc ctctactagc taggatgagt
tgtttgcaat gtcgtaagat 88020ttttccaact ccatctaggt aactaatggt tgcagctgtg
tgtctggagt gtagatgctg 88080tggtgactac actatagatg ggttctttgt ccttgattct
ttttttggag acagggtctt 88140gctctgtcac ccaagctgga gtgcagtggt gtggtctcag
ctcactgcaa cccccgcctc 88200ctgggctcaa gcgatcctct cacctcagcc tcccaagtag
gtgggattat aggcacccac 88260aaccactccc agctaatttt tgcattttta gtagagacca
ggtttcacca ggtcacctag 88320actgttcttg aactcctgac ctcaaactat cctcctgcct
cagcctccca aagtgctggg 88380attatagaca tgagccacca caccctgctg gctctttgtc
cttaatgctt tcttaagaac 88440tctccttgga ggtgctctgg aggagctgtc agcattgaag
gctgaggatg gagtagttca 88500gctgaatata gtagagggaa atggccctct cagcacctgg
agaaatgata gggattgagg 88560cctcaggctc tttgtcttgg cagcctttcg agttctgttt
gagatgacat ccaggtgacc 88620tatagggcaa gggctgagag agcctgtctt gcaggagagt
ggggtgaccc aggagtacac 88680ttttcattgg aagaaagccc tcaacagcac ataaaggcca
atcccatcat gtacctgccc 88740agactttgga atacagactg tactcaccac cttgggcttt
agtgaattca cctggaatga 88800tggccttagc gttctcttag actcttagac tatgatgcat
ttggagtaaa tgctcttgaa 88860gggagcattt ataatgtaat taattaattc cagtcaagta
taggttcaca tgaaacccaa 88920cccaattacc ccccaaaaat ttcagagatg agaacagtga
ctcaagtttt agatggaaat 88980cattctactt tgtcccaaat ccatgtatct aagaatgatt
ttcgtccctt gaaaaaacag 89040tttggctgtg gatttgaaat cctggaactg catattttat
tctgagggat agtggcccat 89100tcagcccccg aaaggactca atgtccagag attgaaatgt
gtttgtttcc tattaaagag 89160actaagtgta tataaggtca gcatttttat tttgctaaag
gtgtgatgtc ccagacccag 89220ctgtatggct gaaggggcca ggtgggagtc ccattcaggc
tgttaaactt ggttccaggg 89280ctccttattc tagacacctt gtgtgtgcca tcatgggagg
gtaggagagg tgatcatcaa 89340tgtatgtggc ttgatgtcag tcttgctggg cacagagaag
tgattatgta tttctcacct 89400atctgtcacc tataggtcac agtcctcttt gcaggacagc
acatctccaa gagcccattt 89460gaagtgagtg ttgacaaggc ccagggagat gccagtaaag
tcactgcaaa aggtccaggg 89520ttggaagctg tagggaacat cgccaataag cccacctact
ttgacatcta tacggcaggt 89580aacgtgcctc tcctccatgg atctgacctt tgcgctttct
tccagaggct gaaatataat 89640cctcggggac ttgaaggcct gaccttttgt cttttaaatc
aaataaataa tcacaaagac 89700aattttttca aatgtgttat attagatttt tcaaaaccag
cttttcttct ctaaaatact 89760caggcttcac ttgaataaga catacttctt gaattgttgg
cttcttttcc atgtagtaaa 89820tagaaaatgc agaagaagga aacattcaac cataaaccct
tcaaccccta gaaaatagtt 89880gttaacatct tggtgtggac ctctctgagg gcctgtctcc
tgtttacttg ttttgttgtt 89940gttgttgggg gaacagagaa tcactctatt gcccagactg
gagtgcagtg gcgtgatctt 90000ggctcaacgc aacctccgcc tcctgggttc aagcgattct
catacatcag cctctcaagt 90060agctgggatt acaggcgtgc gccaccatgc ttggctaatt
tttgtatttt ttttagtaga 90120gacggatttc accatgttgg ccaggctggt ctcgaaatcc
tgacctcaag tgatctaccc 90180acctcggcct ctcgaagtgc tgggattaca agcatgagcc
accacactgg tcctgtttgc 90240attttgcact cagcagcagt gagctttcag agagggtgac
ttgggctcat ggaatgcttg 90300ctttcttgta ggagctggtg tgggtgacat tggtgtggag
gtggaagatc cccaggggaa 90360gaacaccgtg gagttgctcg tggaagacaa aggaaaccag
gtgtatcgat gtgtgtacaa 90420acccatgcag cctggccctc acgtggtcaa gatcttcttt
gctggggaca ctattcctaa 90480gagtcccttc gttgtgcagg ttggggaagg tgagtgctgg
gctgctggcc acatgtgctt 90540ctcataggga agctgactgc acagctgggc agggaggcca
ggaaaacagt cagggcccaa 90600cattgacctt atgcctatcc cttttctgcc agggctactt
cagcagtaag tggcttactt 90660tgtcctcaat atattaatat taatatcttc tatgagccac
gcagagacct aaatgctttg 90720cttatattaa ctcatttact tctctccaaa acacatgtac
aggagagtaa ttatcctcat 90780ggagggaggt gggactgagg cagtgggagg actcggtagc
ataactgaag ttagcagcag 90840caacatgggc cctgcagcct ccattgcttg gcctttactg
gcccaggcac ttaccatgac 90900tgcatctaat cattgcacca gcctgtgtgt tgcaggtgct
attattatcc ctagcttgca 90960ggtggagatg ctgaggctta gatagcgtta ggtatcagta
ctacaaggca tcagcagggc 91020tagaaccaca gactctgttg gccttaccct taactactct
gctaaactcc ctctggcgct 91080gggggtacgc atttttctca aatgttagac tctctccctc
tgactttgtt gccccttttt 91140ttctgttttg ttttgttttg ttttgttttc caactgtact
accttttcta acccacactt 91200gcctttccct gttctgtcct ctgaatctgc gtctgcagac
gtggcttcct cttccgaatc 91260ctacctctgg gccagcctgg accctgaagc tgttggcttc
ctagttgaga ccactgggcc 91320agaggcctct tgcttggtaa gggctggttg ggtgggactt
ccttgccagt tctttgtgct 91380gcttgtgaat gttagctggg cccgtgttct gtgtgatttt
aggaaactct gtgcaggtgt 91440tattattaca gcctgtccag ccggaaccca aacccactgt
ctaattgcct ttaaacacat 91500ctagggcttt tttagatggt gaaggagctg gtggtgccct
tcagactcta gccccattta 91560atgtttatat gaactcagca attactcttt tgatgttgag
actgttgcac atgttcataa 91620tttccatgag tgtgtgtgtg tttcttaaga cacattaaag
ccctccgagg aagtcctgtc 91680attgtattgt gactgacttc tggtatgacc aacttttctc
cccttgacaa agaaaaaaca 91740ggcaaaaaaa attctaacat attcctaagc aaagctcttt
tttacataag agagcatttt 91800gaatagcttt cctaattcta ctattgtttt ccaacctttc
ctcactcgtg gacttccttt 91860ttcttttctg gcctgtacat cctatactat ttagcattta
atgaataacc tttttctttt 91920aatttactaa catcctctct cccacctaaa tgattttaca
tatgtaaaaa aaaaatatat 91980atatatttgc aggggcgcgg tgggaaggat acagggtctc
actctgtctt ttgggctgga 92040gtgcagtggt accatcatgg ctcacttgta gcctcgacct
cccaggctca aatgatcctc 92100ccacttcagc ctcttgagta gctaagactg tagatgtgcg
ccaccatgcc tggttacatt 92160ttttaccctt tttttttctt tttctttttc tttttttttt
tgttttgttt tgttttgaga 92220cagagtctca ctctctcacc catgctggag tgtggtggtg
tgatcttggc tcactgcagc 92280ttctgcttcc ctggttcaag tgattcttgc ctcagccacc
tgagtagctg ggactacagg 92340tgcacaccac cacgcctggc taagtttttt tgtactttta
gcagacacag ggtttcacta 92400tgttggccag gctggtctcg aactcctgat gtcaagtgat
ccacctgcct cggcctccca 92460aaatgctggg tttacaggca taagccacca tgcctgacct
aatttttctt ttttttgtag 92520aggtggggtc tcactctgtt gtccagactg gtcttaaacc
cctggactca agcaatctcc 92580ccgcctcagc ctcccaaagt gctgggttta cagatgtaaa
ttattttatg ttaaaagaaa 92640ctttatatca ctttcacaat ggaaaaccaa agtcacttgc
cataaagtgc caccgtaagc 92700ttatgttcat ccataaacca tctaaaatca tctctaactc
caagggtatg tgtatgactc 92760tttgggaagc agttgtttgc caaatagcca gctaaggcca
ttgcaggaag gaggaaccag 92820aggaggaatt accttccgtc tgtggagtag agtcccgtct
tctggagtct gtgaccttcc 92880tgtatagaga tttgtcaaat tttcagtgtt agatttggaa
aggaaaagcc acttaataac 92940atgacatttt ccccactagt ctcccgtttc tatttactga
aaaggttgtc cgtgctgggc 93000agaagattta ttctagggca taaaggtatc ttttatcaac
ctctagatac catggaacag 93060tagttctgtg gacatttcaa gtaaggcata ttggaagcta
tcttcgccct taacttttag 93120acttacaact ctaggttttc aagctagacc cggaaatgaa
atcagcaatg gtgtttactg 93180ctaattattg cctttatagc cacccacatt ctgaaggcct
tgtaacagac agcacgaaaa 93240gattggtctg cctcagccaa ggtggggctg aactggtctc
tttccaagct gtgttggttg 93300tttttgcctg gttgttcagg cggaagacaa caacatttag
acacttaaaa atggctgacc 93360caggttttgg aacccagaca ggcattttca agtactgcat
tttccaagaa gacttgaaaa 93420agtccagtct atccaattac tgagcccttg agtatggcag
tgaggtttga ataatgtcca 93480gcactcggcc ttaactccct ttcacaaatg aaaggttaaa
tgctggaagc aggagcacag 93540catggatttg ctgtgctctc ctgttttctt tgccaaagtc
acttttctcc agtccttctg 93600tggtgtcact ggacaaagtt atattgtgtc tgtatttgct
agcctggtgt gctccctgag 93660tgggacccct ggtcttgggc aactactgca tactatttgt
gcaaagcaaa tattttcttg 93720gcgggtggct ccaggttacc ttggctttca cgactctgac
taaagaatga aagattgaat 93780tgatgtcaaa actgtgcttg cagcctgcaa tccaaatgcc
tgccgggcca gtggccgagg 93840cctacaaccc aaaggcgtcc gtatccggga gaccacagat
ttcaaggttg acaccaaagc 93900tgcaggaagt ggggagctcg gtgtaaccat gaagggtcct
agtaagtgtt cctttgtttc 93960tctatctcag gtgtggtttt ggctaacttt gcagccatgg
catatggatt tcatcccacg 94020gccagttgtc ctcaataatc ccagaaggct atgtcaagga
tttgaggcta tctgggctcc 94080ttggggaaga cggcagtgat tgattagtaa tgtctgccct
ggatgcggcc agtgggtggc 94140ttgacagctt tacattacat caagacttct gggagtagaa
aaagcagtga tgtaaaggag 94200ttggggaaat gctgctgttg gaacaagtgg ctcatttttt
attttagaca tctgggctca 94260gagaggaagg ctcttgccta aggtcataca gcgtttgtaa
tcatctgagc tggaattcaa 94320gcacagtctc caaagccagt gattttccca ctacaggtta
cattttatag agtatgaaat 94380tatgtcaagt acttaattac tatgatcagt gcttatagaa
ggagaataaa attccctaag 94440attaagtttt ctttgtagat aaatgccatt tgtggaggta
caggttaaac cctgcaaccc 94500attctctctc cctcttttgg ggaaggagac agcagatgtg
gggatgggtg tcttcacttt 94560tttcgttgga acagagaagc atttcagcac ttctagtctc
gggtgtagca gcctttggtg 94620gttttactcc catgcctgtg gaatcttgag cttcctgtac
caggattgct cttaccttct 94680gtgttcccaa caggctgggg caggagcatt ctgagctcca
gaaagttaat atttgacttc 94740acagcaccag gctttgggtc aggctgtgcc ctgagggtag
ccgaggttct agactgccca 94800gacctggagt caagctgctt ggggactgtc ttccctccca
gattattcca acaggagcca 94860aggagggtgt gtgtgtgtgt gtgtgtgtgt gtgtgcacgc
gcgtgcatgc ctctgcgtat 94920gtgtgcgtac gtgtgtgttt tctcctgacc ttgaatactt
gcttgactca acggctttcc 94980tggccaaacc tcagggctca acacaaaaca agttcctgcc
tgatggctgg gtttggagtt 95040tgcagcgtca catctaaaac ctgtcctctt gcagatagcg
tctgaggact ttcttgcttt 95100tgttgtccag ctttagatgg aaaagtatac gctggaacac
tgaacctaaa actcatacca 95160aatacttcta aaggtttact tcttccccag tttttgtggg
ggactaggaa gggtagctat 95220gattattggg aaatactgaa atgtgactgg atttatcttt
atgcaggccc agggagttca 95280ggacctcagg gcccctcgta gccaagcaag atttctaaag
ccaattagct gggaaatcct 95340ccatttcctc ataccttgaa gcagagatgg ctgtgttttt
agctttgaaa taatctccca 95400ggctttgagg ggagaggtcc catactctgg ggcagcccac
ttggttttta tgtatggttt 95460atgttttgtt cagtgtggct gcctctctgt tcttgtcctt
ttgattctca ttttgggcct 95520aggattgtgt tggaaagatt atctccttcc ttcccacaga
gggtctggag gagctggtga 95580agcagaaaga ctttctggat ggggtctacg cattcgagta
ttaccccagc accccgggga 95640gatacagcat tgccatcaca tgggggggac accacattcc
aaagaggtga ggctcctgct 95700gcagaggggt cttctctgga gggtgctcgg cccagggcgg
actcatgggt agttgcttcc 95760cgggctgcag gagggaaaga gatctgcttt gttgaaaact
tttttttttt ttttttcgga 95820gcagcacaga catttggcct gttctcaaaa gcagcagaaa
gttgctgtgg ttttagctga 95880cttgctttaa atcaaatgct ggtggttagg ggctggtggg
aggcagggga ggcagaagga 95940gcagttagag caaatgggct gtgtgtctag atgcccgcat
ataaactgag attctctttt 96000tcaatgaact cctttgttca tgaatgccac ggggcagaat
ctgctgtggt ttacattaag 96060accgtctacg tgagtgctgt caggggccaa gggacgcagt
ctacagcttt gccttgtggg 96120cattgcactt gcccctctgc gttctgtgtt ttccagctcc
cctggaggtg caactttaaa 96180ctccgaataa attcagttag ccttgagaaa tatttgggca
ttattgggtt ccgaatacct 96240accacgcttt tttttttaag cctcccatgc caaggttaca
gcacattcat tcatgtatga 96300gataaagccc attcaaccaa gttttctggt tatagcataa
gcaggatata gtgtgtggac 96360tctctcactt tccagggtca tagtctgggg aggcctgcac
acaaaggtaa agggccagga 96420ggctggtgca aagcagcgtg gcttgagtgc caacccagtg
gccacctgag ctcccagaag 96480cagtcacatt acattatatt gttgacataa cagtagctat
gggtgagagg cctgcaggag 96540gaagggcttg gctgcagttt gggatgccag atgaaaggat
caggcaagtg gaaagaatgt 96600gcaaaggaac tgcagcttat ggctatagtg acaccttact
ttactcttct ttgatgcttc 96660ttctattcct ttccctgtag cccctttgaa gttcaagttg
gccctgaagc gggtatgcag 96720aaagtccgtg cttggggccc tgggctccat ggtgggattg
tcgggcggtc agcggacttc 96780gtggtagaat ccattggctc tgaagtgggg tctctgggta
agtggacaca gctgaccagc 96840atcttctgga ggactgagga ttacagggct tccgggctgt
gtcaggctgg atgttggggc 96900cttgcctagc ctcaatacct ttagcttcct ggcctcctgg
ccaccctaag ccatctctgc 96960gtgctgctgt acatttgcag ttgcctctga taccagcatt
gattcattca ggagaccttg 97020agggcagaaa ccttatgtgg gtattgtgcc taaaacaatg
cttggaacgt agtaaacact 97080tagcaaatag tgttgactga cctttatagt ttagatgaat
gaatgaatga attttgctga 97140aatttggatt tggaagataa atatttcctt tggagcacag
ctgaagtata ttttaaatac 97200atgtctaatg tatatatgat cattttatat caggagtcag
ccagcttttt ctataaaagg 97260ccagatggca aatattttcc acctgtgggc cttatggtct
ctgtcacagt tatttgactc 97320tgccgttgta gcctgaaagc agctatagga atacgtaaac
aaacgtgtgt ggccatgttc 97380cagtaaaact ttatttgcaa aagtaagcaa tgggccagat
gtggccttca gactgtcgtt 97440tagcaacccg ttttaggtaa tagcaataag caaaagagaa
aaataagaaa tcacatttaa 97500ttttcccttc tagagagatg atatgaatcg tcttgtatat
tcttagtcta gagataatat 97560taagtctttt agtgtatcct tctagacttt tttctctata
tatgcatgca aatattgatt 97620tggtacagaa aatatcttag acaagtcttt atatctttat
gcgtaaatat agggtatgcc 97680ttcattttcc atagcttcca tggaattcca ttgtatggct
ctatccattg tcaggctctt 97740cagttatttc cagggttttg ctataaaaac agtgctgact
gtgtatcctt ggtaattgcc 97800ttcagataaa aacccagaag tggatttggt ggtgctaaga
gtgggtgttg gttcaaggct 97860tttgccacat gttgccacat ctccaacaga agggtttgct
ggttggactt cccctgttgg 97920atgatgataa aatacatata atgtatttaa tactatatat
atatatatat atatatatcc 97980tcctggcctc aagtgatcca cctgcctcgg ccctcccaaa
gtgctgggat gacaggtgtg 98040agccaccaca cccagcccag gcctacattt gaaaaaaaaa
aaatatatat atattttcca 98100ccccttccat ctctactgaa gacttaatga gcttggtttt
ggaagaaagg gatacaaaca 98160gatttcaatc ttctggccaa cacttggctt ttagggaggc
agcgggaatg agctgtcgta 98220acatagaata ggtgctttcc accatataac cagggagacc
cttccacctc caccccctag 98280ggtttgccat tgaaggcccc tctcaggcaa agattgagta
caacgaccag aatgatggat 98340cgtgtgatgt caaatactgg cccaaggagc ctggcgaata
tgctgttcac atcatgtgtg 98400acgacgaaga catcaaggac agcccgtaca tggccttcat
ccacccagcc acgggaggct 98460acaaccctga tctggtgaat cagctgctgt gcttctgtct
tcttgtccct ggcccctggt 98520tcctcacccc catgcccgaa gttgccttaa gcagcatgtt
gagagatggc agagaggaat 98580catttggatt ttaggaagga aacaggcctg catttgtttg
tttgtttgtt tgtttgtttg 98640tttgttttga gacagactct tgctctgtcg cccaggctgg
ggtacggtgg catgatcaca 98700gctcactgga acctctgcct cctgggttca agtgattctc
gtgccttagc ctcccaagta 98760gctggaacta caggcatgtg ccaccacagc tggctaatct
ttgtattgtt tagtagagat 98820ggggtttcac catgttggcc aggctggtct cgaactcctg
gcctcaagtg atccacccgc 98880ctcggccctc ccaaagtgct gggattacag gtgtgagcct
ccacacccag cccaggccta 98940catttgaatc ctggtagtag cacttagcac ttttatagtg
ttgggcaagt aacttaccta 99000tctgactctt ggtgtcttcc tctataagac aggaatgata
gtagtctctg cttctagaga 99060gcttctagga tgattcagga ggtggcatgc ataaagaccg
cctttggctt atgcctggcc 99120catgcaggga gctccataag ctgttatttt cttgcaactc
cggggatcat atgtcagtct 99180tacagccatt ttctatagtt attatttcaa ggtgctccat
agataaagga tttttttttc 99240ctagttccgt gtctcttaag ttggagcaat gtttccaaga
gtgtcctctc aaacccttag 99300caggctgata agcatcaagt ctgagccagc ctggctgaca
gggagttggc cccagaggcc 99360acgtgtgcta ctgttggccc acacgggcag ctgtccatag
gctgatgtca gtctgggctg 99420gtagctaccc cgttttggcc aaatgatatt cctttgccct
ctagggcaaa tgttgtccgt 99480ggtaaagatt ctgagtcccc tcaaagtggg aacgttgaaa
ctgggcatga ctagaggtct 99540ctgccccagt tgttagaagt tctttaggtc aactcagaat
aaggcaggga gcatgggtta 99600gtttgggcat ggttttagaa caggggtttc caatattttg
ccttccctgg gccacactgg 99660aaggagaaga attgtcttgg gccacacata aaatactaat
gatagccgat gaacaaaaac 99720aaaaacaaaa aaaaaattgc aaaaaatttt ataacatttt
aagaaagttt acaaatttgt 99780gttgggctgc attcaaagcc atcctgggcc gcatgcgggc
ttcaggccgt gggttggatt 99840tgtttagaga gttttctccc ttatgaggga gagacatttg
tttttaagtt acaacctact 99900ttagcacttt acttcccata accaacctct tatgtggata
ctgtaaaacc agacacaggt 99960cattttgttc ttcccccacc ccctggttac ctgtctttgt
ataagggttt agttggggca 100020ttacacagaa agagacttac tatctgcctt tgcttcaggt
tcgagcatac gggccaggtt 100080tggagaaatc tggatgcatt gtcaacaacc tggccgagtt
cactgtggat cctaaggatg 100140ctggaaaagc tcccttaaag atatttgctc aggtaaattt
cagggggcca cctgtgcagg 100200taattgtcag gtaacaagat ctgaccacgt aatggcaagt
tgctgagtcc atctgatctt 100260cagtttcctc atctgcaccg tggaaatgat aagaagatta
tcttataggg ttatgtgagg 100320gttcagtgag actaccatgt agagtactgg gctttaaaaa
aatcagcttt ctgatttata 100380ttctgtggaa atgaggcttg tttgtttcag gttattctat
aatgtctttt ggtgtggctg 100440aagctgctga ggccatgggg ggagatttgt aaacaaggat
ttaaaaagta tgtttattta 100500atctaattga atttggccaa aggacttaaa tgcaggaatt
gagtggccaa agctttgttt 100560ttgggtcact tgctcttaat aactaaaaat aaataaatgc
atgtcatatt ttgtcactgg 100620ttgtcaccgt gttgtgaaaa tatggcacat tgtagttggt
ccatgaagtt ttgttgtata 100680agcaagtggt gacttggctg tcttgggagg ccacagtgac
cctgtctgat agagacagtg 100740tgagggccac ctctggtcct agctctggct tttttgcagg
atggggaagg ccaacgcatt 100800gacatccaga tgaagaaccg gatggacggc acatatgcat
gctcatacac cccggtgaag 100860gccatcaagc acaccattgc tgtggtctgg ggaggcgtga
acatcccgca cagcccctac 100920agggtaggtt gtgaggcaga atcctggctg ttttatggaa
atgcctggtc atacaccagg 100980tctgggatcc atgcctgaca gccaaggcag acatatggaa
ggaacccatc cctggtgggc 101040cttgaatgat ggaggggccc gaagggcaga gtgctccagc
ctgctcagaa gaactatttc 101100taacaatgtt ttttaatagt attttactgg gtccaagtgg
aggagaactt gatgaccttc 101160tccatgtctt ctctaggtca acatcgggca aggtagccat
cctcagaagg tcaaagtgtt 101220tgggccaggt gtggagagaa gtggtctgaa ggcaaatgaa
cctacacact tcacggtgga 101280ctgtactgag gctggggaag gtgagaaagg gctttgttca
acccagtgat cattgctccg 101340tggggaaggc agttcttttc ataacgtttc aatgcctttt
gaactaggaa gtagtccatc 101400tgaataggta atcatctact gagcctctga gtcattcctt
agtgatatct ttgctaatcc 101460atcatccctt tccccaaatc cttactcttt ctcaggtttc
ttactagaaa cttcccaatt 101520gctttttgag ggtgttaacc tgagctggaa gagattgcac
aggacatgct gtttcttgta 101580agctggtgct aataagctgg tctgttccag gtgatgtcag
tgttggcatt aagtgtgatg 101640cccgggtgtt aagtgaagat gaggaagacg tggattttga
cattattcac aatgccaatg 101700atacgttcac agtcaaatat gtgcctcctg ctgctgggcg
atacactatc aaagttctct 101760ttgcatctca ggtacgtggt ggggcctggg aggagatggg
tggagtaggc ctggattctc 101820tttggccact tgtgtgcatg tctcatctac tttttggtgt
tttgttagta ttattatttt 101880tgagatggag tctcactctt tcacccaagc tagagtgcag
tggtgtgatc ttggctcact 101940gcaacctctg cctcccaggt tcaagtgatc ctcccacctc
agcctcccaa gtagctgggg 102000actacaggct cataccacca cccagctaat ttttttttaa
tttgttttta tttttttatt 102060ttttttttga gatggagttt tgctcttgtt gcccaagctg
gagtgcaatg gcatgatctt 102120ggctcactgc aacctctgcc tcccgggttc aagtgattct
cctgcctcag cctcccaagt 102180agctgggatt acaggccacc acgcctggct aatttttttg
tatttttata gaaatggggt 102240ttcaccatgt tagccaggct ggtctcaaac ttctgacctc
agatgatacg cctgccttgg 102300cctcccaaag tgctgggatt ctaggtgtga gccaccgtgc
ctggccactc agctaattgt 102360tttgcatttt tagtagagac ggttgcccag actgctctcg
agctcctgac ctcaggccca 102420cctggcctcc caaagtgttg ggattatagg catgagccac
cacatttggc ctcctttttg 102480gtgttttact gacagggaag ttgtcttgag aacactgctc
aatcgttttc tctctggctc 102540cttacaacca agaaggaaaa aaaatttacc cagagctaaa
ttattaccac tttctaacaa 102600aagtgaggca gtgtgttcag tggttaaaag caggggtctg
gagagagact agtttgtaat 102660aaattttcat caatattttg gttgaaatgc agttagcttc
tagatatgtt ctactttgat 102720gcctttgaag caatgactgt ggtctccacc cttaaatttt
tatagagaga ggtgatttga 102780agtttcaggt atgcaatagt gaagataggg tgagcaggat
cctgaaagag agaattttga 102840aatcctaggg attaaaatta accttacata aaaatggaaa
tcttagtaga atgttctgtg 102900cctaaaggta gtggtcttga catccattta acctcttctg
cctttattcc aatagtctgc 102960aacattcttt ttgaagaatt ataatcattc tgtctctgat
cacttcttgc atttccccag 103020accttagctc tcagctgtcc ctggaggaca tttccttccc
ccagccccat gtattattgt 103080cgtttttggt tttattcttg ttggcatttt tcatcctgag
tactcaacat tcagtattaa 103140aggctcaaag tcctcgggtt tgtttgtgac atcagggatc
caggcattag agagtgacct 103200gttatagaag gccctttccc aatgctgggc ccttttggct
tatcttaccc ttctgtttac 103260ctgtggtaat agaagtctgc tcaccactcg ctaagtcaga
gtgatgctaa ggttcaccct 103320ttgttgaagg ctccctgagc tctggctgtt gcttcagggg
ctttcctact aagactgtgt 103380ctctgctaca ggaaatcccc gccagccctt tcagagtcaa
agttgaccct tcccacgatg 103440ccagcaaagt gaaggcagaa ggcccagggc tcagcaaagc
aggtaagatg gcacgtctag 103500gttgtcctgg gcccctctgc cagccggtgg cactgggcgt
gtttcatcca cggccttgag 103560gaacttcatc tccaccaaca ccaacaccaa gctggcaggt
tttctgtgca gctctgatgc 103620agcagtggct ggccaggccc gttgctggct gtcataatag
acctggtgct gttgaacctg 103680tctgacgggt tctcaaagtg aaactactcc agctggtctg
tctcctcact tcacagtata 103740tctttccagg tgtggaaaat gggaaaccga cccacttcac
tgtctacacc aagggggctg 103800ggaaagcccc gctcaacgtg cagttcaaca gccctcttcc
tggcgatgca gtgaaggatt 103860tggatatcat cgataattat gactactctc acacggttaa
atatacaccc acccaacagg 103920tagggtcctt ctcccctctg ctcccctggc ccccagccag
gcccctttct atgcagtcgg 103980tgctgggtca ctgtggacac caaggggtgt gagaggtgct
ctgccaaagt gctccctgat 104040gggaggcagc tcctggcact ttgaacccct ctgggagcac
ctataggaag cccaatgggt 104100tctatcaggt gaactgcaga attccccaaa agcaagcagg
aagctggtcc catatctcca 104160cctttggttt gcattttatc agagaaatgc tcagttcttg
atattcaggc cctaatatct 104220atctttctgt tacacatgtg cacacatgtg cacacacaca
cacatacaca cacacacgtg 104280cattccctcg cggcctcacc agctgccttt tagtcttttc
attaattacc cacagaaaaa 104340gagctgctac acctttgtgt ttccttcctg gtccttttag
cttagtttac cctttttatg 104400aggtgttgga atgaggtctt ttctcaaaga gccagttcag
cctttcgtcc ctaaggccca 104460gcacactatt tagggcagca aattattccc ctttacaaaa
tgcaggattt cacatgtgat 104520cttaccatct aggctggctt actctgatta tttcaggcca
taagggcctt aaaactgcct 104580ctctgtacaa gttaatgttt atttgtttaa aaacattaaa
aaaaatttgt atcgtggtaa 104640aatacacata acacaaaatt taccgtctta accattttta
agtgtatagt tcattagtgt 104700taagtgcatt cattatgtcg tgcacccatc accaccatcc
atctccataa ttctttacat 104760cttgtaaaac tgaagccctg tatccattat atttgtttaa
aattttgttt cgcttcatgt 104820tcacacctct ggggtctgga gagcagacat cctggcagaa
aagtctggat tttaatactt 104880aagcctagtg ttcgaagtgg ttgttccaag cctctgagat
tcctttattc ttaagggaaa 104940tgatcctgct gtgtttgaaa tgccatttgt aggagaagaa
gggcaacgct ttctgcagaa 105000gcactgctca gaagccttgc tcccgtctgg gtcctctcag
cgaggagcag tcaagagtca 105060agtggggaag aaagaggatt atagtgagga aggggtcatg
gtgtaactgt cccctgagtt 105120tgggggctgc actcccttgg agatggaatc cttactgtga
gaacatccct gcagtgggag 105180ggattccctg ggcgaaggga ttctgtgtgt cgtgttataa
atgtggcccc ttacatccag 105240gcttgctgct gtttgtgctt tcttccccaa atttttattt
ttatttattt attttttaga 105300caaaagtctt gctctgttgc ccaagctgga gtgcagtggc
atgatctcag ctcactgcaa 105360cctctgcctc ccaggttcaa gcgattctcc tgcctcagcc
tcccgagcag gtgggattac 105420aggcacatgc caccacacct ggctaatttt tgtatttttg
gtagagacgg ggtttcgcca 105480tgttggccag gctggtctcc aactcctggg ctgaggcaat
cctttcacct cagcctccaa 105540acctgcggat attacaggca tgagccactg cgcctgacct
cagtatttgt ctttttgtga 105600ctgatttatt tttcttccta tatgtcctcc atgttgtagc
acgtgtcaga acttcattcc 105660ttttcgaggc tgcattccac tgtatgtata tatgttttgc
ttctctcttc gtctgttttt 105720tgtttgtttt ttcttgagac tcgctctgtt cctcaagctg
gagtggcact gtctcggctc 105780actgcaacct ctgtctcctg ggttcaagtg attgtcctgc
ctcagcctac cgagtagctg 105840gaagtacagg cacgtgccac catgcccagc taatttttgt
atttttagta tagatgtttc 105900accatgttgg ccaaggtttc accatggggt ttcaccatgt
tggccaggcc ggtcttgaat 105960tcctgatctc aggtgatctg cccacctcag cctccgaaag
tgctgggatt ataggcatga 106020gccaccgcgc ccggccatct tcatttgttg aagaacattt
gggttgcttc cgtcttttgt 106080ctgttgtgaa taatgctggg tgtacaaata tctctttgag
tctctgcatt taattcttgt 106140gattataaac ccgaaatgga attgctggat catatggaaa
tctcttttta attttttgag 106200aaactactat actgtattcc acagtggctg cactacttta
cagtcctgcc aacagcatgc 106260aagggtcctg gtttctccac atccttgcta acatttgttt
tttttctgtt tttttttttt 106320gttgttgttg ttgttgttga tagtgaccat cctgttgagt
gtaagatggt gtcttattgt 106380ggttttgatt tgcattttcc taatgattag tgatgctgat
catcttttca tgtgcttatt 106440ggtcctttgc atattttctt tggagaatta tctacttgcc
catttttata tcaaccttct 106500taattttatg ttgagtttta ggaattctcc atgtattctg
gatattagtt ccttatcaga 106560taaatgattt gcaaatatat tctctcactc cttggtttgc
cttttcacgc cgttaacagt 106620tctcgtgtgc aggttataaa cgcggcttct tatctccaga
cttgctcttc ctgtgcttta 106680aaataaaaaa tccaaaacaa aacattcatt attagtaatg
ataaaactaa cacttttata 106740gatagagcat tcttttctca tcaggccact caatagtaag
taggtaatta ttttcctgct 106800gatggttctg agggttggtg ggagccttac tactgggtgc
accacgctga atcttctttg 106860ttgccaaatt ctccatattc tttaggagaa agcaccagaa
agccatagct gtctgcgtac 106920aatgactggg atcacaaggc catgacgtct tctaaaaaca
ttttgtgact tctgctttat 106980tctatgtcta tatgcctttt agtgttttgg ctgagccgtt
agaaagtaag ttgcagatat 107040caggacaggg tcagggtttg acctgcatcc ttggaaagga
ctgcagaacc cagtacccca 107100gacgtcccct gctgctggtt gaggcagaag tggagattag
gagcctaggt ccggttttgt 107160cccctttgaa gtaatgctgg agtgggaggc tccttacttc
agagtcaccc caaggtcaca 107220ttcatccagt tctctgatag cagcaggttt gagaactgct
gccatgctga gtactcactt 107280agggctttgt gtccggatgc tcccaggatg cattcaagga
gccgggtggg ccttggtggc 107340ggtcgttgcc accaagtggc aacatccaag ctgcttgaag
ccacccacaa ccccacaacc 107400aagagaagag aagaccaaag tcctcaggta aatcacaagt
gtgaatgact tgcagggtgg 107460cactggggtc cttcttgttg tttgttgctt ggagctgggt
ttattgtttc attatttggg 107520caacttgcaa ttctgcctat ttttctatgg caaagaacac
attaaatctc tccttagatt 107580gaatttcctt cccaccccca cccccagcac agagcctggc
cctataagtg ctctgtgtgg 107640attaatggct gtgagtgagc gaataaatga catggcgcct
ggattcacaa gcggagatgg 107700cctaagaacg ttgtaatctg gtagaggagt gatgccaaca
cctcctcatt ctcctttgaa 107760ctctgttttc tgaagagcag ctaaaagctc aagactgggc
taaggaagtg tgcccttgga 107820tgtggttaag agacctgggt cagcccagaa agccaccccc
tgacacgggg gagggagcat 107880actttgaggg ctgacaccca caggcacacc ttctcatggt
agttttaggg tataacaggc 107940tggaaatccc cagaaaggtg gctgcttggg catgggtgtg
tcctggcctg gtgtgggcgc 108000ttccccctca gaacacaggc tgtgccacgt ggggagccga
ggtcctgcct gagtaaccca 108060ggtccctgat tgctggtttt gctccctgac acctgcaggc
ctgccactcc acctcgcaaa 108120gtccctgagt gacagcttgc aggtgcttgc ctgcctgggg
tggatgagtg atgtggatgg 108180ctgtaggatc ctgtgagtcc cttgaggatg caaaagtaga
gcgcgttttg ccttagagga 108240atggacttgt tggcttgggg cttgaggacc ctcccagagg
tcaaagactc ggttttatag 108300aagggaagtg atttccctga ggactttggt cttctcttct
cttggttgtg ggtggcttca 108360agcagcttaa atttctcacc gcacgttccc ctgcgcagag
cagtttgaga agctggtggc 108420aatgtctcca ttacgtgctg tgctgggagc cactaggatt
ggggaccact ccatgtagta 108480ctctggcacc tttagaaatc cctgtgagct cacagaccct
cacagagtaa cagcttctac 108540cttgaaatgt tcttaacgtg gtggtcctgg ctgctcctgg
agggccctaa aagggatggt 108600gctgagggtg gctctctcag tcccatcctc ttctgagctg
tctggtcagt gtcttgtgta 108660tgtatatttt gaagaataag attcaggttt cagaagcatg
tagaggagag tgaaactgtc 108720ttgcagcctg cgaagtcgtg gcgaaatgca ctggccatca
ctacccagac atccctcact 108780tcatagccct gttggggaat aaacacagtc cattccttag
ttggggcctc aggggacact 108840ttaaaatgct gtaggcattg taggtgtaaa tctccgagat
tttttccctc ccccttctta 108900ggttatttaa ggtacagttc attttctatc tgagtttttg
ttttgttttt gactggtaac 108960aagagcatac tttcttttat gggatgggtg ggcttaactg
gaagagggtt tttccctctc 109020ttttttagca cttcagagaa gaggccagaa aactttatgc
gggtgaggga ggaggtatcc 109080ccaagacctc tggttagcct gaggtctgct tagtgagccc
ctgaattgtt aggggctgtg 109140gggaaacgga agctcgggaa gagttggcac gttgggaatg
ccacgttggc tgaagtagcg 109200agtcagtcct gccttaaaca gtacaaaaag gagacctttc
ctgccccttg gctggctccc 109260agctctgttg aatttgacct gtacacattt taccaggaaa
tgttgttcac atgaggcagg 109320gggccaattg gttttgtgtg cagtgcttaa aaatgctgga
aaattaatcc tctcttcatt 109380gatgcaacca gttttttttt ttttttcttg gcctttaccc
ccttccttat tacaaaagga 109440atgtgacaaa atatacatag gccaaatgct acaccctttt
aacacttgat cagcaacagc 109500tttcagcagg gcctgcattc cagcaaggct gctggattct
tggggggaac tcgtctctcc 109560ctcacacttt cctgttacat tatgcctggc cgattgtggt
gaaggggatc ttgatctact 109620gagacagcca tgagatttct tggagcctcg atttggaggg
agggaacttg gccaaccatg 109680gagagaagaa gccggctgtg tgccagcctg gaaccggcga
gaggagagaa atggcgcaca 109740catggctatc gcgtgccacc cggccacccg tgagggtgcc
tgccaatcct gcaagcacca 109800tctgccttca cacttgcaat tttattttct ttcacatgga
aatggaagtt cagatattgt 109860gcgatggtct tagcacaggt ctaggtgaac tcttgcaaat
ccctgttgca gcctgggggc 109920ctcaaactga ttcctaggac agaaatggtt ctgtttggtg
agtggcccca ggcccagctg 109980cactggctgg cactgggtat gatgatgggg aggtggtgtg
gcagagcagc taggacacag 110040atttgggggc catgggtatg aggcccagct cgcaccctta
ccaaggtgtg tgacttgggg 110100cacgttcctt taccagtctg agccacagtt tcctctcctg
aaaaaatgag atgacagtag 110160gaactacccc ttaggactgt tttgatcttg aattgaggaa
atgcataaaa gcacatagca 110220tggtgcttgg tgtgtagaaa atgctcatta agttgcttct
gttattatta gctgctctta 110280tttgatctaa tttttctgtt attcttgcct tgtggtcaaa
agctagaaga aatagatcta 110340agatactttc tacattgatt ggaatcaagt ctcccctgtc
cgtgagaaga atgagggatc 110400ttgaggggat tttaaatgcc aagttagctt tttggtaccc
aaaggtaaac tgagttttct 110460ctcttgttcc agggcaacat gcaggttctg gtgacttacg
gtggcgatcc catccctaaa 110520agccctttca ctgtgggtgt tgctgcaccg ctggatctga
gcaagataaa actcaatggg 110580ctggaaaaca gtaagtgcct gaatggagag cagatgggtt
gttgatgacc ccccaacgtg 110640gctgctggtt agattttctt caaaaggtga aatttgcaga
gaagcaaatt ctatgttaag 110700agactttgca gttgcacaga ctttggttcg aattaaggcc
gtggtgtgaa gtaactgtga 110760ctgtgtctgc cccttagcca caccgagact cagctttctc
atttgtacag tggggggtgg 110820tcggcgggga gaggttgaga acacccatgg gaatattttg
aaaattatat gagctaatgg 110880ttcagaggct ggcacgtagt cagccccctg gcattgcagt
aggaagtttt cattaaaaag 110940agaatttggg ctatgttgct ttctgatgag tttctaactg
tgccagctat ccttggcaac 111000tgaatccgca ctaaggttgc gagtcaagca taaatgccaa
atccctggca ctcagaagtc 111060actaccacca cacctctgcc ccatcccaat gttcctttag
cttgttaggg attttactag 111120tataagctca tttcgcttat tttcaatttt ctgattattt
tttagtaggg aaaatttcaa 111180acagaaaagg aaagagaata gtataacatg aacactgatg
tacttatcac tcagcttcag 111240atgtgcaaca catgctcata aaatgatttt tttatacaag
taaaaatata tccatttttc 111300atctaaaaaa cattacagtt aagggataat tccactttaa
ccctcacctc tccttctccc 111360tagggttaac caaagttttc aattcagttt ctgttcttcc
agatcttctc tctgcatcta 111420tacatataga tgtgcctgtg gaacacattt ggctgtattt
attttgcatt aaagttgccc 111480tgctgtataa acctacttct tcggcctgcc ttccaacagt
gcatctcggg aatcattcac 111540tcctacatct tttccgtctg tgtttactgc tgagtggctc
cagactggat gtacctcagg 111600gctcacattc acctggtttc aggcttactg aggcagggct
gagtgcatac ccccaggacg 111660gggcctcctg tattcacctg tgagggtttc tccagagtac
cactagcagt gccattagtg 111720agcatcttcc ttcactcgtg acccaagtgc acaagttgca
agcaaggcca gctcccagtt 111780gcagagatcc aaagtgagag ctcactgttg gcttttgtgg
ctggagcagc cagctctgag 111840tgtgtaaacg tccactgccc aaccctgtca tgtgtcccct
tgtcactcct ttccccaaga 111900cactgagagc tttgactcca gaacaggaaa agcagggtgc
caattaggaa agcctctttt 111960ccggtgggaa gtagcgatcc gggacctcct tgcctgtggt
tcggcagtgt ccatcttgcc 112020aggccctatg ttccttcaga gtcaaggttc tctgggttgt
ggcaggggcc ctgtgttccc 112080agtgcttttg ttttgggtaa agtcctttcc ctgttcttgt
ctaatctaac acttgggctt 112140cctgcagccc tgctttgcag agaccttttg gaaaccatca
cggtacagtc agttctcagc 112200acttgcttca atcggctcgc atttggcagc tctgtgactt
ctgctttctt gagggggagg 112260ggtgcctata agatggagtt ggctgccaag aattagtaaa
taaaacattg acttatgagg 112320gtgtttggat atcaagttaa caccaaaagt aagtaaataa
gagacgacag tgtcagatta 112380caactttctg gtcagcaaag attgtggggt caggtaaatt
tcactttgag tcccagcttg 112440gcaggctgct gcatatgtca ccctggacaa gttacttaac
ctctctgagc atcagtttcc 112500ccatctgtga aagccattgg ttaataataa ataccccata
ggattgtggt gaaaattaag 112560acaataacct atttgtgctt ggcatataaa atgcattcag
taaatgatag ccgttattgc 112620tgtcatcact aattgattat tgtgccgaca cttgttgtta
ctgaggctga gatgctgatg 112680atacttactc agctttgctg cttgtcctct gcagcagctg
ttgcttacag tggaggctga 112740gataagtccc cgtgtccaaa gaaccattgc ttctgtgctc
tggattgttc ctgctgctga 112800aaagggtcag ctcttcacct cagcttgtgt ttcttttcca
ggggtggaag ttgggaagga 112860tcaggagttc accgttgata ccaggggggc aggaggccag
gggaagctgg acgtgacaat 112920cctcagcccc tctcggaagg tcgtgccatg cctagtgaca
cctgtgacag gccgggagaa 112980cagcacggcc aagttcatcc ctcgggagga ggggctgtat
gctgtagacg tgacctacga 113040tggacaccct gtgcccggga gcccctacac agtggaggcc
tcgctgccac cagatcccag 113100caaggtcagc ctttgctttt gtcccagaac ttgtctcatt
gctgtcaaac atgacaccat 113160agtccttctc tggttcttcc tggcaaagac cttctgaaaa
tcgttttgtg atgaaagtta 113220gcacaattca ctgtgaaagg tcccctgggt aggtgggtca
caaccctgct cctcctcttg 113280ctctctgact acaagacttt ggtgaggggc tccctgtccc
agagtcttct ttcttcgctt 113340gttagcataa tcacagtcct cactacaaag ccagcctgta
aggggtaggt gagttagcaa 113400acgtggaggc ctctgcccag cacccagctc acagacggag
ctcaccctcc agaagctaga 113460atcatgtaat ataaaaatac attattctgg ccaggcgcgg
tggctcatgc ctgtaatccc 113520agcactttgg gaggccgagg cgggcggatc atgaggtcag
gagatcaaga ccatcctggc 113580taccacggtg aaaccccgtc tccactaaaa atacaaaaaa
ttagctgggc atggtggcgg 113640gcacctgtag tcccagctac tcgggaggct gaggcaggag
aatggtgtga acctgggagg 113700cggagcttgc agtgagctga gatcacacca ctgcactcca
gcctgggcga cagagcaaga 113760ctccgtctca aaaaaaaaaa aaaaaaaacc acaaaaaaaa
acattattct tggctgggcg 113820cagcggctca cgcctgtaat cactgcactt tgggaggcca
aggtggatgg ataacttgag 113880gtcaggagtt tgagaccaac ctggccaaca tggtgaaacc
ccatctctac taaaaataca 113940aagattagct gggtgtggtg acgcatgcct gtaatcccag
ctactcggga ggctgaggtg 114000ggataatcgc ttgaacctgg gaggcagagg ttgcagtgag
ctgagattgt gccactgcac 114060tccagcctgg gcaacagagt gagattccgt cccctccaaa
aaaaaaaaaa aaagttcatc 114120gtcatttctt catagtaacc ctgactcaag gggttttgga
agatttccag tggtctcaat 114180ggtgtgaatc ctatgaaggt gtcttatttg ttgaattaga
ggtgaaagcc tccttcctca 114240ctctttttta gaaacagttt agttttatta ttatgcagaa
tttgttgagc aaattgcaac 114300agcccaagcc acagctagct ccacaagagc ccttccatga
gccctcaacc tgggatctcg 114360tgtatctttg ttggaatgga cattaggttt ccaagtccag
gcctgtgatt tagaagggtc 114420aggttgggta ggagagagga gagtcttgga ggggctgctc
catgggggtc acacctctct 114480cctgtgggtt ttcgctggtg attgagttct gaggcatttg
ctgcattgac tgttgtagct 114540ttaactcgtg tgcacgtgtg acacataaag ccccaagaga
agggctgcct ggctcagatg 114600cacttccatg ctgattatat gcatgggtgt tgaaagcagt
gctggctgag cagcgatccc 114660agtgcagttt gactttattc tttgctcaaa taggtgaagg
cccacggtcc cggcctcgaa 114720ggtggtctcg tgggcaagcc tgccgagttc accatcgata
ccaaaggagc tggtactgga 114780ggtctgggct taacggtgga aggtccgtgc gaggccaaaa
tcgagtgctc cgacaatggt 114840gatgggacct gctccgtctc ttaccttccc acaaaacccg
gggagtactt cgtcaacatc 114900ctctttgaag aagtccacat acctgggtct cccttcaaag
ctgacattga aatgcccttt 114960gacccctcta aagtcgtggc atcggggcca ggtctcgagc
acgggaaggt gggtgaagct 115020ggcctcctta gcgtcgactg ctcggaagcg ggaccggggg
ccctgggcct ggaagctgtc 115080tcggactcgg gaacaaaagc cgaagtcagt attcagaaca
acaaagatgg cacctacgcg 115140gtgacctacg tgcccctgac ggccggcatg tacacgttga
ccatgaagta tggtggcgaa 115200ctcgtgccac acttccccgc ccgggtcaag gtggagcccg
ccgtggacac cagcaggatc 115260aaagtctttg gaccaggaat agaagggaaa ggtgggtttc
atttaaaaaa aaaaaaaaaa 115320aaaaaaagac aagctgggac ttaagggcta cctgaaactt
ggagctgcaa actcagccac 115380ctgcaggagc caggtgacat ataaggcggt gctcacctgt
tccctctgcc tcggggagta 115440gttggggggc cctggtgaag gttaagcaca ttgcatttct
ggggaccgtg ctactcaacc 115500cctgttttct gtttctccat ggggaacagg acctagcatt
gtcagcagaa tctctagttt 115560tttggcaaag gcagaaatct tgatttttct ctggaaactc
aacatacaac atgttggcat 115620ttaattggaa aaaagtttaa aatgtagtgt tgtctaacac
ctgcatgcca cacagcaggt 115680tagtcttcaa cctttaacct gtcctcgagc ccggtgtgag
cagtcgtgtt gtcacttagc 115740cgtggctact ctagaaaggc cttctttggg atggaggggg
ttaatattct tgatttgaga 115800gttagaaaaa ccagttttcc agttactgaa attggacttc
atgtgtcctg aagtgccaag 115860aaccttggtt ctggggtttg cttttgggtc tggggtactg
gtggcagtgt tagctatgtg 115920cttgctctgc agatgtgttc cgggaagcta ccaccgactt
tacagttgac tctcggccgc 115980tgacccaggt tgggggtgac cacatcaagg cccacattgc
caacccctca ggggcctcca 116040ccgagtgctt tgtcacagac aatgcggatg ggacctacca
ggtggaatac acaccctttg 116100agaaaggtga gccgccctgt cctcggactg gaccctcgtt
cagagctgcc cttggtcatt 116160gcctcctggt ggctggtact gatgcctgcc ccatgtgcta
ggcctgtctc agcagggcca 116220cgtgcagagt gacagagtgg aagtcagcgt ccgctgcagt
cacctgccca ctcagtgcct 116280ggcttgctgg ccttgtgtaa taggtgggct gggtttagcc
tcagtctcac ctcagcaagt 116340tatggggtaa tgtcatgatg ttgctcattt gtgccatttt
tctttgcgta tgaatttctt 116400tcttcttgag tattaggaat tataaaaaat ttcaataaat
agaaaaccat aaagaaaaaa 116460aagtgccatg tatatctcca ctacctggag atcggaagcc
tgcgatattc tgatatagat 116520attttcagtc ttcttgtgga tgcctgtttc ttctgtttca
cgggtttcgc tttttctttt 116580ggttaatggc tggatggtgt tttcccgaat gagagtagtc
tgtttaggat gactgacttg 116640aatatttgct tggttggggt ggagtggctt atgtgactgc
agatagacgg tttgtattat 116700ttaaaagtca gatcatacct acattactgt gggattgttt
tgttttgttt tgaaacagga 116760tgtcactctg ttgcccaggc tggagtgcag tggtgtgatc
acggctcact gcaggctcaa 116820cctcctgggc tcaaatgatc ctcctgcctc agccccctga
gtagctggaa ctgcaggtgt 116880gcaccaccac actcagctaa tttttgtatt ttttgtagag
atggggtctc gccatgttgc 116940ccaggctggt cttgaactcc tggactcaag tgatctaccc
acctcggcct cccaaagtgc 117000tgggattata ggtgtaagcc actgccccca gccacattac
tgtgttttta accccctttt 117060ccaaataaca tagtatagca tgcagacttc gatgctagat
gaaactctga agtagagaat 117120catttttcac aaatagggga tttgtatgca aatatgcgtt
tctgtttgtt gttttgagca 117180ggtctccatg tagtggaggt gacatatgat gacgtgccta
tcccaaacag tcccttcaag 117240gtggctgtca ctgaaggctg ccagccatct agggtgcaag
cccaaggacc tggattgaaa 117300gaggccttta ccaacaagcc caatgtcttc accgtggtta
ccaggtaggc aaggccctac 117360atttggtgtc ttgagtctca cttttgtggc tagattctac
ctatgtgtca tggtttccta 117420acttttgata agatgaattt ttatttttat aacatgtatt
tccttctgta gagacttatg 117480ttacatagaa agaccaagca tacctaaaaa acataccaaa
gcacttgata atggtcatga 117540aactatttag caaaccagga gtcaatcaag ctctataact
tgataatgta aaaatttgta 117600gccaaccttg taagtatttt tattaaagtt ggttgcaagg
catatgcctg cgttgtactt 117660gcagtcctag ccagtgcaat tagataagaa aaataggctg
ggtgtggcgg ctcacacctg 117720taatctcagc acttcaggtg gccgagacgg gacaattgct
tgaggccagg agtttgagac 117780cagcctggcc aacatggcaa aaccccatcc ctacaagaaa
tataaaaatt agctgggctt 117840ggtagtacac gcctgtaatc ccagctacta cttgggaggc
tgaggcatgt gaattgcttg 117900aacccaagag acataggttg cagtgagccg agaccgcgcc
actgcactcc agcctgggca 117960atggagtgag actctgtctc aggaaaaaga aaaataaatg
aagcataagc attgaaaatg 118020aggggtcaga gtgtctttac ttacattata ctaatgtgaa
attccctatg tgagaggtgt 118080agtaattgag ttggggtggc tacgtggaat agtttataaa
gggaatttgc atgaattttg 118140gcaataagca gaccagcata aataaatggt gcacatttca
ctttcttttc cactctttcc 118200agaggcgcag gaattggtgg gcttggcata actgttgagg
gaccatcaga gtcgaagata 118260aattgcagag acaacaagga tggcagctgc agtgctgagt
acattccttt cgcaccgggg 118320gattacgatg ttaatatcac atatggagga gcccacatcc
ccggtgagct attcctcaga 118380gaggacccca gagaataatt gattttgcag gaaaatgggt
ttgattttgg ttatctctct 118440gagtggggaa aacaatctga tatttgtaat agctgcaaaa
ggagagtttt tcttagggct 118500acatctccaa gattatctca actcccagta gaaccggtaa
catggcaaaa agcatcggct 118560tagaattttg actggaaaca gttgtgcgtg tgttggagga
cctagttctt gattcagggg 118620aaagctggtt ctttacaaag ttgaaaatca cagtggctca
cacctgtaat ccccaaactt 118680tgggaggcca aggcatgcag attgcttcag gtcaggagtt
tgagaccagc ccaggcaaca 118740tggggaatcc ccatctttac aagaaataca aaacttagct
gagtgtgatg gtgcgtgcct 118800gtaatcctag ctatgtgggg tgggggctgt gatgggacga
tgtctgagat gggagcctgg 118860gaggttgagt gagctgagat tgcgccactg cgctccagct
tgggtgacag aggaagaccc 118920tgtctcaaaa aaaaaaaaaa agaaaaagaa agaaaatttc
taccttattt tgtgcttggc 118980tccttattca tgtgtcttgg tttctttttt ttcactgaca
atactagtag ctgatcaaga 119040tatgcagatt caaattcttt cttttgtatt tagtgatgtc
atgtgtaatc actgtgaaac 119100acggtttctc aactccggca ctatgacact ttgggctaga
tgattctttg tggtgtgggg 119160ctgtcctgtt cattgtagac ttttgtcagc atccctgccc
tgtacctgct agatgcccat 119220agcagacttc tccttcccca ttcttatttg tggcaaccaa
aaatgtctcc atatcttgcc 119280agatgtctta agggacaaaa tcacttcagc ctgaaccact
gctgtaaaga ttcaaacaat 119340aaataaatat atgacttaag tagtgaaaga ccctcctcca
tttgttttgg ggggaggact 119400ctccataggt tctagttatc tactcaaatg attgtcaccc
ccacacattt tatttattta 119460tttcaatagc tttggggtac aagtcgtttg tggttacatg
gatgaattct atagtggtga 119520attctgagac cacctccccc gcccccattt ctaaaagggc
aggcaagtgt gtggtgtgga 119580cagaagaccg agggctgggg ctgttctggg ccacttatgc
cttgtcttag gtgtggtgtg 119640aagagggcaa agccccaccc caggacccca ggagcagaaa
gagcctcagc ggggtcttgt 119700tcttctttct ctgggtcacg ctgagagggg aagggcaggt
tgaggggccc actgctgggt 119760tctgggttaa ctctcaggca gctggagtgt ccactgacca
cacgctttcc tgattccatt 119820cctgcttccc ccttaccaca tggaaatgtg cacacacact
cacactcact ctctctcaca 119880ctgatcagaa agtattgaca ttcaactcag actgattcta
ctcagatact catttaagcc 119940tcaagtcatt taaaacaaca tgtttctcct caaacttgtg
cttgcggctc attcaatata 120000gatttaaaaa attcctataa tcactagtct aggggacttc
agctgtgggc aagacaaagt 120060tcctgccctc agggagctta ctgtctaggg cttttacaac
taaaacttgt gatgactgct 120120atgaagaatg agaatggggc tcggtgacag aattcagagc
tacgggcttg ttttggagtt 120180ttgtaacact tgcgttagga gagagttggg cacaggaaac
gggtagaagg ctgctcccag 120240gaggggtgat gtggctccga cctggcaggc aacagtggag
atgaacatct cctgtggcaa 120300tgaaactttt tgactatggg gaaaggctgg tgagtgccac
cagcttccga atccccctta 120360cagaaagggg tcagagtttg tcccctgtgg ccgacctgtg
agcttaaagc aaatggtcgt 120420ctttgagcat aacaacagaa agacactcat ttgtggtttt
cccatcaggt gtggatggtg 120480cctttttatg tttcaggctc tctgttgcct cccagagagc
caaatgccgg cttttccaga 120540accccagaac tttcccaggc agagatattt agtgaagtgt
tggttggttt tctaagcatc 120600aggcttctta gctaaggcaa cctatggggg tactgccggg
aaacagtcgg ctacctgcca 120660ccttctaatt tgctttcatg gtaattctgg gtgcttaaat
attagcctag tttttcctgg 120720cctggttaaa aacccggagt ggagttattt ttaacaacgt
gtcctgtctt acccgtaatg 120780gcatgttgat ttcctgtggt aggccagctg tggttggttg
gtggcggctc cctagaccac 120840tggattgact ggggttcaga gtgcatgagg aagaagatct
ggcatgaggg aatggtgaca 120900tgtgtctggg catggaacag gggagtggcg gataatgctt
ggggtctgcc atcttggaca 120960gtttatctta cccgggtttg ttggtttttg gctactctca
tgctgagctc agacaacttc 121020tagtggaggc tctgacttaa agattggcct cagaggtagt
cccttgccat cagctgttga 121080cattgaaatc ctcaactgtc actctctaaa gtaaagcccc
cttttgttcc tctcacccca 121140gtgtggaggc ctgtgcttgt ttgccagggc cagccattta
tttcacgtag ctaaagacct 121200ggatgccgtt gaaacccagc tgttgttaga aagccaggga
ctcaattctt tgtgtgtctt 121260ggctgtctac catctctaat tctacaaagt ataaattctc
tgggatgcaa agcagagatc 121320cctcagcttt cacggcagtc attaactttg ccagatacca
tggggagcac caggactccc 121380atgcgaggca gaggtgcacg tagccccttg gtgatgggcg
tggtagcctg aggcatgctg 121440ccgttcgctg gatggggagg tccccctcca cagtggagtc
catgagtgtc cttggcctag 121500cccttgtttc tctgtttagc acttctctag caaatcacta
tctcctctcc tcgactcctc 121560tgtgcttcat ctttaaaact gacaccctca aggagtcaga
ggccctcagg gtcccccggg 121620gggtcagcca tgtagcagga gctcagctta cactcaggaa
gacggcaagg cttcaccagg 121680tggccgagtg accgagaagg ctgagtgtgg tcagaaggtg
ccagctgcat tggagggaga 121740ggagtctggg ggacacacag gagccatgtg tgggggacag
ggctggatgt gggctgcagg 121800gcctgcccat ctctctccgt tctgttgttc caccacttgg
cttcctcctt cagttgctcc 121860agcagcctgt ctcctccctc gcctctaggc tcctgcatgt
gctgaggcct ctctacttga 121920agcacctctc tgtctgctcc ctcttgtgcc gcaactgaga
tgttactgga aagctttctc 121980tggtctcccg cagaccaggt taattgcctc ctgagtgctc
caccttccac accccaaata 122040tgttatgtag gatgttagag tgacttgctt gcctcatcct
tctcctgcag ttgtgggttc 122100ctggggggtg ttaaccgctc aggatccagc acgtggcaca
acatctgcac gtagtaggtg 122160ttctgtgaga atggttgaca acaatgagta ggcacatgag
cagtgcacac agtgaggcag 122220ggggagctga ccgaggcctg catggccgag gtcccggggg
agcagcagtg ctattctggg 122280tgtgcacaag gtggtctcca attcccagct tgtgctcaga
atcccacaac ctctcttcca 122340ggcagcccct tcagggttcc tgtgaaggat gttgtggacc
ccagcaaggt caagattgcc 122400ggccccgggc tgggctcagg cgtccgagcc cgtgtcctgc
agtccttcac ggtggacagc 122460agcaaggctg gcctggctcc gctggaagtg agggttctgg
gcccacgagg taagtgtgca 122520ccctgccttc ctgcagacat tcatctgccc caggcagggg
cagctgtaac ccagagcaga 122580tgctttgctt ttgagtttgc tcatgagctt aaaattaaat
taaaaaaaat tattgtttca 122640tttctagtta aacagtagaa attcctgctt acaagtaagc
aggcttgtta tttctccagt 122700gatctgtccc cccatttaat aatatggcta tcaatttctt
agaggaagca gcagtatttg 122760ggctgtcata tgtaatatgg tggcgactgt ttcattatgt
gtttcagcat ttgtgagggg 122820gtgggttgct ctggatgtgg cagatggtgg ggtttggagg
tgataactca ttgagatatc 122880ttggtgtcca tgtggtacat accagaacct ctgggaatgc
caggcacatg atgcacgtga 122940tacgtggctt tgtcattgtc ttagttcccc agagagagag
tgtgtcttgg ggaatgggct 123000ttgttggcaa tttggcctgc cttgttggca gcttggaact
tgggtttggt aaggctagcg 123060ggccatatag ggacaaagcc ctgaagtgca ttggaacttg
ccttttttga taagtgacca 123120tgtttcctcc tccagcactt aaaatgtgcc tttctcccac
atagaggaca gtgtgcctaa 123180tttcttacgt aatctggatt ttcctcgcca atgatatgtt
cttggattca cagaagtggc 123240aaatggggtt ttccctcttt gaagaggaac cttctccttc
atggggttca gcaggaggtt 123300ttatcttttg aagctcaggg cagaaatggt ttgggggaaa
ttaggtcatg ggtctgggat 123360cagattctgt gaagttactg agcttcagga cctgcatgtg
tttgtgtgca tgtatgtgtc 123420cctgtgtatg tgtgaatgag agagggagaa aaagaagaaa
gagaagcttt acttggatat 123480ctgcctctat tatgaaggac tctcaagtaa cagccttttg
attttagctg acgacacgga 123540ttcccagtca tggcgcagcc ccttgaaagc cctttcagag
ttctttaaag gtgacccgaa 123600gggtgacttt aataagacag gtttgcattt tcccatggct
gctgaattat gtaacccaaa 123660tgcttcttgc tggcctcact tctaaaattg cttacacctg
cctcatctgc tttgcttaat 123720gagcatgcca tcctttgatt aacctaccct ggagttgacc
catccttgac tgtcacgttg 123780gaagctggga tctggactct gcaacccaac gcgtgccttg
attatgtttt agcataatct 123840ctaacatctc cacaggcttc accttgaggg tccccttgcc
ccatgagatt ggcaccctca 123900cctgccctgc acctatgccc cagcatgctg gtaccacagt
gttctttgct caaaggtggc 123960cacaagtctt gactagccag cccattggtt aatttttgct
cttcacaatt ctggactctt 124020tggcagtgtc tcagctgtag agtaaaattg ccacatccta
agcgtgccta accagcttga 124080aaggttatat tgtgtcttca acacacatca tccacataca
ccctccagca gcaagcacag 124140gcagtctcct taattatact ctagggcaga ctgagtgtat
tttagccaac aaaaagctaa 124200aggtgtctct cggggtcatt tctgcaacca tgaattgggg
atcctgtgat ttttttcagg 124260cctgtgatta tggttgctgg cctttttgtt actcatcagt
ggaaaccaat agctcttggg 124320gatggatgtg gtcctatttc agactcagcc aagggtggag
taaaggtgag gccaggcagc 124380tccttaaacc tctcatctct gtcctcaggc ttggtggagc
cagtgaacgt ggtggacaat 124440ggagatggca cacacacagt aacctacacc ccatctcagg
agggacctta catggtctca 124500gttaaatatg ctgatgaaga gattcctcgc aggtaagctc
catccatctg cccatccatt 124560cctccatcag tctatctgtc cacccatcca ttcctccatc
agtccatcca cccatccgtt 124620cctccatcat tccatccatc cactcatcca ttcctccatc
agtccatcca tccacccatc 124680cattcctcca tcagtccatc catccatcca ttctttcatc
attccatcca tccacccatc 124740cattcctcca tcagtccgtc tacccattca tagaggcagc
aagtattaca tagaacctgc 124800aacttgtcac cacacactag ccttgatatt tgtggctccc
gctctctcac tcccccagtt 124860cctttcagac atctttagtt taaaggtgag ctgaaattaa
gaagttggaa atcctaacca 124920cgtgtggtgg gattcgcctg taatcccagc tacttgggag
actgagatga gaggatcact 124980tgagcccaag agtttgaggc cagcctgggc aacatagacc
ctcccctgac atctctggaa 125040aaaaaaaaaa aaaaaaaaaa aaaaaagcaa tagtagtaga
caatcattga tgaaataaat 125100aatttattag tttattagag gcttcctttt ggtgttttgg
tgaacctgca agtagttttc 125160tgattgggac aggacaaagg tctttacttc agggtttgct
tgataaaagc atttccaaaa 125220ggttttacat agaaaccttg ttccttgttg atattaatac
aaaaaaaaat gttacataag 125280ctcttcacct cttggaacaa tctctaaggg ttttcttttc
tttttttaaa aaatcatgcc 125340ccttaagatg aaaaactttc acccatatcc cctaacacat
attttatata gagataagca 125400tattagctct atgtagaaat atgtaattta taaattacat
ttgtatattg ctttactaat 125460ataccatgta ccatatgaag catactatag aataattata
gatacagaat atagaataag 125520atgagatata aatattaaaa ctgaagttcc agtattctct
ttccatttgg tgaccatgat 125580cttagcataa caaaagtggg gtaaatgtgt ttaaccctgt
gtttcccaaa ctaatttgtg 125640aactcttcct ccccaaacta cttgtatccc ttggaacaga
ggtccccaac ccttggagcg 125700tggactggtg tgggtgcacg gcatgttagg aattgggccg
cacggtggtg ggtgagccat 125760cattactgcc tgagccctgc ctcctgtcag atcagcagct
gcattagatt ctcataggag 125820tgcgaaccct attgtgaact gcacatgaga aggatctaga
ttgcacactc cttgtgagaa 125880tctaactagt gcctgatgat ctgaggtgga acagttttat
cctgaaagca ttcccccacc 125940aggccccctg gtcttctacg aaaccagtcc ctagtgccaa
aaaggttggg gaccgctgcc 126000ttggaacaca ctcaggacaa aaccagtctg tcatatgatg
gttactacct catagttgta 126060aatttctgct agacttaggc accttgacta actcactgtc
ttatctgctg tagaaatccc 126120cttttccatc ccactcttat gtgtaagaaa agtcagatgc
agctgggttg acatgtatct 126180ttattgacta gggtgtgtgt gtgtgtgtct atcaagtccc
ttcaaggtca aggtccttcc 126240cacatatgat gccagcaaag tgactgccag tggccccggc
cttagttcct atggtgtgcc 126300tgccagtcta cctgtggact ttgcaattga tgcccgagat
gccggggaag gcctgcttgc 126360tgttcaaata acggtaactt ggagttattt tctgagccaa
accttaatcc taagacttaa 126420tttctgggcc agatttaaga acaagggttt caataaccga
tttctgactc aatgcaagtt 126480gtttgttaga ttttcccacc aaagagtcag taaatgtgca
gaagcagaag cagctcacct 126540gagagatttg agggtgtagc tccaagaacc actttttggt
gaattttcat gtttttttac 126600tacatctatt cctatgtttt tatttttatt ttttttaaag
atggggtttc accatgttgc 126660ccaatctggt cttgaactct cttgggttca agcagtctgc
ctgcctcaac ctcccaaagt 126720gctgggattg cagacatgag acactgtgcc cgtcccctat
gtttttattt ttaaatgttt 126780taaattactc tttggttcat ttaagactaa gttatgctgc
atatcacagt aaaccttaaa 126840ataagagtgg ctgaaataaa tgagattatt ctctcttgtt
aaggaacccc aggctaagcc 126900acctgggtgc cctgcagctc accaaggaag tcagctccat
ctctctgctc ctctacctag 126960catgtggctt ctgtccttaa ggtctcctcc tggaccataa
ggctgccagt gctctggcca 127020tcacatccac atggcaggcc agaaggagga agaaagaagg
gaaaaagggg tcctcccagc 127080tcagtgggct ctcttaagca gccctgccaa aagtccatca
tagacttcca ttcccttctg 127140atttgttggg ggttggtcac aattcacatt acctagtggc
aaggatgcta ggaagtggat 127200tcccatcttc tgggagcggt gcacctagct aagagttatg
gtcctgttaa taaagagaaa 127260agggagactg gatgtggtgg tgtgtgagca gaagcctctg
cctcctcccc tccctacatt 127320tcagaggatt tcgagctaaa acactcttgg ttcacctgac
aacaaaatta ctaaaaattg 127380gccatgtctg tcatggtgtt aaagggatct gtgaccctct
actctcccta ccaaaaaaca 127440aaacaaaact agattgtatt aagccatcaa ttctgtctgt
ttccactaga ggcactaatt 127500ggaaaatatg tcagggtttt ccatgaatgt tttctacatc
ttgacaacat cctaaatagc 127560atttctctat gatccacagg accaagaagg aaaacccaaa
agagccattg tccatgacaa 127620taaagatggc acgtatgctg tcacctacat ccccgacaag
actgggcgct atatgattgg 127680agtcacctac gggggtgacg acatcccact ttctccttat
cgcatccgag ccacacagac 127740gggtgatgcc agcaagtgcc tggccacggg tgagtacagg
gcatctcaag gtcaggggca 127800caggctttgc aatcagaaag ccgggccgta gcccttctct
gtgacttaca agctacatga 127860tctgggcacg ttgctcaacc tcactgaact tcagtttgac
atagattgaa gctctttgtt 127920tttatttgga gaacatttag atccaagaag ctcttctaag
gaacagagac tgttttacag 127980ggttactgca aagattagat gaggtcaggc atgaaaaatg
cttagcacag tgctaggtac 128040atgataacta ttattatatg cttttgaaat gttgagaacc
caactctgat ggcggctccc 128100atgaaaagca gcacatttct gccttttatg agtagatagt
tactcaggat tcattcaaga 128160gcatttcagg tcagcattag agaaacacat ttaaggatct
aggttttttt catcatgcat 128220atgtaaacct ctcaggaatt ctccatgaat atttgagcat
cacagtttct ttggtttctt 128280tctttttttt tcccctcctt tttccttcag tttctaagac
acaactattg actgtcacag 128340gccattcttt tttttttttt tttttttttt gagatggagt
cttgctctgt tgcccaggct 128400ggagtgcagt gacgcaatct cagctcactg cagcctcagc
ctcctgagta gctgggacca 128460caggtgccca cgaccatgcc cggctaagtt ttgtattttt
agtggattca gggtttcacc 128520ataattggcc aggctggtct cgaactcctg gcctcaagtg
atctgccctc ctcagcctcc 128580caaagtgctg ggattacagg tgtgagcacc acgcctggcc
ggcctttcag tttttaagaa 128640cagcccttgg gcagctcagt gctgctgctc aagcagattt
taaaacacga atccccatct 128700ctaaaatgag acagatttac ttctttttaa ataagaagac
taaacacagg accacccttg 128760atgtgttctg tttctctctt agcccatctt tttttgaatg
gagaaaatct gggctttcac 128820ggcaaggttg tgaattgctc agcgtggccc tttttggctc
acccatggca aaaaatggaa 128880aaattttgga atgcaggcca atccaccacc tcctaggtct
atgcagctgc cagcgacaac 128940cagatcatct ttactaattg atggcatgtt aacgttggat
ggggacttcc cccttgcctt 129000gcaggcccta tttcctcccc cagcttgggc agaagcctga
gctgaatact tgccttttgg 129060ccacacctct gggtctgtca ttcagggtct tccacagatt
gactccagtc ttctcttcca 129120ctcctccctg aacaaactgt tcttgccacc ctccctatta
ctcctacgca cttggctcat 129180atctaccaat gtgcttttag ttcatgcttt tctgcatttc
ctgatatgtg gatcctgtgt 129240aaaggggcgc cagaaatcaa gagagagact ggtcactggg
gagaggttgc aagtctccct 129300tagctaacag cacccatcct tcagggttca gccatgtttc
ctttctttag gaagcccttt 129360gtcagtgcgg caaccctggg atataaattc ttagaacctt
tgcctagata tgctgccaga 129420cacttctctg aggaacagtt tgttattttt tctgtaactt
agttcctctt cagcatttcc 129480actgcagttg gaaatgtcgt tcttggtgcc tggccctgtt
aacatcttga gagcagggac 129540tgtgtcttgc ccacctttat gtgtacctgg cacttaagaa
aatgcccaat atgtttgcta 129600ttgaaagtca accttcattg ccataccttt aaatgctggc
aaacccaggc taacctttag 129660tcaacactca gagcttacag atgctcctta tttagtaagt
aattgatgac gtaacccttt 129720gagcaacacc tgatcagggg atctttggga tatccctctg
aatggcagca gttggaggcc 129780taacatttac aggcacagac aacatggatg ggtatgattt
gttcttgggc ctccaggatg 129840tgtgtccata cttccattct cttcccctga actcttctcc
aggtcctgga atcgcctcca 129900ctgtgaaaac tggcgaagaa gtaggctttg tggttgatgc
caagactgcc gggaagggta 129960aagtgacctg cacggttctg accccagatg gcactgaggc
cgaggccgat gtcattgaga 130020atgaagatgg aacctatgac atcttctaca cagctgccaa
gccgggcaca tatgtgatct 130080atgtgcgctt cggtggtgtt gatattccta acagcccctt
cactgtcatg gtaaggaaaa 130140ttccttctcc cgagcatgct gttattggtg gaaactgtaa
cagctgccgt ttgttgaacc 130200ctgactagga tatcctcttc accttttttt tcctttggaa
aaaaatttgt taagcagtca 130260tgaccttgta gagtcccaga gtaatctcta gaaactcaga
gaccctttgg ctgtaagggt 130320ttttagggaa tcttactggc caccaaggtg tctatcataa
taagggactt gggcaatatc 130380ctggcctaag cccaggcatt ttgaaagata actcctcaga
aaaacacacc tttatgaaaa 130440tgtttctaca taaaacatga caggttttta accggccagc
tcttccttct tccatcttca 130500tggccattct ccatggctgg aggagagagc ttcctgatgc
tgttttgttt ggagacttga 130560ctctgaaatc ccaggactca aagtacctcc acttgtgttt
tggaaagatt cacactttat 130620gtatgagggg gaaatacctc gtcttttgca gctaggaaca
tctggaataa aaggaggaaa 130680ccattatgca aacacctggg ttagtgaatg accaaggtct
ttcattttca gttgtgagtt 130740acttatagat cttcctctgt ttatttattt ttattattac
ataatagatc ttcttctgaa 130800tattcttcaa ccaggaaaag ggttagaaac cttggggaca
ttacctcatt gaaccctcaa 130860aaccaagcat cgttggcttt tttacaaatg aagcatgctt
ggtctagaca gacaccaaat 130920accatgctgt catcctcact ggtgtccttt gatactgtgg
tcagcagccg cacttgacca 130980caaggtttat aggcccttaa tgacctggcc ttgtgcacag
ccgacaaagc accttctaat 131040tatttcattt tgtgcagcaa tggagaggtg catgaagact
ccattccaaa ctccaaagct 131100cagggacttt cttccgaaca gtctatactc tgttgtagta
ttattccctt ccatcgacgt 131160ctgtttatct gtaaacagca tgccagagat ctggaggctc
ttttatgtct caagtatgta 131220aatgtaaaca cttgtcaact tttgacattg ttcatttaag
agtgtttttc tcctgtagga 131280agaaagaaat acagctggga agttgatgtc cttattcaca
gagaagggta ccagttgtag 131340ttttcagaat ctgtttttag cccatagtgg gttttatctg
gttggttaga attaggtgga 131400aggagggaag agcagccaag cactgagcag tggtcatggg
cctgctggtg caatgatttg 131460ggggtaagag aagaccatat tgggaaggtc tacgtgagaa
agtcagagta aaaaaattga 131520ggaccctttt tgcagaagtg gaggcttcca aactcagtaa
taagtgtctt ctagcccctg 131580aatacacaca aagcaagaat actttgtgtt tacccactgc
cccctgacca ctgctgaagg 131640cagaaaggga cgatcaccta cagtacctgg tttgggtctt
tattctctca ttccagggag 131700agaaccttaa ctagatggac tgactgactg ttcattggct
ttggttgggt agattccctg 131760cttccctcta taagtttgac gccaaaaaag gacaccgacc
agcactgcag tcatagcaaa 131820tgtctcaagg agacccacag ggtggtttct tcaaatacac
tactcacaca cagcacatgg 131880agtcatggac aaacagctta actgcccatt gcctttgaga
agtcctggac caaaggccat 131940agctcagcca ttgaaagatc ttccttctga ctgatatgtc
cctgcatagc tccaacctgt 132000gcaggcagag gatagggctg ttccaaatgt cgctcacaga
gctgcctttg cctttctgca 132060gatcccaaga tacacacaaa gcagttaaca tgggtaaata
ggccttcctc tgtaggagag 132120ggcttctgat tcttattctt tcttatggcg gaagagggtg
ttgagagggg ttcccttgct 132180gttggttctg ttgaatcagg agcattaaat cttttttgtt
tttttttgag acagaatctc 132240actctgtcac ccaggctgga gtacagtggt gcaatctcag
ctctctgcaa cctccacctc 132300ctgggtttaa gcgattctcc tgcctcagcc tcccgagtag
ctgggattat aggcacctgc 132360caccacgcct ggctattttt tgtatattta gtagagatgg
ggtttcacca tgttggccag 132420gctggtaact cctgacctcc agtgatccac ctgccttggc
ctcccaaagt gctgggatta 132480ccggcatgag ccactgcgcc cagccatgag cattaaagct
aagatttgtt gaaaatgaat 132540ttataaaaaa ctttagaaac attaactgct gagcatggtg
gctcatgcct gaaatctcag 132600cagtttggga ggccaaggtg agagggttgc tggatcccag
gagtttaaga ccagcctggg 132660caatacagtg agaccccatc tctaccaaaa aaaaaaaata
ataattagcc tggtgtggtg 132720gtgcacgcct ctagtcccaa ctgctcagga ggctgaggtg
ggaggatcac ctgggcccag 132780aaggttgagg ctgtagtaag ctgagattgc gccactgcac
tccagcctgg atgacagagc 132840aaaactctgc ctcaaaaaaa attaaataat taaccacagt
agacatttat caagtaaaaa 132900aagaactttt tcctgattct gtgctgcaga gatgccttgt
gttagttttt acctacttac 132960acttcacaca cctcactttc atgcctgggg tcacaccgta
catactgctt tcgcaccttg 133020cttccttccc tcaatgtgtc ataggtaccc ttacatattg
attcattgga cctgactgcc 133080atgttccact ggacagactc accagaattt atttgaccaa
atcccttcca gatggacatt 133140gggttgcttt agttttgcac gaccacagac agcaccagtc
aaggtcctta cacacatcaa 133200ttaactatgg agtctcccgc cagcttaggt ctgcgtgcta
caagtggggt tgtgggctca 133260cagggcatgc gcatctgaca gttgaagaga ggacaccaac
tgccttccaa aagggcagta 133320agaaagtgtc cttcgctaga gtgagtggct cactgcagtt
caagatggag cagtggggga 133380agcagctctg tggtggtagt ctactgagtg tatccttcca
gtatggttcc caactaatct 133440ccatttgcca ctgaccaggc cacagatggg gaagtcacag
ccgtggagga ggcaccggta 133500aatgcatgtc cccctggatt caggccctgg gtacaatttt
ggttttttcc tttttgtgtt 133560tctgtgttta ctcagccttc atttcagaaa atctgccatc
tgcttctggg attgcttaag 133620ccctgtgggt gtcctggtca ttggtgtgcc cctcactgat
cagcccatca cgatgatccc 133680tgctttttct gtaataagat cacctttgcg tcaccatccg
tgctccacga atcgccagcc 133740gtcgtgtctg tgatcacgct cggtgcagtt tgtctctgtg
tttaaagaga aagacagaca 133800gctgtctgca gccctcctgc tgcctctcaa agccgccact
tgcacattca gtttctgttc 133860agggggaaag ccacccactg ctactctctg ccacttaaaa
tgcaccttct tttccaggcc 133920acaagcaact aaacctttcc agatggagcc tcttgggact
catagacatt gctgtctctc 133980acttttccac tttcccgtgg gtgctgctgg gaattttaca
aacagactcc cgagtgattg 134040ctaacagttg gtcagcatga cctctccagt ccctcaggtt
ctaccctggg tctggagcca 134100cttagacaaa gcccatacca caatgggcag ccgcattccc
aaatcccggc ctcactggct 134160tgtagaattc ccagcagctc taacccctgt agcttcacca
gctcccgctg ttgtctgctt 134220tacccagtga ccactgcctt ctgtttttag gtgaccgaag
aggcctatgt cccagtgagt 134280gacatgaacg gcctgggatt taagcctttt gacctggtca
ttccgtttgc tgtcaggaaa 134340ggagaaatca ctggtaagca cttgccataa aggccgtctc
attctcactt gctctcacga 134400gcttcccaga atggtgctgg ggaggtgtgt ccactgtccc
ccagacccag gctccttaac 134460ccagggtcac gagttcttgg tctccggtgt tgggccgtgg
gctcctgaaa ctacagaata 134520tgccacgtgt gtgtttctct gaagaagtgg ctcactgaca
acttgcatta ctttcttgag 134580cagtcccatg attctctcta ggttaaaaac tgctgtgttt
agatacctca tgactgtcgg 134640gttcttgttt gccccttttt cctgccttct cttatttgac
ttttccagat gtgactttga 134700cactgagtct gtcatacagg agttcctttc tcccctcagc
ctcttttcaa tggcccactt 134760ctctttggtt tgatgctcta tgtatccagc tggtttcatg
gtgttctcaa gtcctttctg 134820agcttgattt tgccagttgt agaaaactct ttaagagttg
tctgctatat tttgtggaag 134880ccaaatggaa ctggaaaaaa aaaaaagaaa agagcaaatg
gtctctccca ttgtgggact 134940tgaatgtttt aggcagcaac gaatgttctt gggtctggaa
acctttattt tgaatacatc 135000tgtgccttgg gctctgcttc tctggggaag gttgctggtg
ggcttcattg ccccgtctct 135060ctgtgctcca taggagaggt ccacatgcct tctgggaaga
cagccacacc tgagattgtg 135120gacaacaagg acggcacggt cactgttaga tatgccccca
ctgaggtcgg gctccatgag 135180atgcacatca aatacatggg cagccacatc cctggtaagc
tgagtcagca ggcccagcag 135240ggctccacca ttcaggggca tccgggcagc ctgcagacac
tcctcagccg ctttgcaggg 135300agcagctctc ggcagcaggc tggagaatgc agcgttggta
cccctgtgaa accaaacagt 135360ctgggaccct agcaggtcca gctgatttct ggaagggatg
atgtagctca gtgtcttggg 135420tcacagtgca ggcctttggg tctgtggttg tttatctttg
tcactacgct gagtgtggcc 135480agaggtcaag ctgggagaaa aatgggaggc atggtgaggg
actttccagc ctggcctgca 135540gagccctgtg tgggctggag gcttggggcc aggtcagagg
tggaagaaga ggaccagcag 135600ccctggaaga agaggaccag cagccctcta caagggaagc
cagcccaggt ttcatgggtc 135660accaaccagc acagtgtcac cagttcattc tttctttttg
tagttgtatt tgttttttaa 135720tttagtattt tgaataggta acacattctc atggttcaaa
aataaaaatg atacgaagaa 135780agttttcctt cctacccctc tccttgaact agactatcat
aaattttttt atgttcgatt 135840tcagagtttc agggttttat tttttatttt tttgtggaga
tagggtctca ctgtgttgca 135900cagattggtc tcaaactcct gtcctcaagc agacctcccg
cctttgtctc ctaaagtgtt 135960gggataacag gcatgagccg ccacgcctgg ccaatttcag
agtattttta agactctcca 136020tgcaaacgga aatacagata tataagagag tgtcttccca
gccttccctc atgtggacga 136080accattacat atttgaccat ttccctattg gagggcattt
tggttcttcc tgccctcgct 136140gtccccagtg ttgctgcgca aatcgacttt tcccctagtc
acctcacact cacaaagatg 136200tatctgtgag atttagttac cagaggaggc aatgctaggg
ccccagtgca ggcatctatg 136260attttgacag atcttgccaa attgcccttc agaggggctg
ttgcagttca cacgccctct 136320ggccatggag aagagcacct tcttttccac aaaatttgcc
agtagaatat ggtatcaaat 136380ttttggagct ttgccagtct gatggttgga aagaaacaga
atctcagcgt tgctttattt 136440gtatttctct tgtgaatgag accacacaac tttccctatg
tctatttgta tttctttttc 136500tgtgaactga acatttggat ccacggcctg tttttctatt
tggttattgg cctttgtcat 136560atagtttcta agagcaatgt aaacattgga gagattagcc
ctttgtggta ggagttgcaa 136620atgtttctct gagattggca tttactttag ttgtctgtat
gtaatattgg tttaaagcaa 136680aaatgtatta tctgcttcta tttaaatatt ctaaagcggc
agatggagag agaggaaaaa 136740atgtctttct cacatctgcc atccacttcc actgctggtg
tgagttgtgt atcttttcag 136800atgtttctct ctgtatctac aaacatacat ataattttat
tctattttgt ttttaaagga 136860atagcataat ggtattcata gtttatagca acttgctttt
tttcttttta atgcatcata 136920ttatggataa tttctcaagt cagtaaacat gggtcttcct
cactcttttt aatggcccat 136980gagtagatca gcatttattt aaccggtccc ctgttgtgaa
cacttaggtc ttttcctgat 137040gtgcacccga acactgcaga aatgaaagtg cttacatagg
gctaggagtc ggggtgggca 137100gagaagacca ctgtggggtt gattccttac aggttgaatg
gcatgggcaa atggccttcc 137160aaaagccctt tccacttacc ttccctctgg ccatgggtcc
tttcaccacc cagtgcaaaa 137220gtttcttcct tatttgtcag gttgggctgg taccttacct
tagccccctt cctcatctgg 137280agcagcttcc aggattgttt ttcttatgtt gtgattgaag
gaataatact gcgtagaccc 137340tctctgatgt cctaggatgg cgggggatgg gaggtgcatg
tgcatctcct tctgtctctt 137400catgcctctg cttaggaggc gccagacctg tagagaggtg
gacgtcaaga tgccagttgt 137460ccagggtctt cgttcacccc ttaatgagca ccaattttgt
ttgtgtcctt cgtaaaccca 137520gagagcccac tccagttcta cgtgaactac cccaacagtg
gaagtgtttc tgcatacggt 137580ccaggcctcg tgtatggagt ggccaacaaa actgccacct
tcaccatcgt cacagaggat 137640gcaggagaag gtactgtgtg gtttacgtgt ttatacgcct
ccagctgtcc atttggaggg 137700tgaagtggac acggttccag ggtggctttt aaaagtgaga
caatcgaatg gtagtatttg 137760tcttgtcttt tctctcgtgt aaatctgttt cttctttaga
gccgcttcgt cttctaccca 137820gacagacatt tttgaagtcc tttgtgttct aactgaaatc
agattcatgc tatgaaatac 137880tttatgtgac ttgtctggaa tttaagtgtg ttttggttgg
tgatgttttt gttcttgttg 137940cacatgtatc cacaagacca catgacttac tgagtggctc
tttttgataa agctgtgtgc 138000ccattcccgt ggtattcatg gataatccca aatctgtggt
tctaatggga tttccgtgat 138060ggcagccagt gcctgatggg cagggacaat ccacctctgc
cctccaccac ccaccgtctc 138120ctatgtgtaa ttgatgtaca cggctccttc cttttctcat
cccatgcatc ctgagagtag 138180agagagctcc agggttactt gcagtgaaga actcagatgt
ttggggtttc ttctcagtgg 138240gtgtttttac tgcgtggact gcttcattct gacagatgtc
cctttgccca cagctcacgt 138300ggagtgcgtc aatccattgt ccccagcatc agggctgccc
tggatgagtt gttaaaagga 138360aactcttaaa acaaggcaac tctctcccta acacccctgc
atccctgttc ccacttgtag 138420gtggtctgga cttggctatt gagggcccct caaaagcaga
aatcagctgc attgacaata 138480aagatgggac atgcacagtg acctacctgc cgactctgcc
aggcgactac agcattctgg 138540tcaagtacaa tgacaagcac atccctggca gccccttcac
agccaagatc acaggtaggg 138600ttgtctggct tctggggtct tcctcgtggg aagtatggct
gcctctgact gccaccctcc 138660ttatcagacc cctggcagca ggctagacgt ctctttgagt
ttaggtttca cagagacttg 138720ttgaggagga gcaggggatg gaatgcaatt ttggattagc
taaatccttc tcttgctgat 138780aatccaggaa aatgcgagag ctagtatttg gagcacactt
ttattgtgcc agtgtgactc 138840tagggtgcaa agagaaagct ctcagatgga gtgttcgaat
catacttact gcaatagtgc 138900atgaagtgca tgagcttaga catgcccttc agcgtcacta
ctaggtaaat tttctgctat 138960cccttttaca gatgggaaaa ctgaggcttg gcaaggtagt
ggtgtagcca agttcacata 139020taggtaaaca gatccaggtt atcaaattcc aaagcccatg
ctcctcacct tgctgtgttc 139080aggttatgct ttcagtgggt tataaggaag atgcacaagg
cagatcctgt ttccccaccg 139140tatttagacc tgtctgtgaa gcagccagta gtactgtgtg
gaatgtggtc attgtttacc 139200tagaaatgcc cacagccatg ccaggcaggt atgaggtgcc
ttcaactaac aaaaattcct 139260atattttatt ttatttttga gacagagtct cactctatca
cccaggctgg agttttagtg 139320gcatgatctc ggctcactgt gacctctacc tcctgggttc
aagcgattct cctgcctcag 139380cctcctgaat agctgggatt acagcaccca ccaccacacc
cagcttattt ttgtattttt 139440aatagagatg aagtttcacc atgttggaca ggctggtctt
gaactcctga cctcaagtga 139500ttcgtctgcc tcagcctctc aaagtgttgg gattaggcac
ctggcccaaa gattccttta 139560aaatgtggtc catgaggact caagtctcta ggtcctgcca
gcttcttgtc tttgctgcaa 139620gcaggcatga atcccatcat tcttcattgg ttgggtctac
tcagtgttca aggctcattt 139680ttttttcact taactttgtg taattagttc ttgcgtgttc
atccgtgaac agcatatggc 139740atggcagctc tgtgaagcca gggtaaccac atgtaacggg
agtccttttt gggggatgtt 139800tcccagatga cagcaggcgg tgctcccagg tgaagttggg
ctcagccgct gacttcctgc 139860tcgacatcag tgagactgac ctcagcagcc tgacggccag
cattaaggcc ccatctggcc 139920gagacgagcc ctgtctcctg aagaggctgc ccaacaacca
cattggtgag ctaggctacc 139980cttcctggct ggagccagga catcttgggt gggagatggg
gactcttgca gtcctttctt 140040gggaatgggt agcacaatgg agtgtgatgt gataaacctg
ctgggtcaca cgcacgataa 140100atgcccaagc gtatttgtgc attgtgatat cgacactctg
gattgttggg tgtcaggaaa 140160gaggacatat ttctatttct gagagtgtgt ctctctcctg
cttcctctcc gccatcccct 140220tacaagcccc aatctgtgtt ctggtccagg catctccttc
atcccccggg aagtgggcga 140280acatctggtc agcatcaaga aaaatggcaa ccatgtggcc
aacagccccg tgtctatcat 140340ggtggtccag tcggagattg gtgacgcccg ccgagccaaa
gtctatggcc gcggcctgtc 140400agaaggccgg actttcgaga tgtctgactt catcgtggac
acaagggatg caggtctgtg 140460tggtcccagg ggagaggccc agagcttgtg ggaaccgact
tattttgctg aggcagcgtc 140520atcttttcat cctaccaact ccttttcctt tctgagcatc
cttcaagcta taggtccttc 140580tgcctgcatt gtcttttatg cctcatgacc attggcaaaa
atgggattgt ctttgttttt 140640tagatgatga aactgaggct tgcaaggttt agagccccct
ctgcactagg atctgaaccc 140700agagccacaa cacctcgcaa acccctgttt tcttatctgc
tctcccaccc ttgttctcag 140760cttcccagcg tctctccaag caaagaatgt tgggttgatt
ggccaagacc atggtcatct 140820gagcagagct tttgtggaaa tgaagcatct ctttctgttt
tctctttgag atggtttgag 140880ttagattgtg tctcttccaa gcttgccaca ccccagtgcc
tccagtcatc tgctttcttg 140940aaggatggcc acgctggtga attctagaca aattctaacc
cggggagagg gctggagaat 141000ttctggtcct ggttgggaga tactccctgt taaaccttcg
gatatgctga cctagctgag 141060gtagccaggg gctatttaaa aattcaaaat ctcagatctg
gctgtggata aacccccaag 141120gtggtacgtg cagtacttgg aggcgtgagg gcagaaggtc
ctccccagca gtttgtacgg 141180gacacatcat ctatgggata ttagtaaata tccttaagga
aaggcttctg tggtcaaaac 141240caggttcagc aggttatttc actatggggc ttctcaggac
gcttaaccta ctcatccccc 141300tctgggcttt gcaaacgagg ccgccattgc tttctttctg
ctatgtagaa atagattgag 141360gcgtaagggt cggatgtcct ttctccattc atcaggctcc
ctcttcctga ggagctgctg 141420tcagaacagc ctggggctgc tgtgttgcag gttatggtgg
catatccttg gcggtggaag 141480gccccagcaa agtggacatc cagacggagg acctggaaga
tggcacctgc aaagtctcct 141540acttccctac cgtgcctggg gtttatatcg tctccaccaa
attcgctgac gagcacgtgc 141600ctggtatgtg cattccattc ccctccaggt gggatgcttg
ggttttctgt aaatgctgtg 141660ccttggcctc tggcctgctc acaggagcct tcttgggtct
tgcagggagc ccatttaccg 141720tgaagatcag tggggaggga agagtcaaag agagcatcac
ccgcaccagt cgggccccgt 141780ccgtggccac tgtcgggagc atttgtgacc tgaacctgaa
aatcccaggt gggcgtcggg 141840gactagtagg gtggggaagc cttggctcca gccttcaggg
cagtgggtgc ctttgggaac 141900caagtttagg catggcccag aacacagtat ccaagtcggc
tgtgctgacc ttttcatttc 141960acttcatttc attatgttct tctatgttta ttttcacaga
gtctcatcca agaaaaacaa 142020atgtttacct tgctaccttt ttcctcttcc aaataaaaat
agctttattg tgtcacatgg 142080gggaaacgta gatatgcttt tagattttta gattaactat
ctgtcaaata gaatcatgtc 142140agtgaaagaa ctggccctgc cgatgccagg gtctggaagt
atttaagagg tggcagccca 142200gcggcatcct tctagtattt ctctttcatt cctgaaatta
gaacgagggc tgtgctgcag 142260aactcgctgg gccacatcta gccctttggt ggtgaattgt
tcttcttggg ccccgattag 142320ccagtcaaca ggtcacacag tctgtctgaa atgtgttcca
agttctttct ataaagaatc 142380cttccagagg gaagccactg tgagtgaaaa ttttgaggct
cctctgccca gaagttggca 142440tgtcctgtgg aattgcacaa attctacaga gaagggaaat
ctaaatcgtc ttcagatgga 142500gcttgtgttg cgagctctgg agagggggtt gtctttctac
actgcatctc ccatccttcc 142560taacgagtca cggagctgtc gactccgcct tcttggcttt
agttaacagg ttcttcttgt 142620gtagtcacat caacgtcggg tcacatggga atgtggtaaa
gcctcattac tgtagagttc 142680agacatgatc acttaaaaag agctttattg ggccgggcgc
ggtggcttac tcctataatc 142740ccagcacttt ggggggccga ggcaggcaga tcacctgagg
tcaggagttc gagaccagcc 142800tggctaacat ggcaaaaccc tatctcttct aaaaatacaa
aaataagcag ggcgtggtgg 142860cgggcacctg taatcccacc tactcaggag gctgaggcac
aagaattgcg taaacctggg 142920aggtggaggt tgcagtgagc tgaaattgca ccgctgcact
ccagcctggg caacaaagtg 142980agactccttc tcaaaaaaaa aaaaaaaaaa aaaaaagagc
tgtactgatc gtttgtagtc 143040ataaacagtt cgtgtgcctc aaggtggggg gaggaagtgt
cacctcccag agagagcttg 143100gttcacattt taggtacaga gttggaccct ggctgcccca
tcctcatagc cacgtctgct 143160cactttccag tcacattggt gtactcatcc actgtttttg
tgggcatctt cccacctcaa 143220aaaatagaca tccacatcat ctctttcatg accctgataa
aatgccattt cattcaatgg 143280aactattggt gatagaaaaa gagagattcc atttcatgtc
tagatgcatc aaccttcgtt 143340actcatctct gtgcctcagc tcccatcatc agggctgctg
tgacatttgc caccctgtgc 143400tcaggctgtg ggctggatgc ccaggagtgg gctgggctgg
tgcatttcag atgctgccat 143460gccttggcag accgccctcc acatttctcc atactccccc
accagcactg gggctgtctc 143520tccttctcac tttggccaac ctgatggaaa aacatggcat
tcagtgttca gtttcatatc 143580ttcgattact agtgatatgt gtactgtgtt ttcttttcat
ttgctttaca tttctcattt 143640ggcaaaattt ctgtgctctg cttatttctt gaggaactag
caagtatctg cagtgtggac 143700gtttaccctt tctcttaagt ctcttccagc tcttggccat
tttgttattc ttttagttac 143760ttagtaccag atgactctgg gtgaggctcg attttccact
cattacccaa atgatcctct 143820cggagatccc ctcctcctta atggaggaca gctcactaac
ttcagatgtc ctccggaccc 143880aggttttgcg gggcatcttt gtcagtttgg gctgctgtag
caaaatcaca tgaactaggt 143940ggcaaccaac agaaatgtat gcctcacagt tgtggaggct
ggaagtccaa gatcaggtgc 144000cagcatggcc agattgtggt gagggcctcc ttccaggctg
caaaccgaca gcgtcccctt 144060gtatcctcac atgctggaga acggagggag ccagctgtct
gggactctta caaggccact 144120gaccccatca cagggtcgct ccactttcat gaccttatct
aatcctaatt gcctcctcaa 144180ggcccatgat aatcccatca cattgttggg ggtagggttt
caatatttga attttggagg 144240gacacaaaca ttcagttcat tacatgggtg accctctttt
caacctccct tcccttttct 144300gtcctcaggg gtcagagtca tgaactgctc tgcccagatc
ctgtggggct ggagggtgca 144360gtttcatact ggctctaggt gatggcagtg ctccgtgccc
cgcatgcggc cgcctggcct 144420caccacggca gtgcaggcac agtcgttggc atgacgtgag
cagctcacgg agagtgatgt 144480ggtcttgcgt cctagcactg gtgacccgag acattgcttt
tctgaaagtg tggcccctgg 144540tctttggttt gctcaaagct ttgctcacgc atggtttccc
ctctgccatt gggacttaca 144600tatgttcacc tttttctcta actttgtctt gttgcctaaa
agaaatgcca aagcttcttg 144660acggtaaagg atgatggctc ttgttttcta cccttaccta
tctgtggaaa ggagcccgtc 144720tgtgcatgat ggatgaccac gtcacctttg gcaaaaagtc
tcagtgcccc cagcatgggt 144780ggcctgaagg gccctgccca ctccatgctg gccacagaag
ggcaggcacc cagcctgaag 144840ggaaggaagc ctgggcacct cacgtccacc gggctgcaca
caccttgctc tcggctgctt 144900gccctgcatg tcctgccctg tctcaggccc ttgccctaac
cctcttctct cccccaacct 144960ccctccctct ttcagaaatc aacagcagtg atatgtcggc
ccacgtcacc agcccctctg 145020gccgtgtgac tgaggcagag attgtgccca tggggaagaa
ctcacactgc gtccggtttg 145080tgccccagga gatgggcgtg cacacggtca gcgtcaagta
ccgtgggcag cacgtcaccg 145140gcagcccctt ccagttcacc gtggggccac ttggtgaagg
aggcgcccac aaggtgcggg 145200caggaggccc tggcctggag agaggagaag cgggagtccc
aggtgagcat tgcgggcagg 145260attttcactt gggaagaata gagttgagcc caggcagtgt
gggcacccac atactttttt 145320gccccatttg aaagagaaga cttctgatag gtggcattaa
gggcattatt taaaacaagg 145380catcatgact aagtctggca cagtttgtaa ctaagctttg
ctcacttacg taaagccaaa 145440caggtttctt actgggagcc tccttggagc ccgtatctta
ttagtgtgca cctgagtctc 145500taattgggga gcagagtaat acggtttcca gagcatcttt
cagggctgat gttctgtgga 145560acatactaga aagctacaaa actgactgta agcatccttt
cctgtggttg ccgctggtgg 145620gaagatctgt agggaaaaaa tggaacattc tcatctttct
ctggcttggt taaggtgtat 145680tcatttttta aattttttat ttaatatctt tttctctctt
gtttgttaga gatggggtcc 145740cactatcttg ctcagactgg tcttgaactc ctgggctcaa
gtgatcctcc tgccttggcc 145800tcctaaagtg ctgggattat aggcatgagc cactgtgcct
ggccggttaa gatgtattca 145860gggctgggcg tggtggctca cacctgtaac tctagcactt
tgcaaggccg aggcaggcag 145920actgcctgag ctcaggagtt caagaccagc ctgggcaaca
cggtgaaacc ccatctttac 145980taaaatataa aagaaattag ctgggcatgg cggcatgagc
ctgtagtctc agctactcgg 146040gaggctgaga caggagaatt gcttgaacac aggagatgga
gcttgcagtg agctgagatt 146100gcaccactgc actccagcct gggcagcaga gcaagactcc
gtctcaaaaa aaaaaaaaaa 146160aagacatgtc ttcagaggac tccagatgtc ctgtgaattt
agttatcact agtgatgctt 146220aggaaacttc agcaatggac cttggacctt gcttgggttc
tgcttggggt tggagaaaga 146280ggaaagggct agcaacagac gaaacctagc actgcaggtt
tgaacaagga tggaagaggg 146340acaggggctc tgtggggctc agtcactaac caggtttctc
tttgctctca gctgagttca 146400gcatttggac ccgggaagca ggcgctggag gcctctccat
cgctgttgag ggccccagta 146460aggccgagat tacattcgat gaccataaaa atgggtcgtg
cggtgtatct tatattgccc 146520aagagcctgg tatgtattca gggttcacaa gaggacattt
tccttgtttg aacatgatta 146580ggttgcaagg aacagaaatc catcaagttt gctgaagtca
atgaggaatc tatgtgtatg 146640ggcacatggg acagcctcct agaaatccag ttgcaagata
catggccaga cctcttaagg 146700gtgggaacgc ttgttctggt tgccttttgc ctttctccat
tagcctctct gcttcttgct 146760ttcattcaat tgctccattc tttccaccaa ccagcctctg
tctgcccacc catggctacc 146820ctggctggct gccccagaag agtggccttg gcatctgagc
tccctctagc aggagctctt 146880aaccttttgt gtgccattga ctcttgccat ctggcgaagc
ctatggggac tgttcttggg 146940ataatgtttt aaagcacata aaatgaaata tgtcacatta
taaaagaaat cattgatatt 147000atagtacagt taccaaaatc ttacaagaac aaatatgcaa
catagaaaca tgcatatctt 147060cgttaataca ttaaatcata agatttggtg acagtatatt
aactgtcatc aaagtgacaa 147120agtaataagt gaaaatgata cgtcaaaata actgtaaaat
gacataaaaa tatatgattt 147180ttaatggtga tgtaagtcat atgtacttat aatgtgctgt
gatttcttgt caacatttct 147240gaagaaagga aatggtaaat ttcagttaga gaatggtgaa
aattaaaacg taattttttc 147300cccattgaag tccatggatc tgctgaattc aatacaggcc
atttggggac cctgtgagcc 147360ccggttaaga gtccctggcc ttaccccact aaggaaatca
tatcggccca gcctcagcca 147420ggcgactccc actcaaccaa tcagctgtgg ccattgagga
gggctgggtc tctctgaagg 147480cattttagcc cttggtgaga agcaagagtc cactctgggt
ccagagtctc tgaaatgatg 147540ggactttcct gtcctcatag gtaactacga ggtgtccatc
aagttcaatg atgagcacat 147600cccggaaagc ccctacctgg tgccggtcat cgcaccctcc
gacgacgccc gccgcctcac 147660tgttatgagc cttcaggtga gatgcaagga agcatccatc
tccttggccg caggccacca 147720gtgagacccc tggactcctg aggctgcttc aatgtcccct
taggtgctga ggcccctttt 147780cacattttga ccacagatgt cacccagtca ctggggagct
ttcctgtggc agagtcaact 147840ccccatacac ttagggcgga tgacacttgg ggcgagcaaa
aacagagcca cagtcaacaa 147900cacaccttaa tgtttgggga cacgtttgtt tttaaaggtt
tatttaagag aaacaaagga 147960agcctgttca taactggtta agggataaca agggctttca
aaacaaaacc aacacaaaaa 148020taacagtgca gtgatgtttt agcctgctgt tgttggctgc
ctttcttcaa gaaagtcagt 148080tgcaacttac tgtgattcat taataagtgt gcagggaact
atattaagag ctttatcagt 148140gttacctcag taaatccttg caatagcctg acaagtaggt
tctcttgacc ccattttaat 148200gatggaaaaa cagagataca aggaggtttt gtccactggg
aaccagctag tatgaggcag 148260aacaggcaca gtgtggctcc agaacctgta tttttgtttg
tttgttgttg ttgttgaggc 148320agagtctcgc tctgtcaccc aggctggagt gcagtggcat
gatctcggct cactgaaacc 148380tctgcctccc aggttcaagt gattcttctg cctcagcctc
ctgagtagct gagactccag 148440gcacgcgcca tcacacccgg ctaatttttg gatttttcgt
agagatgggg ttgcaccatg 148500ttggccaggc tggtctcaaa ctcctgacct gaggtgatcc
accccactca acctcccaaa 148560gtgctgggat tacagacgtg agccactgtg cctggccaga
acctgtgccc ttaacggcaa 148620cctctctaac ccccacctga tgttgtggca cacggttgca
tagtccatcc cattaggata 148680ccaggagatg caacattttt cctcgtccta aacaggtcac
ttaattcaag gttgtactag 148740caccttcagc caaactaaga accatcgggg atgcctctgg
gtttttgccc aggacactga 148800aaaataatta ggtgtctgaa ctgggagtag caattaagtt
gtgaaataac atcgaaatcc 148860caaagtatga tttctgggta agagtttcta aatagccttg
agctgccccc agttcttgaa 148920aatattggat tcattaaaat ccaatctgat gtctaagatt
ggtgatatca ttggctttag 148980ttccatacac ttggtttaca tttgagattc taatcttact
ctgaggggaa ctgggatacc 149040tccagttgtt ccaaacatta gtctttcatt tagagacgta
aacagaaccc aaaccagact 149100cagtccacac attgaagcgg cctcatccgg agaataccaa
gggtactaac tggttactgt 149160ggtgtagatg tttttcttgt gtttcattta aaggcttctt
aacagaagtg tcttttgtgg 149220ccaacttaac taaaacctac ggagggagat aaacccagca
cttattgagg gcaggagctg 149280ccctcatgca tctcgaagat ttctttcaaa tctgccgagg
catttatctc cctcttgagg 149340atttagcggc aagcggattc aggtaatgta aatgattctg
tctaaaagga gctggtttgg 149400aaaaatcccc tccaggaaac ttctgtagag tgctctcgtc
atagctgggt cataaatgtt 149460tcagtaagtg cacagcaggc tgtttcttaa gcttttgtaa
ccagctgctg ccgcaggaga 149520agtgtgttca tcagcatcgc cccctgttct tcccgggtca
tttgatgccg agtgatatgt 149580aaattattga tcagagattt tgcggaggcc cacgcaagca
acatctggtg ctggttagca 149640aagagaggca tgtatcgttt tgtcttgctt ttgagacttt
ttaggaaatt ggagtaggct 149700ggcacttggg gtgggggtgg gatgggagtg atctggtgat
caaagaccct ctaattctgt 149760gttctgtcct ccctcctcag tctatatccc ctagggcagc
acagtccaat agtaggttct 149820gcagtgatca aaatgcttca agtctatgct atgcagcatg
atagccacta accatatgtg 149880actattgaac atctgaaatg tggccagagg aaccaaggag
ctggatgttt agttttattt 149940aagtgcatta agttgaaata tatgtatata tggcctcgtg
gctggtgact accaaattag 150000ccagtgcagc tttaggacct tgccatgaag atgtggttct
tgggccagtt cttggacctc 150060agcatcacct gagaacttca gtcccagacc cactggaaaa
gaatctgtat tttaataaga 150120tccccagatg gtttgcttac acattaagtg tgagccatgc
tgcttcagag ttattgcctg 150180aggagtggct gtccgaccaa gtctaaatca aaattactga
cttgtaaaat gctgctgttc 150240aggattggct agtcttaaaa tatctcaaat gttgttgctc
agctttgttc ttaaccatct 150300gaacttctaa tcccctcctc ccagaagagg agatagtttc
caagacaaag tatggggagt 150360gaaactgatc cagggaagag caaaagctat gtctttctat
ggcttcttgt ggggatacaa 150420cctctaaatg catattaata tttaataata agctgacgtt
ttcgagcctc tctgtgtatg 150480ggctaggccc tgtgataaat gttttgcatg cacagcttca
tttgatcttt atagtagccc 150540tcgagataga tcgttattat gcccatttta cagatgagga
aactgagact cgaagaggtt 150600tggcacccta gatatatagc taggaaatgg taggaaatcc
agatccagct gattcttaac 150660tgctatggag tactgccttc tttgcacacg tagcccttta
taatatgttc ctccaggtct 150720gcccttgaga taacaaacag cataacataa aactgtgttc
gtgttcgtga gtgcatgact 150780ttgttagctg cagtatcctc ttaaaagagg acactttttt
gacctggaac atactgggtt 150840ttctggcctg catgggcatt attttggatg ctgagatgat
agtccttttg accaggatgt 150900ctcaagtatc caagcccaga aatcatctct tctaggctga
atcaagatgg tttgcataag 150960agaccatgca gatgcacgtc tctgctatct tacattaaaa
atgcagaatg gctcacctgc 151020cctttgttgt catatgttat atagaaaaac ctatttgcat
gagaactgtc acccacagtt 151080ttgggtaggg tcagtgtgtg ccactgagca ggaacgccga
gggccataac ctgtctgatg 151140tattaaattc tcaggaatcg ggattaaaag ttaaccagcc
agcatccttt gctataaggt 151200tgaatggcgc aaaaggcaag attgatgcaa aggtgcacag
cccctctgga gccgtggagg 151260agtgccacgt gtctgagctg gagccaggtg agcaggaggc
ctgctggggg gtcccagcac 151320cagcactttc cagcagaatg ttcctgtaaa tgtgtgtccc
aagggagggc tgatcagttt 151380cattactgcc agtgagcctc tgaattccct ttgctgttgc
cagatattgt ttataaatta 151440gggtttaaac atgtgccagg gatagggaga ccctttatgc
taggagagaa tgctcattct 151500ttctttcttt tttaaacaaa tgctgggctg ggtacagtgc
cttaacctga gaggtcaagg 151560ctgcagtgag ctatgatgca gtgagctatg attgtgccac
tgaactccag cctgggtgac 151620agagtgagac cctgtctcca gaaaaaaaac aaaaaaacaa
aaaaacacat acacacaaca 151680caaaaacaaa tgcttctttg ttttctgtta gtttttcaga
ttccttttgc atgacattca 151740tcataatttt tctttcatat tgtaacaaca tcttacagat
ttttattcat tgaccttatg 151800gcacgagtaa gcatattttg atctcacttt actctaaagg
aaaagtaggt taatgttctg 151860taaatttaaa aaagaaaatc tgggtctcta ggccctaatg
tcctaagatt tttcttgctt 151920ggtgccttgg tatatggaat tctctgattt aatcaacttt
aaagagacag tgttaccggt 151980gaacataata aatttattaa gtgtcagaaa cttgaaggaa
ggtataaggc tcaaagagtt 152040gctcaaagtt tagtgaaggc ctggccaaaa agcagatgat
gaccccaaat gatcactagt 152100accacaggag aactgtgaag caaatggtaa agatggtcag
agcaggagag agaaatagtt 152160tctgcctcgg tgagttcagg agggcttctc agaggaggtg
acatttgatg tgggccttga 152220tgtatgagga ggagacctat gattactgcc ttatagggca
tttgttgtgt gcctggctgt 152280atttgtatag tgtagttgga aatctaggct ctgaccaggc
atggtggctc acacctgtaa 152340tctcagcact ttgggaggat cagttgagcc caggagtttg
ggaccaacct gggtaacata 152400gtgagacccc ttctctacaa aaaaaagtaa aaaaaaaatt
agccaggcat ggtggcacac 152460acctgtagtc tacttgtggg ggatgaggtg ggaggattgc
ttatgtccag gaggtcgaga 152520ctgctgtgag ctgtgatcat gccattgcac tccagcctgg
gtaacacagc aagaccctgt 152580ctcaaaaaga aagaaaaagg aatgtaggct ctgtgtgaac
atttagatct atgtttccta 152640gtaggcagaa aggcagtggg gagcctcagg aggaacaagt
gtaaaggatg gggtcagatc 152700ctggttttag tctgaaaggc caagtggcaa gctggtgctc
ccagagtggt ccatttgagg 152760aagcagtggc actggaaatg gagaggaggg acttgaggcc
agagatctat ggtggctata 152820gagagtgaga gagagaatcc attccaaaat gttccacgta
gcttagtgat tgggtcggaa 152880gatgacagtg cagttatcag aactagggcc agccaggcag
agggtgggtg aggattggtc 152940agggccttaa agggtttaat attttacttt gaggggtttt
gaaggatccc caatacccaa 153000atggagatgt ttactagatc actgtgaggt ttggtggcct
cagccccaac agtccctcac 153060tgggtaccct ccctcttctc ttaaagccaa tgtgcttcag
gggaagctaa ctccacccca 153120gacaggattt gaacccctac agatgtatga gatcattagc
atgacacagt tactattgat 153180tgcaaattac agaataccca gctcaagcca actcacacaa
taaaggggcc cagtaagttg 153240cataactaga aagttcaaga catccaagac aggtttcagc
aatttgattt ggtcattgag 153300ctgcgccctg caaggcgtca aatatttctg ctgttctgct
ttgtgggcct ggttctggcc 153360ttcctcttgg tggcaggatg gccttcctct tggtggcagg
atggctgcag cagcaccaga 153420tgtcccacct tcacgccaca tcaattaaga gagacaccct
ctcaggattc ttagaagtcg 153480agagcctcct ttcccagaag tctccagcac gtctgccttc
ccctctcact gacctggaca 153540catgcccact gctgagtcat ttcctgtggc taaagaaatg
ccatgtgctc attgactaag 153600gcttagtgaa gaaggatttt tccctgatcc actcagggac
cacacctgga catggcggtg 153660gagccagctt cccctacaac acattggctt taagggaggc
ggatggggac tgttggagga 153720tgttcagtgc caaaggacgt agggtgcaca gcttcatgga
ggtgcacctc tgtggagacg 153780tccagaggca gggagaagag ctttggggaa cacaaattct
gagagggatg aagagtacta 153840ggcaccaggg agagaccgag agactacctg gagaggtagg
aggagaacag gctctgcacc 153900ctgggcagga gggcttcaag gaggaagcgg cagtcaggtg
gtgcacaatg ggtagatgtt 153960ctaggtgccc acttcagtta acagattacc ttgctacatg
ctgtgaccca aacgcacagc 154020cacaaacctg ccctgtgggg gcagttccta gctttgagct
taattaagga gcattaatgc 154080cagttggaac cgtttttttt ccccttcaag tggccaaata
gagaaacata gaagaagtga 154140ggttttcttt tttcccttca tatatattcc tttttatttc
ttgttatgcc ttcccaaaac 154200agagacattg aacagtagtt agaatggcca tctcccaatg
tttaaaaaca aactgaactc 154260cccaatgggt gaacaaagta aagagtagta acctggagtt
cagctgagta agccgctgcg 154320gagccttaag tggtgaggtc ttccaatttc agagtgctgt
gtcttcaact tgtatcatca 154380ttttagtgga aaaacataat ttaattttgg tgaaatgaga
ttcatctcgt gacaggatta 154440gtaacagcat tcacagaatt tcacactgaa gaagtgaggt
tttctaaaga aaggaagtgt 154500tcttctgagg caggggtcag agtcttgtcc tgtgtttata
ggatttgcaa tgtggatgcg 154560tttcccttgg ggctgatgag ggatacccag ggggtctgtc
tggttctgaa atccaggatg 154620ctgagtgcca ggctccctgt agaactgttg attttaaatg
ggccatctca gcttggcctc 154680catcctttat cctcactgaa ctcaggggtg tccatttgct
tgatttcacc ctgtgccttt 154740gctcattctc ctagataagt atgctgttcg cttcatccct
catgagaatg gtgtccacac 154800catcgatgtc aagttcaatg ggagccacgt ggttggaagc
cccttcaaag tgcgcgttgg 154860ggagcctgga caagcgggga accctgccct ggtgtccgcc
tatggcacgg gactcgaagg 154920gggcaccaca ggtaacccac tcttctgctt cttgaagcct
taactgaacc agctccaggg 154980accaagccag atggaaatcc tcaagcccca tgaaagcttt
ttacacgtac tccccgtgga 155040aactggggtc atgcacactt cggaggcgct tgctgtccaa
agctgttttg ggagttgcgg 155100tttgacccac gataaatcca gagtgagagc tcgatggccg
tgttatcaca cctcattact 155160gttagttgtg attcagattc cttcctctgc caagtttctt
gactttcaga acaggatgct 155220gatagtcagg gaacacagca cagtgtcatt aattttgagg
gtttctttgc ctgcacagaa 155280ttcatgatgc gtccaagtgg gctcctaccc gtctgttctt
tcatggtacc aggctcccag 155340aaatgcactg aagcagcaat aagacctgtc ccagcctatc
tcctcctctt tttactctca 155400gatcttaatg gaggaggaga aaagactgaa atgttcaaag
aattctgaag ctttttagac 155460ccgttacaat ttacttttat tctttgccac agatgggaca
tgtttgatta tgaaagatac 155520aggcagtgaa gaagtaaata aagtgagact cactccatct
tctctcctcc tcccccacct 155580gggtctggaa gcaaacggct ctgggaaggg aggaccttca
ccctgtctgt catctcattg 155640tctgtcttca ttcttggttg ctgggttggt tagctaattg
gttcattaga caagcagaca 155700cagagttttg cttttgtctt acagaaagaa tcttactgta
tccactgtgt ggtatagctt 155760gtgtttttgc tttgacatct taaagatctt tccatgtcag
aacagatctt cccctccttt 155820tcctggctgt agtgagaatt cctgctgtga atcgcagtta
tttgaacagg tggcatcggg 155880tggtgcgcag tgagtgcgtc actgttatgg aggctgccag
ggtggagagt cagtccttag 155940tctttgcagg ggaagtgcgc agtgtggact cactggggca
tgtttgcatt tggtgttact 156000ttggaccctc ttgggaaagc agtatgtcct ggtttcttga
gtctcttgtg tgtgtacccc 156060caccccgcat aaggagagtg ggatggagca gacttgcctc
ccaggggtga ggggtgagtg 156120gctgcatggt tgcctggcat ccagccctag gagcaagtga
cctgtgtggc caaggggccc 156180tctccgggtg caggagtgac tggtgggctg gcaggctgcc
cgggactctg gccaaagcag 156240tggcctcagc aaagccaccc acaggggtgg tgtgagtgct
gccagactcc ccaggcaaat 156300ccagcccggc tccacgctga actctgggcc tgcggcttgc
cttttgtgaa aggcatggta 156360tcattttacc gtaagtgatg tccattttac agatgtggaa
agtgagatgc agaggttgag 156420tcactcccca aacaacactc ccccaaaaag cagtcagctg
ggaggaggca gaaccaggaa 156480tcagtctaca tccgtgacct cagagcctat gcgctgaacc
cccgagcttg gccccctctc 156540taagtggctg gctcacccag aggcagtgac tgcatcccca
gcccactttg gggatgtcct 156600aaaccaggac ccctgtcctc ccagccactc aggagtactt
tccaggcagc agtgctggca 156660cttgggccct gacaaggtac tcacctttga gggcccaggt
ggggtcctct cggcacttgg 156720agcgcgtggc aggcttcagg ccaggcctca cagcagctgc
tggggtctcc cacactggcc 156780aggaagcatc tcaccctcct gctggctcat gccgctgtgc
ctgggccctc tcccatttcc 156840ttttggctgt tcgcacacct ttttgggagc ttgggtttca
ggctgtgctc tgcaagtgct 156900ggacgctgct gagagaagga gttgctcttg cagggaagct
cctagccagg aggggagagg 156960tacagaaccg cctgcttcaa accctgtgta aatattgctc
ttgtcacagg gaaggcgcct 157020tgtttttcca gccctcctgc tcccaagcct ttccctaaat
atccattctg agattacaca 157080gctgcagtgt gcatggaatg aaaaggtatc tgtgcttggc
cgccagagcg cccagtatcc 157140tgaccttctg aacaaagcaa acctccctct gtttttaatg
ggtgagtttg ctgtatctct 157200tggctcaagc tttaaatggt ccattctgta gattttggag
taggggaatg tggagaattt 157260ggggcgggac cctgctggag gcggcttgag aggctgggag
atagaccagg gagctccaga 157320ttctttggag ccgctgagca attttcctaa tgaaatggtc
caggaacccc agtgtgctcg 157380gggtatacca gaagggcctc cttccttaac tgccttgaag
aacaagcagt gctgcgttta 157440acatgcatta aactcacagg aactgagctg gacatatttg
agggggtggg ggaagaccgc 157500cacgcccaga gatgttttgt ggtgtcagat acaggttata
gctagaggca gtggtgagag 157560acttctgctt gtggattttt ttccttccat cttctctcag
gtaagtgctt tagctccaag 157620ttggacagac tttatgttta aatcccagtt ctgctggtcc
ccagctgtgt gactccagat 157680gaattatctg acttcactgt gcctctgctt cctttcctgt
aaaacaggat taataacagg 157740acccacctaa taggcttgtt tggagctgta gaggaggtaa
cagccaagta gtagctcttg 157800tcccataacc cctgctttct cttttcccac ctcgtcttcc
ctgccctttt gggccctcac 157860agtcaagatg aactgatttt tggttggtca aaatattgca
ttagggccaa atgggtgcgg 157920tggctcatgc ctgtaatcaa agcactttgg aaggccaagg
cagaaagatt gtttgaggcc 157980aagagtttga gaccagcctg ggtgacatag taaaactcca
tctctaccaa aaaaaaaaat 158040ttttaaagac gaacttagga atgaaacagc ttgttaaaaa
atggtggaac tttcccctgc 158100agccacatca tttcaacttc actttaaaaa tatctttttg
gcctggcaca gtggctcaca 158160cctgtaatcc cagcactttg ggaggtggag gtgggaggat
cacttgagcc taggagtttg 158220agaccagccc aggcaacaca gcaaaacccc atctctacaa
aaaaatttaa aaattagcca 158280ggcgtggtgg tgcatgcctg aagtcccagc tactttggag
gctgaggcag gaggatggct 158340tgagcctgga agattgacgc tgtggtgagc tgtgatcatg
ccaccgtact ccagcctggg 158400caacagagga agactttatc taaaaaaaaa aatattagta
ataaggccgg gtgcgttggc 158460tcatgcctgt aatcctagca ctttgggaga ccaaggtggg
cagatcactt gaggtcagga 158520gctcaagacc agcctggcca acatggtgag accccatctc
tactaaagaa atacaaaaat 158580tagctgggca tggtggcgag tgcctgtaat cccagctaat
caggaagctg aagcaggaga 158640atcgcttgaa cctgggaggc ggaggttgca ataagccaag
atcatggtac tgcactccag 158700cctgggcaac agagcgagac tctatctcaa tcaatcaatc
aataaaatat ctttccttat 158760catcacctta cagctgcttc ctggatggac acactgtctc
cttgttgctc acctcccgct 158820tcttccctac gtagccccag gcctcagagc tgctgcttga
ggggcttctt ggctgcacag 158880attagatacc atgatgaggt tgagatagtg ttgggggtgg
accttggggc aggagcctca 158940agagcttcca ggaacagctg ggttgtgttt gagagttgca
cgatagcagc tcttttgttt 159000ttattgatat ccagaacaat aattctttct ctggactagg
agctataatt aaaccaaaat 159060atttcccagc tggggcagtg tctagggctc tggcagaagc
atagccctgc atggggatgc 159120tatgccaggc atgccccata gagggcactg tagcaggcat
gcgccagacc tgatgactga 159180aggaggctct ccctgggcca gctaagttgt ctcagggctg
cagttagggg atctgaggca 159240gctccactgc ccatccaggg gtcaagagat gagcctggca
ccagagccat gcagacatgg 159300ttcaaacccg gctctaccac tttctggttg tgtagcgtga
ctggccccct ccctgagccg 159360cagagtcatt tgtgaagcag gaatcacgga aaggattcca
taccacatgc gtaaatggtg 159420ctgtgcacag gacctggagc cggagtgggg tacgcatgcc
ccgtcagcgg gagctgctgt 159480tctgttcctg tgcttgttgc tggaattcac ggcaaagtgg
gtgggctggc aggtcacagt 159540ggctgcaccc ggtctgcagc acagtgcctg gggtgagggc
tgaggaggaa gggaggagat 159600gcttggcctc cctggcttct ccaagtctac ccggagaaga
aaggacagtc agaggggccc 159660acgcctcccc cacacccctg gagggagagc tggactctgg
tggctgaagc agcacttcag 159720gctcacagtg tgactcaggc ttcttgccct cagccacaat
ggctcatgcc cagaggagag 159780aacagggtgt ccaggctgtt ggtgcttgtg ggcgaaatgt
cagccatgct cctcctgcct 159840tggcctagaa aagggagccc ccaccccgca gggcctgagg
ttctctctgc cagaagttca 159900gagctagtgc cagtgggttc ccatgccacc agggtgagcc
ctctgtaagg ggatctatgt 159960gtgtccctca ccacggcctc agtgctccca ggaaagccct
ccaagtcatc aacacagcat 160020tttctattcc tttctcccag gtatccagtc ggaattcttt
attaacacca cccgagcagg 160080tccagggaca ttatccgtca ccatcgaagg cccatccaag
gttaaaatgg attgccagga 160140aacacctgaa gggtacaaag tcatgtacac ccccatggct
cctggtaact acctgatcag 160200cgtcaaatac ggtgggccca accacatcgt gggcagtccc
ttcaaggcca aggtgacagg 160260taacgaacaa ccaccttcgg agttactctc ccttcctggg
gagctggttg tgtcagatca 160320atcatagtgg aaactatgga tggttttaga tgtgttaaag
ctactttgaa ctttgaatgt 160380cagtaaatag tatgagatgt cagagggcag tgtttgaaac
ttacaaaagt ccacagagtg 160440gagccgtgca gaagttgaga aagcatgtta ggatgttagg
tggttttcta tctctaacag 160500gaaagaatac atattgaaat cttacgtatt tgtttagatc
agggtctgaa aaatcccctg 160560atttctaatt ttcacttgaa aaataatcaa aaagttttcc
tatacttata aaaatgtgtc 160620tcctccaaaa cactggaaaa aataccaaac tatgaaaacc
acttcacagc caccacccaa 160680ggtaaccacc ataaacactg tagtaaatcc cttccacacg
tcatgattca ctgttacata 160740aagaatgtag gttcatcgca ggaaaattag aaaattcaga
tagaaaaatc atcctttctc 160800atccacagaa tcattttttg atatttcatt atatgtcatc
ccaaactttt acactgctta 160860tacatagact attttatgtc aatagaaaga tgtgaattcc
acaggcacat ctttggtggg 160920tagggggtgg ggggattggg agggtccttg gccttgtcag
ccaaggccag actcatccat 160980ttgcccagaa agccagatcc tagttgtatg ggggtgggat
cctaggggtt tagaagacat 161040tatgggtgtg agatacaggt gtggtggctt ttgtgttggg
gtgcgcgggc tctcctgggg 161100ttactgtgta gggtactcgc ctgtcctctg gctgagagac
ccctcttgat ctggccattc 161160atgcctgtcc ccctccctcc tgtatcttag gccagcgtct
agttagccct ggctcagcca 161220acgagacctc atccatcctg gtggagtcag tgaccaggtc
gtctacagag acctgctata 161280gcgccattcc caaggcatcc tcggacgcca gcaaggtgac
ctctaagggg gcagggctct 161340caaaggcctt tgtgggccag aagagttcct tcctggtgga
ctgcagcaaa gctggtaggt 161400gtctgggcct tttcaagggt ggggtggggc aggggcaggc
tgggcaccct gggtacactg 161460gccttccctg ctgaggtctc ctgcagtgcc cacccccatg
taggccagcc gtttgcaagt 161520aaccatcgtc atgaccctgt tctcctgcac ttaatatttt
taaatgattt ccttctcttt 161580tgccttttga acttgggtat ttatttgggt ttcaagggtc
ggttgcctgg gttctggcat 161640ccagtacacc tgggctggaa acctagtacc gccacttcat
tcattcattc gtttgttcta 161700aaacttattt agccatgtga ccttggaaag ttattaaatc
tctttccaaa agtcagtttc 161760ctcttctcgg aagtaccttc cttaaggtgc ttgtgagagt
aaacaagaag attctcatag 161820ccaacactta gaatagccct tactgtgtgc taggttttga
cacccataac tcttaaacct 161880cacaactagt tcgtgaggta tgtgctgttc tcattccctg
tttacagatg gggaagctga 161940gctagggaga ggtgagattc cagtccaagg tcacccaggt
agcaagtggc agggcaggga 162000ttcgaaccca caccgtcagg ctctatgagc ctctgcttgt
aattgccacg ctctcccacc 162060tcttaggggc cccagcatta tcgtggaagc accttacctt
tggctctcat atttcctctt 162120cttcctgtgc ctgtcctgat gcatccgggt ggagtaacca
ccttttgcct cctaggctcc 162180aacatgctgc tgatcggggt ccatgggccc accaccccct
gcgaggaggt ctccatgaag 162240catgtaggca accagcaata caacgtcaca tacgtcgtca
aggagagggg cgattatgtg 162300ctggctgtga agtgggggga ggaacacatc cctggcagcc
cttttcatgt cacagtgcct 162360taaaacagtt ttctcaaatc ctggagagag ttcttgtggt
tgcttttgtt gcttgtttgt 162420aattcatttt atacaaagcc ctccagcctg tttgtggggc
tgaaacccca tccctaaaat 162480attgctgttg taaaatgcct tcagaaataa gtcctagact
ggactcttga gggacatatt 162540ggagaatctt aagaaatgca agcttgttca gggggctgag
aagatcctga gtacactagg 162600tgcaaaccag aactcttggt ggaacagacc agccactgca
gcagacagac caggaacaca 162660atgagactga catttcaaaa aaacaaaact ggctagcctg
agctgctggt tcactcttca 162720gcatttatga aacaaggcta ggggaagatg ggcagagaaa
aaggggacac ctagtttggt 162780tgtcatttgg caaaggagat gacttaaaat ccgcttaatc
tcttccagtg tccgtgttaa 162840tgtatttggc tattagatca ctagcactgc tttaccgctc
ctcatcgcca acacccccat 162900gctctgtggc cttcttacac ttctcagagg gcagagtggc
agccgggcac cctacagaaa 162960ctcagagggc agagtggcag ccaggcccac atgtctctca
agtacctgtc ccctcgctct 163020ggtgattatt tcttgcagaa tcaccacacg agaccatccc
ggcagtcatg gttttgcttt 163080agttttccaa gtccgtttca gtcccttcct tggtctgaag
aaattctgca gtggcgagca 163140gtttcccact tgccaaagat cccttttaac caacactagc
ccttgttttt aacacacgct 163200ccagcccttc atcagcctgg gcagtcttac caaaatgttt
aaagtgatct cagaggggcc 163260catggattaa cgccctcatc ccaaggtccg tcccatgaca
taacactcca cacccgcccc 163320agccaacttc atgggtcact ttttctggaa aataatgatc
tgtacagaca ggacagaatg 163380aaactcctgc gggtctttgg cctgaaagtt gggaatggtt
gggggagaga agggcagcag 163440cttattggtg gtcttttcac cattggcaga aacagtgaga
gctgtgtggt gcagaaatcc 163500agaaatgagg tgtagggaat tttgcctgcc ttcctgcaga
cctgagctgg ctttggaatg 163560aggttaaagt gtcagggacg ttgcctgagc ccaaatgtgt
agtgtggtct gggcaggcag 163620acctttaggt tttgctgctt agtcctgagg aagtggccac
tcttgtggca ggtgtagtat 163680ctggggcgag tgttgggggt aaaagcccac cctacagaaa
gtggaacagc ccggagcctg 163740atgtgaaagg accacgggtg ttgtaagctg ggacacggaa
gccaaactgg aatcaaacgc 163800cgactgtaaa ttgtatctta taacttatta aataaaacat
ttgctccgta aagttg 163856222633PRTHomo sapiens 22Met Pro Val Thr Glu
Lys Asp Leu Ala Glu Asp Ala Pro Trp Lys Lys 1 5
10 15 Ile Gln Gln Asn Thr Phe Thr Arg Trp Cys
Asn Glu His Leu Lys Cys 20 25
30 Val Asn Lys Arg Ile Gly Asn Leu Gln Thr Asp Leu Ser Asp Gly
Leu 35 40 45 Arg
Leu Ile Ala Leu Leu Glu Val Leu Ser Gln Lys Arg Met Tyr Arg 50
55 60 Lys Tyr His Gln Arg Pro
Thr Phe Arg Gln Met Gln Leu Glu Asn Val 65 70
75 80 Ser Val Ala Leu Glu Phe Leu Asp Arg Glu Ser
Ile Lys Leu Val Ser 85 90
95 Ile Asp Ser Lys Ala Ile Val Asp Gly Asn Leu Lys Leu Ile Leu Gly
100 105 110 Leu Val
Trp Thr Leu Ile Leu His Tyr Ser Ile Ser Met Pro Val Trp 115
120 125 Glu Asp Glu Gly Asp Asp Asp
Ala Lys Lys Gln Thr Pro Lys Gln Arg 130 135
140 Leu Leu Gly Trp Ile Gln Asn Lys Ile Pro Tyr Leu
Pro Ile Thr Asn 145 150 155
160 Phe Asn Gln Asn Trp Gln Asp Gly Lys Ala Leu Gly Ala Leu Val Asp
165 170 175 Ser Cys Ala
Pro Gly Leu Cys Pro Asp Trp Glu Ser Trp Asp Pro Gln 180
185 190 Lys Pro Val Asp Asn Ala Arg Glu
Ala Met Gln Gln Ala Asp Asp Trp 195 200
205 Leu Gly Val Pro Gln Val Ile Thr Pro Glu Glu Ile Ile
His Pro Asp 210 215 220
Val Asp Glu His Ser Val Met Thr Tyr Leu Ser Gln Phe Pro Lys Ala 225
230 235 240 Lys Leu Lys Pro
Gly Ala Pro Leu Lys Pro Lys Leu Asn Pro Lys Lys 245
250 255 Ala Arg Ala Tyr Gly Arg Gly Ile Glu
Pro Thr Gly Asn Met Val Lys 260 265
270 Gln Pro Ala Lys Phe Thr Val Asp Thr Ile Ser Ala Gly Gln
Gly Asp 275 280 285
Val Met Val Phe Val Glu Asp Pro Glu Gly Asn Lys Glu Glu Ala Gln 290
295 300 Val Thr Pro Asp Ser
Asp Lys Asn Lys Thr Tyr Ser Val Glu Tyr Leu 305 310
315 320 Pro Lys Val Thr Gly Leu His Lys Val Thr
Val Leu Phe Ala Gly Gln 325 330
335 His Ile Ser Lys Ser Pro Phe Glu Val Ser Val Asp Lys Ala Gln
Gly 340 345 350 Asp
Ala Ser Lys Val Thr Ala Lys Gly Pro Gly Leu Glu Ala Val Gly 355
360 365 Asn Ile Ala Asn Lys Pro
Thr Tyr Phe Asp Ile Tyr Thr Ala Gly Ala 370 375
380 Gly Val Gly Asp Ile Gly Val Glu Val Glu Asp
Pro Gln Gly Lys Asn 385 390 395
400 Thr Val Glu Leu Leu Val Glu Asp Lys Gly Asn Gln Val Tyr Arg Cys
405 410 415 Val Tyr
Lys Pro Met Gln Pro Gly Pro His Val Val Lys Ile Phe Phe 420
425 430 Ala Gly Asp Thr Ile Pro Lys
Ser Pro Phe Val Val Gln Val Gly Glu 435 440
445 Ala Cys Asn Pro Asn Ala Cys Arg Ala Ser Gly Arg
Gly Leu Gln Pro 450 455 460
Lys Gly Val Arg Ile Arg Glu Thr Thr Asp Phe Lys Val Asp Thr Lys 465
470 475 480 Ala Ala Gly
Ser Gly Glu Leu Gly Val Thr Met Lys Gly Pro Lys Gly 485
490 495 Leu Glu Glu Leu Val Lys Gln Lys
Asp Phe Leu Asp Gly Val Tyr Ala 500 505
510 Phe Glu Tyr Tyr Pro Ser Thr Pro Gly Arg Tyr Ser Ile
Ala Ile Thr 515 520 525
Trp Gly Gly His His Ile Pro Lys Ser Pro Phe Glu Val Gln Val Gly 530
535 540 Pro Glu Ala Gly
Met Gln Lys Val Arg Ala Trp Gly Pro Gly Leu His 545 550
555 560 Gly Gly Ile Val Gly Arg Ser Ala Asp
Phe Val Val Glu Ser Ile Gly 565 570
575 Ser Glu Val Gly Ser Leu Gly Phe Ala Ile Glu Gly Pro Ser
Gln Ala 580 585 590
Lys Ile Glu Tyr Asn Asp Gln Asn Asp Gly Ser Cys Asp Val Lys Tyr
595 600 605 Trp Pro Lys Glu
Pro Gly Glu Tyr Ala Val His Ile Met Cys Asp Asp 610
615 620 Glu Asp Ile Lys Asp Ser Pro Tyr
Met Ala Phe Ile His Pro Ala Thr 625 630
635 640 Gly Gly Tyr Asn Pro Asp Leu Val Arg Ala Tyr Gly
Pro Gly Leu Glu 645 650
655 Lys Ser Gly Cys Ile Val Asn Asn Leu Ala Glu Phe Thr Val Asp Pro
660 665 670 Lys Asp Ala
Gly Lys Ala Pro Leu Lys Ile Phe Ala Gln Asp Gly Glu 675
680 685 Gly Gln Arg Ile Asp Ile Gln Met
Lys Asn Arg Met Asp Gly Thr Tyr 690 695
700 Ala Cys Ser Tyr Thr Pro Val Lys Ala Ile Lys His Thr
Ile Ala Val 705 710 715
720 Val Trp Gly Gly Val Asn Ile Pro His Ser Pro Tyr Arg Val Asn Ile
725 730 735 Gly Gln Gly Ser
His Pro Gln Lys Val Lys Val Phe Gly Pro Gly Val 740
745 750 Glu Arg Ser Gly Leu Lys Ala Asn Glu
Pro Thr His Phe Thr Val Asp 755 760
765 Cys Thr Glu Ala Gly Glu Gly Asp Val Ser Val Gly Ile Lys
Cys Asp 770 775 780
Ala Arg Val Leu Ser Glu Asp Glu Glu Asp Val Asp Phe Asp Ile Ile 785
790 795 800 His Asn Ala Asn Asp
Thr Phe Thr Val Lys Tyr Val Pro Pro Ala Ala 805
810 815 Gly Arg Tyr Thr Ile Lys Val Leu Phe Ala
Ser Gln Glu Ile Pro Ala 820 825
830 Ser Pro Phe Arg Val Lys Val Asp Pro Ser His Asp Ala Ser Lys
Val 835 840 845 Lys
Ala Glu Gly Pro Gly Leu Ser Lys Ala Gly Val Glu Asn Gly Lys 850
855 860 Pro Thr His Phe Thr Val
Tyr Thr Lys Gly Ala Gly Lys Ala Pro Leu 865 870
875 880 Asn Val Gln Phe Asn Ser Pro Leu Pro Gly Asp
Ala Val Lys Asp Leu 885 890
895 Asp Ile Ile Asp Asn Tyr Asp Tyr Ser His Thr Val Lys Tyr Thr Pro
900 905 910 Thr Gln
Gln Gly Asn Met Gln Val Leu Val Thr Tyr Gly Gly Asp Pro 915
920 925 Ile Pro Lys Ser Pro Phe Thr
Val Gly Val Ala Ala Pro Leu Asp Leu 930 935
940 Ser Lys Ile Lys Leu Asn Gly Leu Glu Asn Arg Val
Glu Val Gly Lys 945 950 955
960 Asp Gln Glu Phe Thr Val Asp Thr Arg Gly Ala Gly Gly Gln Gly Lys
965 970 975 Leu Asp Val
Thr Ile Leu Ser Pro Ser Arg Lys Val Val Pro Cys Leu 980
985 990 Val Thr Pro Val Thr Gly Arg Glu
Asn Ser Thr Ala Lys Phe Ile Pro 995 1000
1005 Arg Glu Glu Gly Leu Tyr Ala Val Asp Val Thr
Tyr Asp Gly His 1010 1015 1020
Pro Val Pro Gly Ser Pro Tyr Thr Val Glu Ala Ser Leu Pro Pro
1025 1030 1035 Asp Pro Ser
Lys Val Lys Ala His Gly Pro Gly Leu Glu Gly Gly 1040
1045 1050 Leu Val Gly Lys Pro Ala Glu Phe
Thr Ile Asp Thr Lys Gly Ala 1055 1060
1065 Gly Thr Gly Gly Leu Gly Leu Thr Val Glu Gly Pro Cys
Glu Ala 1070 1075 1080
Lys Ile Glu Cys Ser Asp Asn Gly Asp Gly Thr Cys Ser Val Ser 1085
1090 1095 Tyr Leu Pro Thr Lys
Pro Gly Glu Tyr Phe Val Asn Ile Leu Phe 1100 1105
1110 Glu Glu Val His Ile Pro Gly Ser Pro Phe
Lys Ala Asp Ile Glu 1115 1120 1125
Met Pro Phe Asp Pro Ser Lys Val Val Ala Ser Gly Pro Gly Leu
1130 1135 1140 Glu His
Gly Lys Val Gly Glu Ala Gly Leu Leu Ser Val Asp Cys 1145
1150 1155 Ser Glu Ala Gly Pro Gly Ala
Leu Gly Leu Glu Ala Val Ser Asp 1160 1165
1170 Ser Gly Thr Lys Ala Glu Val Ser Ile Gln Asn Asn
Lys Asp Gly 1175 1180 1185
Thr Tyr Ala Val Thr Tyr Val Pro Leu Thr Ala Gly Met Tyr Thr 1190
1195 1200 Leu Thr Met Lys Tyr
Gly Gly Glu Leu Val Pro His Phe Pro Ala 1205 1210
1215 Arg Val Lys Val Glu Pro Ala Val Asp Thr
Ser Arg Ile Lys Val 1220 1225 1230
Phe Gly Pro Gly Ile Glu Gly Lys Asp Val Phe Arg Glu Ala Thr
1235 1240 1245 Thr Asp
Phe Thr Val Asp Ser Arg Pro Leu Thr Gln Val Gly Gly 1250
1255 1260 Asp His Ile Lys Ala His Ile
Ala Asn Pro Ser Gly Ala Ser Thr 1265 1270
1275 Glu Cys Phe Val Thr Asp Asn Ala Asp Gly Thr Tyr
Gln Val Glu 1280 1285 1290
Tyr Thr Pro Phe Glu Lys Gly Leu His Val Val Glu Val Thr Tyr 1295
1300 1305 Asp Asp Val Pro Ile
Pro Asn Ser Pro Phe Lys Val Ala Val Thr 1310 1315
1320 Glu Gly Cys Gln Pro Ser Arg Val Gln Ala
Gln Gly Pro Gly Leu 1325 1330 1335
Lys Glu Ala Phe Thr Asn Lys Pro Asn Val Phe Thr Val Val Thr
1340 1345 1350 Arg Gly
Ala Gly Ile Gly Gly Leu Gly Ile Thr Val Glu Gly Pro 1355
1360 1365 Ser Glu Ser Lys Ile Asn Cys
Arg Asp Asn Lys Asp Gly Ser Cys 1370 1375
1380 Ser Ala Glu Tyr Ile Pro Phe Ala Pro Gly Asp Tyr
Asp Val Asn 1385 1390 1395
Ile Thr Tyr Gly Gly Ala His Ile Pro Gly Ser Pro Phe Arg Val 1400
1405 1410 Pro Val Lys Asp Val
Val Asp Pro Ser Lys Val Lys Ile Ala Gly 1415 1420
1425 Pro Gly Leu Gly Ser Gly Val Arg Ala Arg
Val Leu Gln Ser Phe 1430 1435 1440
Thr Val Asp Ser Ser Lys Ala Gly Leu Ala Pro Leu Glu Val Arg
1445 1450 1455 Val Leu
Gly Pro Arg Ala Asp Asp Thr Asp Ser Gln Ser Trp Arg 1460
1465 1470 Ser Pro Leu Lys Ala Leu Ser
Glu Phe Phe Lys Gly Asp Pro Lys 1475 1480
1485 Gly Asp Phe Asn Lys Thr Gly Leu Val Glu Pro Val
Asn Val Val 1490 1495 1500
Asp Asn Gly Asp Gly Thr His Thr Val Thr Tyr Thr Pro Ser Gln 1505
1510 1515 Glu Gly Pro Tyr Met
Val Ser Val Lys Tyr Ala Asp Glu Glu Ile 1520 1525
1530 Pro Arg Ser Pro Phe Lys Val Lys Val Leu
Pro Thr Tyr Asp Ala 1535 1540 1545
Ser Lys Val Thr Ala Ser Gly Pro Gly Leu Ser Ser Tyr Gly Val
1550 1555 1560 Pro Ala
Ser Leu Pro Val Asp Phe Ala Ile Asp Ala Arg Asp Ala 1565
1570 1575 Gly Glu Gly Leu Leu Ala Val
Gln Ile Thr Asp Gln Glu Gly Lys 1580 1585
1590 Pro Lys Arg Ala Ile Val His Asp Asn Lys Asp Gly
Thr Tyr Ala 1595 1600 1605
Val Thr Tyr Ile Pro Asp Lys Thr Gly Arg Tyr Met Ile Gly Val 1610
1615 1620 Thr Tyr Gly Gly Asp
Asp Ile Pro Leu Ser Pro Tyr Arg Ile Arg 1625 1630
1635 Ala Thr Gln Thr Gly Asp Ala Ser Lys Cys
Leu Ala Thr Gly Pro 1640 1645 1650
Gly Ile Ala Ser Thr Val Lys Thr Gly Glu Glu Val Gly Phe Val
1655 1660 1665 Val Asp
Ala Lys Thr Ala Gly Lys Gly Lys Val Thr Cys Thr Val 1670
1675 1680 Leu Thr Pro Asp Gly Thr Glu
Ala Glu Ala Asp Val Ile Glu Asn 1685 1690
1695 Glu Asp Gly Thr Tyr Asp Ile Phe Tyr Thr Ala Ala
Lys Pro Gly 1700 1705 1710
Thr Tyr Val Ile Tyr Val Arg Phe Gly Gly Val Asp Ile Pro Asn 1715
1720 1725 Ser Pro Phe Thr Val
Met Ala Thr Asp Gly Glu Val Thr Ala Val 1730 1735
1740 Glu Glu Ala Pro Val Asn Ala Cys Pro Pro
Gly Phe Arg Pro Trp 1745 1750 1755
Val Thr Glu Glu Ala Tyr Val Pro Val Ser Asp Met Asn Gly Leu
1760 1765 1770 Gly Phe
Lys Pro Phe Asp Leu Val Ile Pro Phe Ala Val Arg Lys 1775
1780 1785 Gly Glu Ile Thr Gly Glu Val
His Met Pro Ser Gly Lys Thr Ala 1790 1795
1800 Thr Pro Glu Ile Val Asp Asn Lys Asp Gly Thr Val
Thr Val Arg 1805 1810 1815
Tyr Ala Pro Thr Glu Val Gly Leu His Glu Met His Ile Lys Tyr 1820
1825 1830 Met Gly Ser His Ile
Pro Glu Ser Pro Leu Gln Phe Tyr Val Asn 1835 1840
1845 Tyr Pro Asn Ser Gly Ser Val Ser Ala Tyr
Gly Pro Gly Leu Val 1850 1855 1860
Tyr Gly Val Ala Asn Lys Thr Ala Thr Phe Thr Ile Val Thr Glu
1865 1870 1875 Asp Ala
Gly Glu Gly Gly Leu Asp Leu Ala Ile Glu Gly Pro Ser 1880
1885 1890 Lys Ala Glu Ile Ser Cys Ile
Asp Asn Lys Asp Gly Thr Cys Thr 1895 1900
1905 Val Thr Tyr Leu Pro Thr Leu Pro Gly Asp Tyr Ser
Ile Leu Val 1910 1915 1920
Lys Tyr Asn Asp Lys His Ile Pro Gly Ser Pro Phe Thr Ala Lys 1925
1930 1935 Ile Thr Asp Asp Ser
Arg Arg Cys Ser Gln Val Lys Leu Gly Ser 1940 1945
1950 Ala Ala Asp Phe Leu Leu Asp Ile Ser Glu
Thr Asp Leu Ser Ser 1955 1960 1965
Leu Thr Ala Ser Ile Lys Ala Pro Ser Gly Arg Asp Glu Pro Cys
1970 1975 1980 Leu Leu
Lys Arg Leu Pro Asn Asn His Ile Gly Ile Ser Phe Ile 1985
1990 1995 Pro Arg Glu Val Gly Glu His
Leu Val Ser Ile Lys Lys Asn Gly 2000 2005
2010 Asn His Val Ala Asn Ser Pro Val Ser Ile Met Val
Val Gln Ser 2015 2020 2025
Glu Ile Gly Asp Ala Arg Arg Ala Lys Val Tyr Gly Arg Gly Leu 2030
2035 2040 Ser Glu Gly Arg Thr
Phe Glu Met Ser Asp Phe Ile Val Asp Thr 2045 2050
2055 Arg Asp Ala Gly Tyr Gly Gly Ile Ser Leu
Ala Val Glu Gly Pro 2060 2065 2070
Ser Lys Val Asp Ile Gln Thr Glu Asp Leu Glu Asp Gly Thr Cys
2075 2080 2085 Lys Val
Ser Tyr Phe Pro Thr Val Pro Gly Val Tyr Ile Val Ser 2090
2095 2100 Thr Lys Phe Ala Asp Glu His
Val Pro Gly Ser Pro Phe Thr Val 2105 2110
2115 Lys Ile Ser Gly Glu Gly Arg Val Lys Glu Ser Ile
Thr Arg Thr 2120 2125 2130
Ser Arg Ala Pro Ser Val Ala Thr Val Gly Ser Ile Cys Asp Leu 2135
2140 2145 Asn Leu Lys Ile Pro
Glu Ile Asn Ser Ser Asp Met Ser Ala His 2150 2155
2160 Val Thr Ser Pro Ser Gly Arg Val Thr Glu
Ala Glu Ile Val Pro 2165 2170 2175
Met Gly Lys Asn Ser His Cys Val Arg Phe Val Pro Gln Glu Met
2180 2185 2190 Gly Val
His Thr Val Ser Val Lys Tyr Arg Gly Gln His Val Thr 2195
2200 2205 Gly Ser Pro Phe Gln Phe Thr
Val Gly Pro Leu Gly Glu Gly Gly 2210 2215
2220 Ala His Lys Val Arg Ala Gly Gly Pro Gly Leu Glu
Arg Gly Glu 2225 2230 2235
Ala Gly Val Pro Ala Glu Phe Ser Ile Trp Thr Arg Glu Ala Gly 2240
2245 2250 Ala Gly Gly Leu Ser
Ile Ala Val Glu Gly Pro Ser Lys Ala Glu 2255 2260
2265 Ile Thr Phe Asp Asp His Lys Asn Gly Ser
Cys Gly Val Ser Tyr 2270 2275 2280
Ile Ala Gln Glu Pro Gly Asn Tyr Glu Val Ser Ile Lys Phe Asn
2285 2290 2295 Asp Glu
His Ile Pro Glu Ser Pro Tyr Leu Val Pro Val Ile Ala 2300
2305 2310 Pro Ser Asp Asp Ala Arg Arg
Leu Thr Val Met Ser Leu Gln Glu 2315 2320
2325 Ser Gly Leu Lys Val Asn Gln Pro Ala Ser Phe Ala
Ile Arg Leu 2330 2335 2340
Asn Gly Ala Lys Gly Lys Ile Asp Ala Lys Val His Ser Pro Ser 2345
2350 2355 Gly Ala Val Glu Glu
Cys His Val Ser Glu Leu Glu Pro Asp Lys 2360 2365
2370 Tyr Ala Val Arg Phe Ile Pro His Glu Asn
Gly Val His Thr Ile 2375 2380 2385
Asp Val Lys Phe Asn Gly Ser His Val Val Gly Ser Pro Phe Lys
2390 2395 2400 Val Arg
Val Gly Glu Pro Gly Gln Ala Gly Asn Pro Ala Leu Val 2405
2410 2415 Ser Ala Tyr Gly Thr Gly Leu
Glu Gly Gly Thr Thr Gly Ile Gln 2420 2425
2430 Ser Glu Phe Phe Ile Asn Thr Thr Arg Ala Gly Pro
Gly Thr Leu 2435 2440 2445
Ser Val Thr Ile Glu Gly Pro Ser Lys Val Lys Met Asp Cys Gln 2450
2455 2460 Glu Thr Pro Glu Gly
Tyr Lys Val Met Tyr Thr Pro Met Ala Pro 2465 2470
2475 Gly Asn Tyr Leu Ile Ser Val Lys Tyr Gly
Gly Pro Asn His Ile 2480 2485 2490
Val Gly Ser Pro Phe Lys Ala Lys Val Thr Gly Gln Arg Leu Val
2495 2500 2505 Ser Pro
Gly Ser Ala Asn Glu Thr Ser Ser Ile Leu Val Glu Ser 2510
2515 2520 Val Thr Arg Ser Ser Thr Glu
Thr Cys Tyr Ser Ala Ile Pro Lys 2525 2530
2535 Ala Ser Ser Asp Ala Ser Lys Val Thr Ser Lys Gly
Ala Gly Leu 2540 2545 2550
Ser Lys Ala Phe Val Gly Gln Lys Ser Ser Phe Leu Val Asp Cys 2555
2560 2565 Ser Lys Ala Gly Ser
Asn Met Leu Leu Ile Gly Val His Gly Pro 2570 2575
2580 Thr Thr Pro Cys Glu Glu Val Ser Met Lys
His Val Gly Asn Gln 2585 2590 2595
Gln Tyr Asn Val Thr Tyr Val Val Lys Glu Arg Gly Asp Tyr Val
2600 2605 2610 Leu Ala
Val Lys Trp Gly Glu Glu His Ile Pro Gly Ser Pro Phe 2615
2620 2625 His Val Thr Val Pro 2630
239560DNAHomo sapiens 23gcggccaggg gcgggcggcc gcagagcagc
accggccgtg gctccggtag cagcaagttc 60gaaccccgct cccgctccgc ttcggttctc
gctccttcgg cccttgggcc tccaaacacc 120agtccccggc agctcgttgc gcattgcgct
ctccccgcca ccaggatgcc ggtaaccgag 180aaggatctag ctgaggacgc gccttggaag
aagatccagc agaacacgtt cacacgctgg 240tgcaacgagc acctcaagtg cgtgaacaaa
cgcatcggca acctgcagac cgacctgagc 300gacgggctgc ggctcatcgc gctgctcgag
gtgctcagcc agaagcgcat gtaccgcaag 360taccatcagc ggcccacctt tcgccagatg
cagctcgaga atgtgtccgt ggcgctcgag 420ttcctggacc gtgagagcat caagctcgtg
tccatcgata gcaaagccat tgtggatggg 480aacctgaagc tcatcttggg tctggtgtgg
acgctgatcc tccactactc catctccatg 540cccgtgtggg aggatgaagg ggatgatgat
gccaagaagc agacgccaaa gcagaggctg 600ctggggtgga ttcagaacaa gatcccctac
ttgcccatca ccaactttaa ccagaactgg 660caagacggca aagccctggg agccctggta
gacagctgtg ctccaggtct gtgcccagac 720tgggaatcct gggacccgca gaagcctgtg
gataatgcac gagaagccat gcagcaggca 780gatgactggc tgggtgtccc acaggtcatc
actcctgaag aaatcattca cccggatgtg 840gacgagcact cagttatgac ttacctgtcc
cagttcccca aagccaagct caagccgggg 900gctcctctca aacccaaact caacccgaag
aaagccaggg cctatggcag aggaatcgag 960cccactggaa acatggtgaa gcagccagcc
aagttcactg tggacaccat cagcgccggg 1020caaggagacg tgatggtgtt tgttgaggac
ccagaaggga acaaagagga ggcacaagtg 1080acccctgaca gtgacaagaa caagacatac
tctgtggagt atctgcccaa ggtcaccggg 1140ctacacaaag tcacagtcct ctttgcagga
cagcacatct ccaagagccc atttgaagtg 1200agtgttgaca aggcccaggg agatgccagt
aaagtcactg caaaaggtcc agggttggaa 1260gctgtaggga acatcgccaa taagcccacc
tactttgaca tctatacggc aggagctggt 1320gtgggtgaca ttggtgtgga ggtggaagat
ccccagggga agaacaccgt ggagttgctc 1380gtggaagaca aaggaaacca ggtgtatcga
tgtgtgtaca aacccatgca gcctggccct 1440cacgtggtca agatcttctt tgctggggac
actattccta agagtccctt cgttgtgcag 1500gttggggaag cctgcaatcc aaatgcctgc
cgggccagtg gccgaggcct acaacccaaa 1560ggcgtccgta tccgggagac cacagatttc
aaggttgaca ccaaagctgc aggaagtggg 1620gagctcggtg taaccatgaa gggtcctaag
ggtctggagg agctggtgaa gcagaaagac 1680tttctggatg gggtctacgc attcgagtat
taccccagca ccccggggag atacagcatt 1740gccatcacat gggggggaca ccacattcca
aagagcccct ttgaagttca agttggccct 1800gaagcgggta tgcagaaagt ccgtgcttgg
ggccctgggc tccatggtgg gattgtcggg 1860cggtcagcgg acttcgtggt agaatccatt
ggctctgaag tggggtctct ggggtttgcc 1920attgaaggcc cctctcaggc aaagattgag
tacaacgacc agaatgatgg atcgtgtgat 1980gtcaaatact ggcccaagga gcctggcgaa
tatgctgttc acatcatgtg tgacgacgaa 2040gacatcaagg acagcccgta catggccttc
atccacccag ccacgggagg ctacaaccct 2100gatctggttc gagcatacgg gccaggtttg
gagaaatctg gatgcattgt caacaacctg 2160gccgagttca ctgtggatcc taaggatgct
ggaaaagctc ccttaaagat atttgctcag 2220gatggggaag gccaacgcat tgacatccag
atgaagaacc ggatggacgg cacatatgca 2280tgctcataca ccccggtgaa ggccatcaag
cacaccattg ctgtggtctg gggaggcgtg 2340aacatcccgc acagccccta cagggtcaac
atcgggcaag gtagccatcc tcagaaggtc 2400aaagtgtttg ggccaggtgt ggagagaagt
ggtctgaagg caaatgaacc tacacacttc 2460acggtggact gtactgaggc tggggaaggt
gatgtcagtg ttggcattaa gtgtgatgcc 2520cgggtgttaa gtgaagatga ggaagacgtg
gattttgaca ttattcacaa tgccaatgat 2580acgttcacag tcaaatatgt gcctcctgct
gctgggcgat acactatcaa agttctcttt 2640gcatctcagg aaatccccgc cagccctttc
agagtcaaag ttgacccttc ccacgatgcc 2700agcaaagtga aggcagaagg cccagggctc
agcaaagcag gtgtggaaaa tgggaaaccg 2760acccacttca ctgtctacac caagggggct
gggaaagccc cgctcaacgt gcagttcaac 2820agccctcttc ctggcgatgc agtgaaggat
ttggatatca tcgataatta tgactactct 2880cacacggtta aatatacacc cacccaacag
ggcaacatgc aggttctggt gacttacggt 2940ggcgatccca tccctaaaag ccctttcact
gtgggtgttg ctgcaccgct ggatctgagc 3000aagataaaac tcaatgggct ggaaaacagg
gtggaagttg ggaaggatca ggagttcacc 3060gttgatacca ggggggcagg aggccagggg
aagctggacg tgacaatcct cagcccctct 3120cggaaggtcg tgccatgcct agtgacacct
gtgacaggcc gggagaacag cacggccaag 3180ttcatccctc gggaggaggg gctgtatgct
gtagacgtga cctacgatgg acaccctgtg 3240cccgggagcc cctacacagt ggaggcctcg
ctgccaccag atcccagcaa ggtgaaggcc 3300cacggtcccg gcctcgaagg tggtctcgtg
ggcaagcctg ccgagttcac catcgatacc 3360aaaggagctg gtactggagg tctgggctta
acggtggaag gtccgtgcga ggccaaaatc 3420gagtgctccg acaatggtga tgggacctgc
tccgtctctt accttcccac aaaacccggg 3480gagtacttcg tcaacatcct ctttgaagaa
gtccacatac ctgggtctcc cttcaaagct 3540gacattgaaa tgccctttga cccctctaaa
gtcgtggcat cggggccagg tctcgagcac 3600gggaaggtgg gtgaagctgg cctccttagc
gtcgactgct cggaagcggg accgggggcc 3660ctgggcctgg aagctgtctc ggactcggga
acaaaagccg aagtcagtat tcagaacaac 3720aaagatggca cctacgcggt gacctacgtg
cccctgacgg ccggcatgta cacgttgacc 3780atgaagtatg gtggcgaact cgtgccacac
ttccccgccc gggtcaaggt ggagcccgcc 3840gtggacacca gcaggatcaa agtctttgga
ccaggaatag aagggaaaga tgtgttccgg 3900gaagctacca ccgactttac agttgactct
cggccgctga cccaggttgg gggtgaccac 3960atcaaggccc acattgccaa cccctcaggg
gcctccaccg agtgctttgt cacagacaat 4020gcggatggga cctaccaggt ggaatacaca
ccctttgaga aaggtctcca tgtagtggag 4080gtgacatatg atgacgtgcc tatcccaaac
agtcccttca aggtggctgt cactgaaggc 4140tgccagccat ctagggtgca agcccaagga
cctggattga aagaggcctt taccaacaag 4200cccaatgtct tcaccgtggt taccagaggc
gcaggaattg gtgggcttgg cataactgtt 4260gagggaccat cagagtcgaa gataaattgc
agagacaaca aggatggcag ctgcagtgct 4320gagtacattc ctttcgcacc gggggattac
gatgttaata tcacatatgg aggagcccac 4380atccccggca gccccttcag ggttcctgtg
aaggatgttg tggaccccag caaggtcaag 4440attgccggcc ccgggctggg ctcaggcgtc
cgagcccgtg tcctgcagtc cttcacggtg 4500gacagcagca aggctggcct ggctccgctg
gaagtgaggg ttctgggccc acgagctgac 4560gacacggatt cccagtcatg gcgcagcccc
ttgaaagccc tttcagagtt ctttaaaggt 4620gacccgaagg gtgactttaa taagacaggc
ttggtggagc cagtgaacgt ggtggacaat 4680ggagatggca cacacacagt aacctacacc
ccatctcagg agggacctta catggtctca 4740gttaaatatg ctgatgaaga gattcctcgc
agtcccttca aggtcaaggt ccttcccaca 4800tatgatgcca gcaaagtgac tgccagtggc
cccggcctta gttcctatgg tgtgcctgcc 4860agtctacctg tggactttgc aattgatgcc
cgagatgccg gggaaggcct gcttgctgtt 4920caaataacgg accaagaagg aaaacccaaa
agagccattg tccatgacaa taaagatggc 4980acgtatgctg tcacctacat ccccgacaag
actgggcgct atatgattgg agtcacctac 5040gggggtgacg acatcccact ttctccttat
cgcatccgag ccacacagac gggtgatgcc 5100agcaagtgcc tggccacggg tcctggaatc
gcctccactg tgaaaactgg cgaagaagta 5160ggctttgtgg ttgatgccaa gactgccggg
aagggtaaag tgacctgcac ggttctgacc 5220ccagatggca ctgaggccga ggccgatgtc
attgagaatg aagatggaac ctatgacatc 5280ttctacacag ctgccaagcc gggcacatat
gtgatctatg tgcgcttcgg tggtgttgat 5340attcctaaca gccccttcac tgtcatggcc
acagatgggg aagtcacagc cgtggaggag 5400gcaccggtaa atgcatgtcc ccctggattc
aggccctggg tgaccgaaga ggcctatgtc 5460ccagtgagtg acatgaacgg cctgggattt
aagccttttg acctggtcat tccgtttgct 5520gtcaggaaag gagaaatcac tggagaggtc
cacatgcctt ctgggaagac agccacacct 5580gagattgtgg acaacaagga cggcacggtc
actgttagat atgcccccac tgaggtcggg 5640ctccatgaga tgcacatcaa atacatgggc
agccacatcc ctgagagccc actccagttc 5700tacgtgaact accccaacag tggaagtgtt
tctgcatacg gtccaggcct cgtgtatgga 5760gtggccaaca aaactgccac cttcaccatc
gtcacagagg atgcaggaga aggtggtctg 5820gacttggcta ttgagggccc ctcaaaagca
gaaatcagct gcattgacaa taaagatggg 5880acatgcacag tgacctacct gccgactctg
ccaggcgact acagcattct ggtcaagtac 5940aatgacaagc acatccctgg cagccccttc
acagccaaga tcacagatga cagcaggcgg 6000tgctcccagg tgaagttggg ctcagccgct
gacttcctgc tcgacatcag tgagactgac 6060ctcagcagcc tgacggccag cattaaggcc
ccatctggcc gagacgagcc ctgtctcctg 6120aagaggctgc ccaacaacca cattggcatc
tccttcatcc cccgggaagt gggcgaacat 6180ctggtcagca tcaagaaaaa tggcaaccat
gtggccaaca gccccgtgtc tatcatggtg 6240gtccagtcgg agattggtga cgcccgccga
gccaaagtct atggccgcgg cctgtcagaa 6300ggccggactt tcgagatgtc tgacttcatc
gtggacacaa gggatgcagg ttatggtggc 6360atatccttgg cggtggaagg ccccagcaaa
gtggacatcc agacggagga cctggaagat 6420ggcacctgca aagtctccta cttccctacc
gtgcctgggg tttatatcgt ctccaccaaa 6480ttcgctgacg agcacgtgcc tgggagccca
tttaccgtga agatcagtgg ggagggaaga 6540gtcaaagaga gcatcacccg caccagtcgg
gccccgtccg tggccactgt cgggagcatt 6600tgtgacctga acctgaaaat cccagaaatc
aacagcagtg atatgtcggc ccacgtcacc 6660agcccctctg gccgtgtgac tgaggcagag
attgtgccca tggggaagaa ctcacactgc 6720gtccggtttg tgccccagga gatgggcgtg
cacacggtca gcgtcaagta ccgtgggcag 6780cacgtcaccg gcagcccctt ccagttcacc
gtggggccac ttggtgaagg aggcgcccac 6840aaggtgcggg caggaggccc tggcctggag
agaggagaag cgggagtccc agctgagttc 6900agcatttgga cccgggaagc aggcgctgga
ggcctctcca tcgctgttga gggccccagt 6960aaggccgaga ttacattcga tgaccataaa
aatgggtcgt gcggtgtatc ttatattgcc 7020caagagcctg gtaactacga ggtgtccatc
aagttcaatg atgagcacat cccggaaagc 7080ccctacctgg tgccggtcat cgcaccctcc
gacgacgccc gccgcctcac tgttatgagc 7140cttcaggaat cgggattaaa agttaaccag
ccagcatcct ttgctataag gttgaatggc 7200gcaaaaggca agattgatgc aaaggtgcac
agcccctctg gagccgtgga ggagtgccac 7260gtgtctgagc tggagccaga taagtatgct
gttcgcttca tccctcatga gaatggtgtc 7320cacaccatcg atgtcaagtt caatgggagc
cacgtggttg gaagcccctt caaagtgcgc 7380gttggggagc ctggacaagc ggggaaccct
gccctggtgt ccgcctatgg cacgggactc 7440gaagggggca ccacaggtat ccagtcggaa
ttctttatta acaccacccg agcaggtcca 7500gggacattat ccgtcaccat cgaaggccca
tccaaggtta aaatggattg ccaggaaaca 7560cctgaagggt acaaagtcat gtacaccccc
atggctcctg gtaactacct gatcagcgtc 7620aaatacggtg ggcccaacca catcgtgggc
agtcccttca aggccaaggt gacaggccag 7680cgtctagtta gccctggctc agccaacgag
acctcatcca tcctggtgga gtcagtgacc 7740aggtcgtcta cagagacctg ctatagcgcc
attcccaagg catcctcgga cgccagcaag 7800gtgacctcta agggggcagg gctctcaaag
gcctttgtgg gccagaagag ttccttcctg 7860gtggactgca gcaaagctgg ctccaacatg
ctgctgatcg gggtccatgg gcccaccacc 7920ccctgcgagg aggtctccat gaagcatgta
ggcaaccagc aatacaacgt cacatacgtc 7980gtcaaggaga ggggcgatta tgtgctggct
gtgaagtggg gggaggaaca catccctggc 8040agcccttttc atgtcacagt gccttaaaac
agttttctca aatcctggag agagttcttg 8100tggttgcttt tgttgcttgt ttgtaattca
ttttatacaa agccctccag cctgtttgtg 8160gggctgaaac cccatcccta aaatattgct
gttgtaaaat gccttcagaa ataagtccta 8220gactggactc ttgagggaca tattggagaa
tcttaagaaa tgcaagcttg ttcagggggc 8280tgagaagatc ctgagtacac taggtgcaaa
ccagaactct tggtggaaca gaccagccac 8340tgcagcagac agaccaggaa cacaatgaga
ctgacatttc aaaaaaacaa aactggctag 8400cctgagctgc tggttcactc ttcagcattt
atgaaacaag gctaggggaa gatgggcaga 8460gaaaaagggg acacctagtt tggttgtcat
ttggcaaagg agatgactta aaatccgctt 8520aatctcttcc agtgtccgtg ttaatgtatt
tggctattag atcactagca ctgctttacc 8580gctcctcatc gccaacaccc ccatgctctg
tggccttctt acacttctca gagggcagag 8640tggcagccgg gcaccctaca gaaactcaga
gggcagagtg gcagccaggc ccacatgtct 8700ctcaagtacc tgtcccctcg ctctggtgat
tatttcttgc agaatcacca cacgagacca 8760tcccggcagt catggttttg ctttagtttt
ccaagtccgt ttcagtccct tccttggtct 8820gaagaaattc tgcagtggcg agcagtttcc
cacttgccaa agatcccttt taaccaacac 8880tagcccttgt ttttaacaca cgctccagcc
cttcatcagc ctgggcagtc ttaccaaaat 8940gtttaaagtg atctcagagg ggcccatgga
ttaacgccct catcccaagg tccgtcccat 9000gacataacac tccacacccg ccccagccaa
cttcatgggt cactttttct ggaaaataat 9060gatctgtaca gacaggacag aatgaaactc
ctgcgggtct ttggcctgaa agttgggaat 9120ggttggggga gagaagggca gcagcttatt
ggtggtcttt tcaccattgg cagaaacagt 9180gagagctgtg tggtgcagaa atccagaaat
gaggtgtagg gaattttgcc tgccttcctg 9240cagacctgag ctggctttgg aatgaggtta
aagtgtcagg gacgttgcct gagcccaaat 9300gtgtagtgtg gtctgggcag gcagaccttt
aggttttgct gcttagtcct gaggaagtgg 9360ccactcttgt ggcaggtgta gtatctgggg
cgagtgttgg gggtaaaagc ccaccctaca 9420gaaagtggaa cagcccggag cctgatgtga
aaggaccacg ggtgttgtaa gctgggacac 9480ggaagccaaa ctggaatcaa acgccgactg
taaattgtat cttataactt attaaataaa 9540acatttgctc cgtaaagttg
9560242591PRTHomo sapiens 24Met Pro Val
Thr Glu Lys Asp Leu Ala Glu Asp Ala Pro Trp Lys Lys 1 5
10 15 Ile Gln Gln Asn Thr Phe Thr Arg
Trp Cys Asn Glu His Leu Lys Cys 20 25
30 Val Asn Lys Arg Ile Gly Asn Leu Gln Thr Asp Leu Ser
Asp Gly Leu 35 40 45
Arg Leu Ile Ala Leu Leu Glu Val Leu Ser Gln Lys Arg Met Tyr Arg 50
55 60 Lys Tyr His Gln
Arg Pro Thr Phe Arg Gln Met Gln Leu Glu Asn Val 65 70
75 80 Ser Val Ala Leu Glu Phe Leu Asp Arg
Glu Ser Ile Lys Leu Val Ser 85 90
95 Ile Asp Ser Lys Ala Ile Val Asp Gly Asn Leu Lys Leu Ile
Leu Gly 100 105 110
Leu Val Trp Thr Leu Ile Leu His Tyr Ser Ile Ser Met Pro Val Trp
115 120 125 Glu Asp Glu Gly
Asp Asp Asp Ala Lys Lys Gln Thr Pro Lys Gln Arg 130
135 140 Leu Leu Gly Trp Ile Gln Asn Lys
Ile Pro Tyr Leu Pro Ile Thr Asn 145 150
155 160 Phe Asn Gln Asn Trp Gln Asp Gly Lys Ala Leu Gly
Ala Leu Val Asp 165 170
175 Ser Cys Ala Pro Gly Leu Cys Pro Asp Trp Glu Ser Trp Asp Pro Gln
180 185 190 Lys Pro Val
Asp Asn Ala Arg Glu Ala Met Gln Gln Ala Asp Asp Trp 195
200 205 Leu Gly Val Pro Gln Val Ile Thr
Pro Glu Glu Ile Ile His Pro Asp 210 215
220 Val Asp Glu His Ser Val Met Thr Tyr Leu Ser Gln Phe
Pro Lys Ala 225 230 235
240 Lys Leu Lys Pro Gly Ala Pro Leu Lys Pro Lys Leu Asn Pro Lys Lys
245 250 255 Ala Arg Ala Tyr
Gly Arg Gly Ile Glu Pro Thr Gly Asn Met Val Lys 260
265 270 Gln Pro Ala Lys Phe Thr Val Asp Thr
Ile Ser Ala Gly Gln Gly Asp 275 280
285 Val Met Val Phe Val Glu Asp Pro Glu Gly Asn Lys Glu Glu
Ala Gln 290 295 300
Val Thr Pro Asp Ser Asp Lys Asn Lys Thr Tyr Ser Val Glu Tyr Leu 305
310 315 320 Pro Lys Val Thr Gly
Leu His Lys Val Thr Val Leu Phe Ala Gly Gln 325
330 335 His Ile Ser Lys Ser Pro Phe Glu Val Ser
Val Asp Lys Ala Gln Gly 340 345
350 Asp Ala Ser Lys Val Thr Ala Lys Gly Pro Gly Leu Glu Ala Val
Gly 355 360 365 Asn
Ile Ala Asn Lys Pro Thr Tyr Phe Asp Ile Tyr Thr Ala Gly Ala 370
375 380 Gly Val Gly Asp Ile Gly
Val Glu Val Glu Asp Pro Gln Gly Lys Asn 385 390
395 400 Thr Val Glu Leu Leu Val Glu Asp Lys Gly Asn
Gln Val Tyr Arg Cys 405 410
415 Val Tyr Lys Pro Met Gln Pro Gly Pro His Val Val Lys Ile Phe Phe
420 425 430 Ala Gly
Asp Thr Ile Pro Lys Ser Pro Phe Val Val Gln Val Gly Glu 435
440 445 Ala Cys Asn Pro Asn Ala Cys
Arg Ala Ser Gly Arg Gly Leu Gln Pro 450 455
460 Lys Gly Val Arg Ile Arg Glu Thr Thr Asp Phe Lys
Val Asp Thr Lys 465 470 475
480 Ala Ala Gly Ser Gly Glu Leu Gly Val Thr Met Lys Gly Pro Lys Gly
485 490 495 Leu Glu Glu
Leu Val Lys Gln Lys Asp Phe Leu Asp Gly Val Tyr Ala 500
505 510 Phe Glu Tyr Tyr Pro Ser Thr Pro
Gly Arg Tyr Ser Ile Ala Ile Thr 515 520
525 Trp Gly Gly His His Ile Pro Lys Ser Pro Phe Glu Val
Gln Val Gly 530 535 540
Pro Glu Ala Gly Met Gln Lys Val Arg Ala Trp Gly Pro Gly Leu His 545
550 555 560 Gly Gly Ile Val
Gly Arg Ser Ala Asp Phe Val Val Glu Ser Ile Gly 565
570 575 Ser Glu Val Gly Ser Leu Gly Phe Ala
Ile Glu Gly Pro Ser Gln Ala 580 585
590 Lys Ile Glu Tyr Asn Asp Gln Asn Asp Gly Ser Cys Asp Val
Lys Tyr 595 600 605
Trp Pro Lys Glu Pro Gly Glu Tyr Ala Val His Ile Met Cys Asp Asp 610
615 620 Glu Asp Ile Lys Asp
Ser Pro Tyr Met Ala Phe Ile His Pro Ala Thr 625 630
635 640 Gly Gly Tyr Asn Pro Asp Leu Val Arg Ala
Tyr Gly Pro Gly Leu Glu 645 650
655 Lys Ser Gly Cys Ile Val Asn Asn Leu Ala Glu Phe Thr Val Asp
Pro 660 665 670 Lys
Asp Ala Gly Lys Ala Pro Leu Lys Ile Phe Ala Gln Asp Gly Glu 675
680 685 Gly Gln Arg Ile Asp Ile
Gln Met Lys Asn Arg Met Asp Gly Thr Tyr 690 695
700 Ala Cys Ser Tyr Thr Pro Val Lys Ala Ile Lys
His Thr Ile Ala Val 705 710 715
720 Val Trp Gly Gly Val Asn Ile Pro His Ser Pro Tyr Arg Val Asn Ile
725 730 735 Gly Gln
Gly Ser His Pro Gln Lys Val Lys Val Phe Gly Pro Gly Val 740
745 750 Glu Arg Ser Gly Leu Lys Ala
Asn Glu Pro Thr His Phe Thr Val Asp 755 760
765 Cys Thr Glu Ala Gly Glu Gly Asp Val Ser Val Gly
Ile Lys Cys Asp 770 775 780
Ala Arg Val Leu Ser Glu Asp Glu Glu Asp Val Asp Phe Asp Ile Ile 785
790 795 800 His Asn Ala
Asn Asp Thr Phe Thr Val Lys Tyr Val Pro Pro Ala Ala 805
810 815 Gly Arg Tyr Thr Ile Lys Val Leu
Phe Ala Ser Gln Glu Ile Pro Ala 820 825
830 Ser Pro Phe Arg Val Lys Val Asp Pro Ser His Asp Ala
Ser Lys Val 835 840 845
Lys Ala Glu Gly Pro Gly Leu Ser Lys Ala Gly Val Glu Asn Gly Lys 850
855 860 Pro Thr His Phe
Thr Val Tyr Thr Lys Gly Ala Gly Lys Ala Pro Leu 865 870
875 880 Asn Val Gln Phe Asn Ser Pro Leu Pro
Gly Asp Ala Val Lys Asp Leu 885 890
895 Asp Ile Ile Asp Asn Tyr Asp Tyr Ser His Thr Val Lys Tyr
Thr Pro 900 905 910
Thr Gln Gln Gly Asn Met Gln Val Leu Val Thr Tyr Gly Gly Asp Pro
915 920 925 Ile Pro Lys Ser
Pro Phe Thr Val Gly Val Ala Ala Pro Leu Asp Leu 930
935 940 Ser Lys Ile Lys Leu Asn Gly Leu
Glu Asn Arg Val Glu Val Gly Lys 945 950
955 960 Asp Gln Glu Phe Thr Val Asp Thr Arg Gly Ala Gly
Gly Gln Gly Lys 965 970
975 Leu Asp Val Thr Ile Leu Ser Pro Ser Arg Lys Val Val Pro Cys Leu
980 985 990 Val Thr Pro
Val Thr Gly Arg Glu Asn Ser Thr Ala Lys Phe Ile Pro 995
1000 1005 Arg Glu Glu Gly Leu Tyr
Ala Val Asp Val Thr Tyr Asp Gly His 1010 1015
1020 Pro Val Pro Gly Ser Pro Tyr Thr Val Glu Ala
Ser Leu Pro Pro 1025 1030 1035
Asp Pro Ser Lys Val Lys Ala His Gly Pro Gly Leu Glu Gly Gly
1040 1045 1050 Leu Val Gly
Lys Pro Ala Glu Phe Thr Ile Asp Thr Lys Gly Ala 1055
1060 1065 Gly Thr Gly Gly Leu Gly Leu Thr
Val Glu Gly Pro Cys Glu Ala 1070 1075
1080 Lys Ile Glu Cys Ser Asp Asn Gly Asp Gly Thr Cys Ser
Val Ser 1085 1090 1095
Tyr Leu Pro Thr Lys Pro Gly Glu Tyr Phe Val Asn Ile Leu Phe 1100
1105 1110 Glu Glu Val His Ile
Pro Gly Ser Pro Phe Lys Ala Asp Ile Glu 1115 1120
1125 Met Pro Phe Asp Pro Ser Lys Val Val Ala
Ser Gly Pro Gly Leu 1130 1135 1140
Glu His Gly Lys Val Gly Glu Ala Gly Leu Leu Ser Val Asp Cys
1145 1150 1155 Ser Glu
Ala Gly Pro Gly Ala Leu Gly Leu Glu Ala Val Ser Asp 1160
1165 1170 Ser Gly Thr Lys Ala Glu Val
Ser Ile Gln Asn Asn Lys Asp Gly 1175 1180
1185 Thr Tyr Ala Val Thr Tyr Val Pro Leu Thr Ala Gly
Met Tyr Thr 1190 1195 1200
Leu Thr Met Lys Tyr Gly Gly Glu Leu Val Pro His Phe Pro Ala 1205
1210 1215 Arg Val Lys Val Glu
Pro Ala Val Asp Thr Ser Arg Ile Lys Val 1220 1225
1230 Phe Gly Pro Gly Ile Glu Gly Lys Asp Val
Phe Arg Glu Ala Thr 1235 1240 1245
Thr Asp Phe Thr Val Asp Ser Arg Pro Leu Thr Gln Val Gly Gly
1250 1255 1260 Asp His
Ile Lys Ala His Ile Ala Asn Pro Ser Gly Ala Ser Thr 1265
1270 1275 Glu Cys Phe Val Thr Asp Asn
Ala Asp Gly Thr Tyr Gln Val Glu 1280 1285
1290 Tyr Thr Pro Phe Glu Lys Gly Leu His Val Val Glu
Val Thr Tyr 1295 1300 1305
Asp Asp Val Pro Ile Pro Asn Ser Pro Phe Lys Val Ala Val Thr 1310
1315 1320 Glu Gly Cys Gln Pro
Ser Arg Val Gln Ala Gln Gly Pro Gly Leu 1325 1330
1335 Lys Glu Ala Phe Thr Asn Lys Pro Asn Val
Phe Thr Val Val Thr 1340 1345 1350
Arg Gly Ala Gly Ile Gly Gly Leu Gly Ile Thr Val Glu Gly Pro
1355 1360 1365 Ser Glu
Ser Lys Ile Asn Cys Arg Asp Asn Lys Asp Gly Ser Cys 1370
1375 1380 Ser Ala Glu Tyr Ile Pro Phe
Ala Pro Gly Asp Tyr Asp Val Asn 1385 1390
1395 Ile Thr Tyr Gly Gly Ala His Ile Pro Gly Ser Pro
Phe Arg Val 1400 1405 1410
Pro Val Lys Asp Val Val Asp Pro Ser Lys Val Lys Ile Ala Gly 1415
1420 1425 Pro Gly Leu Gly Ser
Gly Val Arg Ala Arg Val Leu Gln Ser Phe 1430 1435
1440 Thr Val Asp Ser Ser Lys Ala Gly Leu Ala
Pro Leu Glu Val Arg 1445 1450 1455
Val Leu Gly Pro Arg Gly Leu Val Glu Pro Val Asn Val Val Asp
1460 1465 1470 Asn Gly
Asp Gly Thr His Thr Val Thr Tyr Thr Pro Ser Gln Glu 1475
1480 1485 Gly Pro Tyr Met Val Ser Val
Lys Tyr Ala Asp Glu Glu Ile Pro 1490 1495
1500 Arg Ser Pro Phe Lys Val Lys Val Leu Pro Thr Tyr
Asp Ala Ser 1505 1510 1515
Lys Val Thr Ala Ser Gly Pro Gly Leu Ser Ser Tyr Gly Val Pro 1520
1525 1530 Ala Ser Leu Pro Val
Asp Phe Ala Ile Asp Ala Arg Asp Ala Gly 1535 1540
1545 Glu Gly Leu Leu Ala Val Gln Ile Thr Asp
Gln Glu Gly Lys Pro 1550 1555 1560
Lys Arg Ala Ile Val His Asp Asn Lys Asp Gly Thr Tyr Ala Val
1565 1570 1575 Thr Tyr
Ile Pro Asp Lys Thr Gly Arg Tyr Met Ile Gly Val Thr 1580
1585 1590 Tyr Gly Gly Asp Asp Ile Pro
Leu Ser Pro Tyr Arg Ile Arg Ala 1595 1600
1605 Thr Gln Thr Gly Asp Ala Ser Lys Cys Leu Ala Thr
Gly Pro Gly 1610 1615 1620
Ile Ala Ser Thr Val Lys Thr Gly Glu Glu Val Gly Phe Val Val 1625
1630 1635 Asp Ala Lys Thr Ala
Gly Lys Gly Lys Val Thr Cys Thr Val Leu 1640 1645
1650 Thr Pro Asp Gly Thr Glu Ala Glu Ala Asp
Val Ile Glu Asn Glu 1655 1660 1665
Asp Gly Thr Tyr Asp Ile Phe Tyr Thr Ala Ala Lys Pro Gly Thr
1670 1675 1680 Tyr Val
Ile Tyr Val Arg Phe Gly Gly Val Asp Ile Pro Asn Ser 1685
1690 1695 Pro Phe Thr Val Met Ala Thr
Asp Gly Glu Val Thr Ala Val Glu 1700 1705
1710 Glu Ala Pro Val Thr Glu Glu Ala Tyr Val Pro Val
Ser Asp Met 1715 1720 1725
Asn Gly Leu Gly Phe Lys Pro Phe Asp Leu Val Ile Pro Phe Ala 1730
1735 1740 Val Arg Lys Gly Glu
Ile Thr Gly Glu Val His Met Pro Ser Gly 1745 1750
1755 Lys Thr Ala Thr Pro Glu Ile Val Asp Asn
Lys Asp Gly Thr Val 1760 1765 1770
Thr Val Arg Tyr Ala Pro Thr Glu Val Gly Leu His Glu Met His
1775 1780 1785 Ile Lys
Tyr Met Gly Ser His Ile Pro Glu Ser Pro Leu Gln Phe 1790
1795 1800 Tyr Val Asn Tyr Pro Asn Ser
Gly Ser Val Ser Ala Tyr Gly Pro 1805 1810
1815 Gly Leu Val Tyr Gly Val Ala Asn Lys Thr Ala Thr
Phe Thr Ile 1820 1825 1830
Val Thr Glu Asp Ala Gly Glu Gly Gly Leu Asp Leu Ala Ile Glu 1835
1840 1845 Gly Pro Ser Lys Ala
Glu Ile Ser Cys Ile Asp Asn Lys Asp Gly 1850 1855
1860 Thr Cys Thr Val Thr Tyr Leu Pro Thr Leu
Pro Gly Asp Tyr Ser 1865 1870 1875
Ile Leu Val Lys Tyr Asn Asp Lys His Ile Pro Gly Ser Pro Phe
1880 1885 1890 Thr Ala
Lys Ile Thr Asp Asp Ser Arg Arg Cys Ser Gln Val Lys 1895
1900 1905 Leu Gly Ser Ala Ala Asp Phe
Leu Leu Asp Ile Ser Glu Thr Asp 1910 1915
1920 Leu Ser Ser Leu Thr Ala Ser Ile Lys Ala Pro Ser
Gly Arg Asp 1925 1930 1935
Glu Pro Cys Leu Leu Lys Arg Leu Pro Asn Asn His Ile Gly Ile 1940
1945 1950 Ser Phe Ile Pro Arg
Glu Val Gly Glu His Leu Val Ser Ile Lys 1955 1960
1965 Lys Asn Gly Asn His Val Ala Asn Ser Pro
Val Ser Ile Met Val 1970 1975 1980
Val Gln Ser Glu Ile Gly Asp Ala Arg Arg Ala Lys Val Tyr Gly
1985 1990 1995 Arg Gly
Leu Ser Glu Gly Arg Thr Phe Glu Met Ser Asp Phe Ile 2000
2005 2010 Val Asp Thr Arg Asp Ala Gly
Tyr Gly Gly Ile Ser Leu Ala Val 2015 2020
2025 Glu Gly Pro Ser Lys Val Asp Ile Gln Thr Glu Asp
Leu Glu Asp 2030 2035 2040
Gly Thr Cys Lys Val Ser Tyr Phe Pro Thr Val Pro Gly Val Tyr 2045
2050 2055 Ile Val Ser Thr Lys
Phe Ala Asp Glu His Val Pro Gly Ser Pro 2060 2065
2070 Phe Thr Val Lys Ile Ser Gly Glu Gly Arg
Val Lys Glu Ser Ile 2075 2080 2085
Thr Arg Thr Ser Arg Ala Pro Ser Val Ala Thr Val Gly Ser Ile
2090 2095 2100 Cys Asp
Leu Asn Leu Lys Ile Pro Glu Ile Asn Ser Ser Asp Met 2105
2110 2115 Ser Ala His Val Thr Ser Pro
Ser Gly Arg Val Thr Glu Ala Glu 2120 2125
2130 Ile Val Pro Met Gly Lys Asn Ser His Cys Val Arg
Phe Val Pro 2135 2140 2145
Gln Glu Met Gly Val His Thr Val Ser Val Lys Tyr Arg Gly Gln 2150
2155 2160 His Val Thr Gly Ser
Pro Phe Gln Phe Thr Val Gly Pro Leu Gly 2165 2170
2175 Glu Gly Gly Ala His Lys Val Arg Ala Gly
Gly Pro Gly Leu Glu 2180 2185 2190
Arg Gly Glu Ala Gly Val Pro Ala Glu Phe Ser Ile Trp Thr Arg
2195 2200 2205 Glu Ala
Gly Ala Gly Gly Leu Ser Ile Ala Val Glu Gly Pro Ser 2210
2215 2220 Lys Ala Glu Ile Thr Phe Asp
Asp His Lys Asn Gly Ser Cys Gly 2225 2230
2235 Val Ser Tyr Ile Ala Gln Glu Pro Gly Asn Tyr Glu
Val Ser Ile 2240 2245 2250
Lys Phe Asn Asp Glu His Ile Pro Glu Ser Pro Tyr Leu Val Pro 2255
2260 2265 Val Ile Ala Pro Ser
Asp Asp Ala Arg Arg Leu Thr Val Met Ser 2270 2275
2280 Leu Gln Glu Ser Gly Leu Lys Val Asn Gln
Pro Ala Ser Phe Ala 2285 2290 2295
Ile Arg Leu Asn Gly Ala Lys Gly Lys Ile Asp Ala Lys Val His
2300 2305 2310 Ser Pro
Ser Gly Ala Val Glu Glu Cys His Val Ser Glu Leu Glu 2315
2320 2325 Pro Asp Lys Tyr Ala Val Arg
Phe Ile Pro His Glu Asn Gly Val 2330 2335
2340 His Thr Ile Asp Val Lys Phe Asn Gly Ser His Val
Val Gly Ser 2345 2350 2355
Pro Phe Lys Val Arg Val Gly Glu Pro Gly Gln Ala Gly Asn Pro 2360
2365 2370 Ala Leu Val Ser Ala
Tyr Gly Thr Gly Leu Glu Gly Gly Thr Thr 2375 2380
2385 Gly Ile Gln Ser Glu Phe Phe Ile Asn Thr
Thr Arg Ala Gly Pro 2390 2395 2400
Gly Thr Leu Ser Val Thr Ile Glu Gly Pro Ser Lys Val Lys Met
2405 2410 2415 Asp Cys
Gln Glu Thr Pro Glu Gly Tyr Lys Val Met Tyr Thr Pro 2420
2425 2430 Met Ala Pro Gly Asn Tyr Leu
Ile Ser Val Lys Tyr Gly Gly Pro 2435 2440
2445 Asn His Ile Val Gly Ser Pro Phe Lys Ala Lys Val
Thr Gly Gln 2450 2455 2460
Arg Leu Val Ser Pro Gly Ser Ala Asn Glu Thr Ser Ser Ile Leu 2465
2470 2475 Val Glu Ser Val Thr
Arg Ser Ser Thr Glu Thr Cys Tyr Ser Ala 2480 2485
2490 Ile Pro Lys Ala Ser Ser Asp Ala Ser Lys
Val Thr Ser Lys Gly 2495 2500 2505
Ala Gly Leu Ser Lys Ala Phe Val Gly Gln Lys Ser Ser Phe Leu
2510 2515 2520 Val Asp
Cys Ser Lys Ala Gly Ser Asn Met Leu Leu Ile Gly Val 2525
2530 2535 His Gly Pro Thr Thr Pro Cys
Glu Glu Val Ser Met Lys His Val 2540 2545
2550 Gly Asn Gln Gln Tyr Asn Val Thr Tyr Val Val Lys
Glu Arg Gly 2555 2560 2565
Asp Tyr Val Leu Ala Val Lys Trp Gly Glu Glu His Ile Pro Gly 2570
2575 2580 Ser Pro Phe His Val
Thr Val Pro 2585 2590 259434DNAHomo sapiens
25gcggccaggg gcgggcggcc gcagagcagc accggccgtg gctccggtag cagcaagttc
60gaaccccgct cccgctccgc ttcggttctc gctccttcgg cccttgggcc tccaaacacc
120agtccccggc agctcgttgc gcattgcgct ctccccgcca ccaggatgcc ggtaaccgag
180aaggatctag ctgaggacgc gccttggaag aagatccagc agaacacgtt cacacgctgg
240tgcaacgagc acctcaagtg cgtgaacaaa cgcatcggca acctgcagac cgacctgagc
300gacgggctgc ggctcatcgc gctgctcgag gtgctcagcc agaagcgcat gtaccgcaag
360taccatcagc ggcccacctt tcgccagatg cagctcgaga atgtgtccgt ggcgctcgag
420ttcctggacc gtgagagcat caagctcgtg tccatcgata gcaaagccat tgtggatggg
480aacctgaagc tcatcttggg tctggtgtgg acgctgatcc tccactactc catctccatg
540cccgtgtggg aggatgaagg ggatgatgat gccaagaagc agacgccaaa gcagaggctg
600ctggggtgga ttcagaacaa gatcccctac ttgcccatca ccaactttaa ccagaactgg
660caagacggca aagccctggg agccctggta gacagctgtg ctccaggtct gtgcccagac
720tgggaatcct gggacccgca gaagcctgtg gataatgcac gagaagccat gcagcaggca
780gatgactggc tgggtgtccc acaggtcatc actcctgaag aaatcattca cccggatgtg
840gacgagcact cagttatgac ttacctgtcc cagttcccca aagccaagct caagccgggg
900gctcctctca aacccaaact caacccgaag aaagccaggg cctatggcag aggaatcgag
960cccactggaa acatggtgaa gcagccagcc aagttcactg tggacaccat cagcgccggg
1020caaggagacg tgatggtgtt tgttgaggac ccagaaggga acaaagagga ggcacaagtg
1080acccctgaca gtgacaagaa caagacatac tctgtggagt atctgcccaa ggtcaccggg
1140ctacacaaag tcacagtcct ctttgcagga cagcacatct ccaagagccc atttgaagtg
1200agtgttgaca aggcccaggg agatgccagt aaagtcactg caaaaggtcc agggttggaa
1260gctgtaggga acatcgccaa taagcccacc tactttgaca tctatacggc aggagctggt
1320gtgggtgaca ttggtgtgga ggtggaagat ccccagggga agaacaccgt ggagttgctc
1380gtggaagaca aaggaaacca ggtgtatcga tgtgtgtaca aacccatgca gcctggccct
1440cacgtggtca agatcttctt tgctggggac actattccta agagtccctt cgttgtgcag
1500gttggggaag cctgcaatcc aaatgcctgc cgggccagtg gccgaggcct acaacccaaa
1560ggcgtccgta tccgggagac cacagatttc aaggttgaca ccaaagctgc aggaagtggg
1620gagctcggtg taaccatgaa gggtcctaag ggtctggagg agctggtgaa gcagaaagac
1680tttctggatg gggtctacgc attcgagtat taccccagca ccccggggag atacagcatt
1740gccatcacat gggggggaca ccacattcca aagagcccct ttgaagttca agttggccct
1800gaagcgggta tgcagaaagt ccgtgcttgg ggccctgggc tccatggtgg gattgtcggg
1860cggtcagcgg acttcgtggt agaatccatt ggctctgaag tggggtctct ggggtttgcc
1920attgaaggcc cctctcaggc aaagattgag tacaacgacc agaatgatgg atcgtgtgat
1980gtcaaatact ggcccaagga gcctggcgaa tatgctgttc acatcatgtg tgacgacgaa
2040gacatcaagg acagcccgta catggccttc atccacccag ccacgggagg ctacaaccct
2100gatctggttc gagcatacgg gccaggtttg gagaaatctg gatgcattgt caacaacctg
2160gccgagttca ctgtggatcc taaggatgct ggaaaagctc ccttaaagat atttgctcag
2220gatggggaag gccaacgcat tgacatccag atgaagaacc ggatggacgg cacatatgca
2280tgctcataca ccccggtgaa ggccatcaag cacaccattg ctgtggtctg gggaggcgtg
2340aacatcccgc acagccccta cagggtcaac atcgggcaag gtagccatcc tcagaaggtc
2400aaagtgtttg ggccaggtgt ggagagaagt ggtctgaagg caaatgaacc tacacacttc
2460acggtggact gtactgaggc tggggaaggt gatgtcagtg ttggcattaa gtgtgatgcc
2520cgggtgttaa gtgaagatga ggaagacgtg gattttgaca ttattcacaa tgccaatgat
2580acgttcacag tcaaatatgt gcctcctgct gctgggcgat acactatcaa agttctcttt
2640gcatctcagg aaatccccgc cagccctttc agagtcaaag ttgacccttc ccacgatgcc
2700agcaaagtga aggcagaagg cccagggctc agcaaagcag gtgtggaaaa tgggaaaccg
2760acccacttca ctgtctacac caagggggct gggaaagccc cgctcaacgt gcagttcaac
2820agccctcttc ctggcgatgc agtgaaggat ttggatatca tcgataatta tgactactct
2880cacacggtta aatatacacc cacccaacag ggcaacatgc aggttctggt gacttacggt
2940ggcgatccca tccctaaaag ccctttcact gtgggtgttg ctgcaccgct ggatctgagc
3000aagataaaac tcaatgggct ggaaaacagg gtggaagttg ggaaggatca ggagttcacc
3060gttgatacca ggggggcagg aggccagggg aagctggacg tgacaatcct cagcccctct
3120cggaaggtcg tgccatgcct agtgacacct gtgacaggcc gggagaacag cacggccaag
3180ttcatccctc gggaggaggg gctgtatgct gtagacgtga cctacgatgg acaccctgtg
3240cccgggagcc cctacacagt ggaggcctcg ctgccaccag atcccagcaa ggtgaaggcc
3300cacggtcccg gcctcgaagg tggtctcgtg ggcaagcctg ccgagttcac catcgatacc
3360aaaggagctg gtactggagg tctgggctta acggtggaag gtccgtgcga ggccaaaatc
3420gagtgctccg acaatggtga tgggacctgc tccgtctctt accttcccac aaaacccggg
3480gagtacttcg tcaacatcct ctttgaagaa gtccacatac ctgggtctcc cttcaaagct
3540gacattgaaa tgccctttga cccctctaaa gtcgtggcat cggggccagg tctcgagcac
3600gggaaggtgg gtgaagctgg cctccttagc gtcgactgct cggaagcggg accgggggcc
3660ctgggcctgg aagctgtctc ggactcggga acaaaagccg aagtcagtat tcagaacaac
3720aaagatggca cctacgcggt gacctacgtg cccctgacgg ccggcatgta cacgttgacc
3780atgaagtatg gtggcgaact cgtgccacac ttccccgccc gggtcaaggt ggagcccgcc
3840gtggacacca gcaggatcaa agtctttgga ccaggaatag aagggaaaga tgtgttccgg
3900gaagctacca ccgactttac agttgactct cggccgctga cccaggttgg gggtgaccac
3960atcaaggccc acattgccaa cccctcaggg gcctccaccg agtgctttgt cacagacaat
4020gcggatggga cctaccaggt ggaatacaca ccctttgaga aaggtctcca tgtagtggag
4080gtgacatatg atgacgtgcc tatcccaaac agtcccttca aggtggctgt cactgaaggc
4140tgccagccat ctagggtgca agcccaagga cctggattga aagaggcctt taccaacaag
4200cccaatgtct tcaccgtggt taccagaggc gcaggaattg gtgggcttgg cataactgtt
4260gagggaccat cagagtcgaa gataaattgc agagacaaca aggatggcag ctgcagtgct
4320gagtacattc ctttcgcacc gggggattac gatgttaata tcacatatgg aggagcccac
4380atccccggca gccccttcag ggttcctgtg aaggatgttg tggaccccag caaggtcaag
4440attgccggcc ccgggctggg ctcaggcgtc cgagcccgtg tcctgcagtc cttcacggtg
4500gacagcagca aggctggcct ggctccgctg gaagtgaggg ttctgggccc acgaggcttg
4560gtggagccag tgaacgtggt ggacaatgga gatggcacac acacagtaac ctacacccca
4620tctcaggagg gaccttacat ggtctcagtt aaatatgctg atgaagagat tcctcgcagt
4680cccttcaagg tcaaggtcct tcccacatat gatgccagca aagtgactgc cagtggcccc
4740ggccttagtt cctatggtgt gcctgccagt ctacctgtgg actttgcaat tgatgcccga
4800gatgccgggg aaggcctgct tgctgttcaa ataacggacc aagaaggaaa acccaaaaga
4860gccattgtcc atgacaataa agatggcacg tatgctgtca cctacatccc cgacaagact
4920gggcgctata tgattggagt cacctacggg ggtgacgaca tcccactttc tccttatcgc
4980atccgagcca cacagacggg tgatgccagc aagtgcctgg ccacgggtcc tggaatcgcc
5040tccactgtga aaactggcga agaagtaggc tttgtggttg atgccaagac tgccgggaag
5100ggtaaagtga cctgcacggt tctgacccca gatggcactg aggccgaggc cgatgtcatt
5160gagaatgaag atggaaccta tgacatcttc tacacagctg ccaagccggg cacatatgtg
5220atctatgtgc gcttcggtgg tgttgatatt cctaacagcc ccttcactgt catggccaca
5280gatggggaag tcacagccgt ggaggaggca ccggtgaccg aagaggccta tgtcccagtg
5340agtgacatga acggcctggg atttaagcct tttgacctgg tcattccgtt tgctgtcagg
5400aaaggagaaa tcactggaga ggtccacatg ccttctggga agacagccac acctgagatt
5460gtggacaaca aggacggcac ggtcactgtt agatatgccc ccactgaggt cgggctccat
5520gagatgcaca tcaaatacat gggcagccac atccctgaga gcccactcca gttctacgtg
5580aactacccca acagtggaag tgtttctgca tacggtccag gcctcgtgta tggagtggcc
5640aacaaaactg ccaccttcac catcgtcaca gaggatgcag gagaaggtgg tctggacttg
5700gctattgagg gcccctcaaa agcagaaatc agctgcattg acaataaaga tgggacatgc
5760acagtgacct acctgccgac tctgccaggc gactacagca ttctggtcaa gtacaatgac
5820aagcacatcc ctggcagccc cttcacagcc aagatcacag atgacagcag gcggtgctcc
5880caggtgaagt tgggctcagc cgctgacttc ctgctcgaca tcagtgagac tgacctcagc
5940agcctgacgg ccagcattaa ggccccatct ggccgagacg agccctgtct cctgaagagg
6000ctgcccaaca accacattgg catctccttc atcccccggg aagtgggcga acatctggtc
6060agcatcaaga aaaatggcaa ccatgtggcc aacagccccg tgtctatcat ggtggtccag
6120tcggagattg gtgacgcccg ccgagccaaa gtctatggcc gcggcctgtc agaaggccgg
6180actttcgaga tgtctgactt catcgtggac acaagggatg caggttatgg tggcatatcc
6240ttggcggtgg aaggccccag caaagtggac atccagacgg aggacctgga agatggcacc
6300tgcaaagtct cctacttccc taccgtgcct ggggtttata tcgtctccac caaattcgct
6360gacgagcacg tgcctgggag cccatttacc gtgaagatca gtggggaggg aagagtcaaa
6420gagagcatca cccgcaccag tcgggccccg tccgtggcca ctgtcgggag catttgtgac
6480ctgaacctga aaatcccaga aatcaacagc agtgatatgt cggcccacgt caccagcccc
6540tctggccgtg tgactgaggc agagattgtg cccatgggga agaactcaca ctgcgtccgg
6600tttgtgcccc aggagatggg cgtgcacacg gtcagcgtca agtaccgtgg gcagcacgtc
6660accggcagcc ccttccagtt caccgtgggg ccacttggtg aaggaggcgc ccacaaggtg
6720cgggcaggag gccctggcct ggagagagga gaagcgggag tcccagctga gttcagcatt
6780tggacccggg aagcaggcgc tggaggcctc tccatcgctg ttgagggccc cagtaaggcc
6840gagattacat tcgatgacca taaaaatggg tcgtgcggtg tatcttatat tgcccaagag
6900cctggtaact acgaggtgtc catcaagttc aatgatgagc acatcccgga aagcccctac
6960ctggtgccgg tcatcgcacc ctccgacgac gcccgccgcc tcactgttat gagccttcag
7020gaatcgggat taaaagttaa ccagccagca tcctttgcta taaggttgaa tggcgcaaaa
7080ggcaagattg atgcaaaggt gcacagcccc tctggagccg tggaggagtg ccacgtgtct
7140gagctggagc cagataagta tgctgttcgc ttcatccctc atgagaatgg tgtccacacc
7200atcgatgtca agttcaatgg gagccacgtg gttggaagcc ccttcaaagt gcgcgttggg
7260gagcctggac aagcggggaa ccctgccctg gtgtccgcct atggcacggg actcgaaggg
7320ggcaccacag gtatccagtc ggaattcttt attaacacca cccgagcagg tccagggaca
7380ttatccgtca ccatcgaagg cccatccaag gttaaaatgg attgccagga aacacctgaa
7440gggtacaaag tcatgtacac ccccatggct cctggtaact acctgatcag cgtcaaatac
7500ggtgggccca accacatcgt gggcagtccc ttcaaggcca aggtgacagg ccagcgtcta
7560gttagccctg gctcagccaa cgagacctca tccatcctgg tggagtcagt gaccaggtcg
7620tctacagaga cctgctatag cgccattccc aaggcatcct cggacgccag caaggtgacc
7680tctaaggggg cagggctctc aaaggccttt gtgggccaga agagttcctt cctggtggac
7740tgcagcaaag ctggctccaa catgctgctg atcggggtcc atgggcccac caccccctgc
7800gaggaggtct ccatgaagca tgtaggcaac cagcaataca acgtcacata cgtcgtcaag
7860gagaggggcg attatgtgct ggctgtgaag tggggggagg aacacatccc tggcagccct
7920tttcatgtca cagtgcctta aaacagtttt ctcaaatcct ggagagagtt cttgtggttg
7980cttttgttgc ttgtttgtaa ttcattttat acaaagccct ccagcctgtt tgtggggctg
8040aaaccccatc cctaaaatat tgctgttgta aaatgccttc agaaataagt cctagactgg
8100actcttgagg gacatattgg agaatcttaa gaaatgcaag cttgttcagg gggctgagaa
8160gatcctgagt acactaggtg caaaccagaa ctcttggtgg aacagaccag ccactgcagc
8220agacagacca ggaacacaat gagactgaca tttcaaaaaa acaaaactgg ctagcctgag
8280ctgctggttc actcttcagc atttatgaaa caaggctagg ggaagatggg cagagaaaaa
8340ggggacacct agtttggttg tcatttggca aaggagatga cttaaaatcc gcttaatctc
8400ttccagtgtc cgtgttaatg tatttggcta ttagatcact agcactgctt taccgctcct
8460catcgccaac acccccatgc tctgtggcct tcttacactt ctcagagggc agagtggcag
8520ccgggcaccc tacagaaact cagagggcag agtggcagcc aggcccacat gtctctcaag
8580tacctgtccc ctcgctctgg tgattatttc ttgcagaatc accacacgag accatcccgg
8640cagtcatggt tttgctttag ttttccaagt ccgtttcagt cccttccttg gtctgaagaa
8700attctgcagt ggcgagcagt ttcccacttg ccaaagatcc cttttaacca acactagccc
8760ttgtttttaa cacacgctcc agcccttcat cagcctgggc agtcttacca aaatgtttaa
8820agtgatctca gaggggccca tggattaacg ccctcatccc aaggtccgtc ccatgacata
8880acactccaca cccgccccag ccaacttcat gggtcacttt ttctggaaaa taatgatctg
8940tacagacagg acagaatgaa actcctgcgg gtctttggcc tgaaagttgg gaatggttgg
9000gggagagaag ggcagcagct tattggtggt cttttcacca ttggcagaaa cagtgagagc
9060tgtgtggtgc agaaatccag aaatgaggtg tagggaattt tgcctgcctt cctgcagacc
9120tgagctggct ttggaatgag gttaaagtgt cagggacgtt gcctgagccc aaatgtgtag
9180tgtggtctgg gcaggcagac ctttaggttt tgctgcttag tcctgaggaa gtggccactc
9240ttgtggcagg tgtagtatct ggggcgagtg ttgggggtaa aagcccaccc tacagaaagt
9300ggaacagccc ggagcctgat gtgaaaggac cacgggtgtt gtaagctggg acacggaagc
9360caaactggaa tcaaacgccg actgtaaatt gtatcttata acttattaaa taaaacattt
9420gctccgtaaa gttg
9434262578PRTHomo sapiens 26Met Pro Val Thr Glu Lys Asp Leu Ala Glu Asp
Ala Pro Trp Lys Lys 1 5 10
15 Ile Gln Gln Asn Thr Phe Thr Arg Trp Cys Asn Glu His Leu Lys Cys
20 25 30 Val Asn
Lys Arg Ile Gly Asn Leu Gln Thr Asp Leu Ser Asp Gly Leu 35
40 45 Arg Leu Ile Ala Leu Leu Glu
Val Leu Ser Gln Lys Arg Met Tyr Arg 50 55
60 Lys Tyr His Gln Arg Pro Thr Phe Arg Gln Met Gln
Leu Glu Asn Val 65 70 75
80 Ser Val Ala Leu Glu Phe Leu Asp Arg Glu Ser Ile Lys Leu Val Ser
85 90 95 Ile Asp Ser
Lys Ala Ile Val Asp Gly Asn Leu Lys Leu Ile Leu Gly 100
105 110 Leu Val Trp Thr Leu Ile Leu His
Tyr Ser Ile Ser Met Pro Val Trp 115 120
125 Glu Asp Glu Gly Asp Asp Asp Ala Lys Lys Gln Thr Pro
Lys Gln Arg 130 135 140
Leu Leu Gly Trp Ile Gln Asn Lys Ile Pro Tyr Leu Pro Ile Thr Asn 145
150 155 160 Phe Asn Gln Asn
Trp Gln Asp Gly Lys Ala Leu Gly Ala Leu Val Asp 165
170 175 Ser Cys Ala Pro Gly Leu Cys Pro Asp
Trp Glu Ser Trp Asp Pro Gln 180 185
190 Lys Pro Val Asp Asn Ala Arg Glu Ala Met Gln Gln Ala Asp
Asp Trp 195 200 205
Leu Gly Val Pro Gln Val Ile Thr Pro Glu Glu Ile Ile His Pro Asp 210
215 220 Val Asp Glu His Ser
Val Met Thr Tyr Leu Ser Gln Phe Pro Lys Ala 225 230
235 240 Lys Leu Lys Pro Gly Ala Pro Leu Lys Pro
Lys Leu Asn Pro Lys Lys 245 250
255 Ala Arg Ala Tyr Gly Arg Gly Ile Glu Pro Thr Gly Asn Met Val
Lys 260 265 270 Gln
Pro Ala Lys Phe Thr Val Asp Thr Ile Ser Ala Gly Gln Gly Asp 275
280 285 Val Met Val Phe Val Glu
Asp Pro Glu Gly Asn Lys Glu Glu Ala Gln 290 295
300 Val Thr Pro Asp Ser Asp Lys Asn Lys Thr Tyr
Ser Val Glu Tyr Leu 305 310 315
320 Pro Lys Val Thr Gly Leu His Lys Val Thr Val Leu Phe Ala Gly Gln
325 330 335 His Ile
Ser Lys Ser Pro Phe Glu Val Ser Val Asp Lys Ala Gln Gly 340
345 350 Asp Ala Ser Lys Val Thr Ala
Lys Gly Pro Gly Leu Glu Ala Val Gly 355 360
365 Asn Ile Ala Asn Lys Pro Thr Tyr Phe Asp Ile Tyr
Thr Ala Gly Ala 370 375 380
Gly Val Gly Asp Ile Gly Val Glu Val Glu Asp Pro Gln Gly Lys Asn 385
390 395 400 Thr Val Glu
Leu Leu Val Glu Asp Lys Gly Asn Gln Val Tyr Arg Cys 405
410 415 Val Tyr Lys Pro Met Gln Pro Gly
Pro His Val Val Lys Ile Phe Phe 420 425
430 Ala Gly Asp Thr Ile Pro Lys Ser Pro Phe Val Val Gln
Val Gly Glu 435 440 445
Ala Cys Asn Pro Asn Ala Cys Arg Ala Ser Gly Arg Gly Leu Gln Pro 450
455 460 Lys Gly Val Arg
Ile Arg Glu Thr Thr Asp Phe Lys Val Asp Thr Lys 465 470
475 480 Ala Ala Gly Ser Gly Glu Leu Gly Val
Thr Met Lys Gly Pro Lys Gly 485 490
495 Leu Glu Glu Leu Val Lys Gln Lys Asp Phe Leu Asp Gly Val
Tyr Ala 500 505 510
Phe Glu Tyr Tyr Pro Ser Thr Pro Gly Arg Tyr Ser Ile Ala Ile Thr
515 520 525 Trp Gly Gly His
His Ile Pro Lys Ser Pro Phe Glu Val Gln Val Gly 530
535 540 Pro Glu Ala Gly Met Gln Lys Val
Arg Ala Trp Gly Pro Gly Leu His 545 550
555 560 Gly Gly Ile Val Gly Arg Ser Ala Asp Phe Val Val
Glu Ser Ile Gly 565 570
575 Ser Glu Val Gly Ser Leu Gly Phe Ala Ile Glu Gly Pro Ser Gln Ala
580 585 590 Lys Ile Glu
Tyr Asn Asp Gln Asn Asp Gly Ser Cys Asp Val Lys Tyr 595
600 605 Trp Pro Lys Glu Pro Gly Glu Tyr
Ala Val His Ile Met Cys Asp Asp 610 615
620 Glu Asp Ile Lys Asp Ser Pro Tyr Met Ala Phe Ile His
Pro Ala Thr 625 630 635
640 Gly Gly Tyr Asn Pro Asp Leu Val Arg Ala Tyr Gly Pro Gly Leu Glu
645 650 655 Lys Ser Gly Cys
Ile Val Asn Asn Leu Ala Glu Phe Thr Val Asp Pro 660
665 670 Lys Asp Ala Gly Lys Ala Pro Leu Lys
Ile Phe Ala Gln Asp Gly Glu 675 680
685 Gly Gln Arg Ile Asp Ile Gln Met Lys Asn Arg Met Asp Gly
Thr Tyr 690 695 700
Ala Cys Ser Tyr Thr Pro Val Lys Ala Ile Lys His Thr Ile Ala Val 705
710 715 720 Val Trp Gly Gly Val
Asn Ile Pro His Ser Pro Tyr Arg Val Asn Ile 725
730 735 Gly Gln Gly Ser His Pro Gln Lys Val Lys
Val Phe Gly Pro Gly Val 740 745
750 Glu Arg Ser Gly Leu Lys Ala Asn Glu Pro Thr His Phe Thr Val
Asp 755 760 765 Cys
Thr Glu Ala Gly Glu Gly Asp Val Ser Val Gly Ile Lys Cys Asp 770
775 780 Ala Arg Val Leu Ser Glu
Asp Glu Glu Asp Val Asp Phe Asp Ile Ile 785 790
795 800 His Asn Ala Asn Asp Thr Phe Thr Val Lys Tyr
Val Pro Pro Ala Ala 805 810
815 Gly Arg Tyr Thr Ile Lys Val Leu Phe Ala Ser Gln Glu Ile Pro Ala
820 825 830 Ser Pro
Phe Arg Val Lys Val Asp Pro Ser His Asp Ala Ser Lys Val 835
840 845 Lys Ala Glu Gly Pro Gly Leu
Ser Lys Ala Gly Val Glu Asn Gly Lys 850 855
860 Pro Thr His Phe Thr Val Tyr Thr Lys Gly Ala Gly
Lys Ala Pro Leu 865 870 875
880 Asn Val Gln Phe Asn Ser Pro Leu Pro Gly Asp Ala Val Lys Asp Leu
885 890 895 Asp Ile Ile
Asp Asn Tyr Asp Tyr Ser His Thr Val Lys Tyr Thr Pro 900
905 910 Thr Gln Gln Gly Asn Met Gln Val
Leu Val Thr Tyr Gly Gly Asp Pro 915 920
925 Ile Pro Lys Ser Pro Phe Thr Val Gly Val Ala Ala Pro
Leu Asp Leu 930 935 940
Ser Lys Ile Lys Leu Asn Gly Leu Glu Asn Arg Val Glu Val Gly Lys 945
950 955 960 Asp Gln Glu Phe
Thr Val Asp Thr Arg Gly Ala Gly Gly Gln Gly Lys 965
970 975 Leu Asp Val Thr Ile Leu Ser Pro Ser
Arg Lys Val Val Pro Cys Leu 980 985
990 Val Thr Pro Val Thr Gly Arg Glu Asn Ser Thr Ala Lys
Phe Ile Pro 995 1000 1005
Arg Glu Glu Gly Leu Tyr Ala Val Asp Val Thr Tyr Asp Gly His
1010 1015 1020 Pro Val Pro
Gly Ser Pro Tyr Thr Val Glu Ala Ser Leu Pro Pro 1025
1030 1035 Asp Pro Ser Lys Val Lys Ala His
Gly Pro Gly Leu Glu Gly Gly 1040 1045
1050 Leu Val Gly Lys Pro Ala Glu Phe Thr Ile Asp Thr Lys
Gly Ala 1055 1060 1065
Gly Thr Gly Gly Leu Gly Leu Thr Val Glu Gly Pro Cys Glu Ala 1070
1075 1080 Lys Ile Glu Cys Ser
Asp Asn Gly Asp Gly Thr Cys Ser Val Ser 1085 1090
1095 Tyr Leu Pro Thr Lys Pro Gly Glu Tyr Phe
Val Asn Ile Leu Phe 1100 1105 1110
Glu Glu Val His Ile Pro Gly Ser Pro Phe Lys Ala Asp Ile Glu
1115 1120 1125 Met Pro
Phe Asp Pro Ser Lys Val Val Ala Ser Gly Pro Gly Leu 1130
1135 1140 Glu His Gly Lys Val Gly Glu
Ala Gly Leu Leu Ser Val Asp Cys 1145 1150
1155 Ser Glu Ala Gly Pro Gly Ala Leu Gly Leu Glu Ala
Val Ser Asp 1160 1165 1170
Ser Gly Thr Lys Ala Glu Val Ser Ile Gln Asn Asn Lys Asp Gly 1175
1180 1185 Thr Tyr Ala Val Thr
Tyr Val Pro Leu Thr Ala Gly Met Tyr Thr 1190 1195
1200 Leu Thr Met Lys Tyr Gly Gly Glu Leu Val
Pro His Phe Pro Ala 1205 1210 1215
Arg Val Lys Val Glu Pro Ala Val Asp Thr Ser Arg Ile Lys Val
1220 1225 1230 Phe Gly
Pro Gly Ile Glu Gly Lys Asp Val Phe Arg Glu Ala Thr 1235
1240 1245 Thr Asp Phe Thr Val Asp Ser
Arg Pro Leu Thr Gln Val Gly Gly 1250 1255
1260 Asp His Ile Lys Ala His Ile Ala Asn Pro Ser Gly
Ala Ser Thr 1265 1270 1275
Glu Cys Phe Val Thr Asp Asn Ala Asp Gly Thr Tyr Gln Val Glu 1280
1285 1290 Tyr Thr Pro Phe Glu
Lys Gly Leu His Val Val Glu Val Thr Tyr 1295 1300
1305 Asp Asp Val Pro Ile Pro Asn Ser Pro Phe
Lys Val Ala Val Thr 1310 1315 1320
Glu Gly Cys Gln Pro Ser Arg Val Gln Ala Gln Gly Pro Gly Leu
1325 1330 1335 Lys Glu
Ala Phe Thr Asn Lys Pro Asn Val Phe Thr Val Val Thr 1340
1345 1350 Arg Gly Ala Gly Ile Gly Gly
Leu Gly Ile Thr Val Glu Gly Pro 1355 1360
1365 Ser Glu Ser Lys Ile Asn Cys Arg Asp Asn Lys Asp
Gly Ser Cys 1370 1375 1380
Ser Ala Glu Tyr Ile Pro Phe Ala Pro Gly Asp Tyr Asp Val Asn 1385
1390 1395 Ile Thr Tyr Gly Gly
Ala His Ile Pro Gly Ser Pro Phe Arg Val 1400 1405
1410 Pro Val Lys Asp Val Val Asp Pro Ser Lys
Val Lys Ile Ala Gly 1415 1420 1425
Pro Gly Leu Gly Ser Gly Val Arg Ala Arg Val Leu Gln Ser Phe
1430 1435 1440 Thr Val
Asp Ser Ser Lys Ala Gly Leu Ala Pro Leu Glu Val Arg 1445
1450 1455 Val Leu Gly Pro Arg Gly Leu
Val Glu Pro Val Asn Val Val Asp 1460 1465
1470 Asn Gly Asp Gly Thr His Thr Val Thr Tyr Thr Pro
Ser Gln Glu 1475 1480 1485
Gly Pro Tyr Met Val Ser Val Lys Tyr Ala Asp Glu Glu Ile Pro 1490
1495 1500 Arg Ser Pro Phe Lys
Val Lys Val Leu Pro Thr Tyr Asp Ala Ser 1505 1510
1515 Lys Val Thr Ala Ser Gly Pro Gly Leu Ser
Ser Tyr Gly Val Pro 1520 1525 1530
Ala Ser Leu Pro Val Asp Phe Ala Ile Asp Ala Arg Asp Ala Gly
1535 1540 1545 Glu Gly
Leu Leu Ala Val Gln Ile Thr Asp Gln Glu Gly Lys Pro 1550
1555 1560 Lys Arg Ala Ile Val His Asp
Asn Lys Asp Gly Thr Tyr Ala Val 1565 1570
1575 Thr Tyr Ile Pro Asp Lys Thr Gly Arg Tyr Met Ile
Gly Val Thr 1580 1585 1590
Tyr Gly Gly Asp Asp Ile Pro Leu Ser Pro Tyr Arg Ile Arg Ala 1595
1600 1605 Thr Gln Thr Gly Asp
Ala Ser Lys Cys Leu Ala Thr Gly Pro Gly 1610 1615
1620 Ile Ala Ser Thr Val Lys Thr Gly Glu Glu
Val Gly Phe Val Val 1625 1630 1635
Asp Ala Lys Thr Ala Gly Lys Gly Lys Val Thr Cys Thr Val Leu
1640 1645 1650 Thr Pro
Asp Gly Thr Glu Ala Glu Ala Asp Val Ile Glu Asn Glu 1655
1660 1665 Asp Gly Thr Tyr Asp Ile Phe
Tyr Thr Ala Ala Lys Pro Gly Thr 1670 1675
1680 Tyr Val Ile Tyr Val Arg Phe Gly Gly Val Asp Ile
Pro Asn Ser 1685 1690 1695
Pro Phe Thr Val Met Val Thr Glu Glu Ala Tyr Val Pro Val Ser 1700
1705 1710 Asp Met Asn Gly Leu
Gly Phe Lys Pro Phe Asp Leu Val Ile Pro 1715 1720
1725 Phe Ala Val Arg Lys Gly Glu Ile Thr Gly
Glu Val His Met Pro 1730 1735 1740
Ser Gly Lys Thr Ala Thr Pro Glu Ile Val Asp Asn Lys Asp Gly
1745 1750 1755 Thr Val
Thr Val Arg Tyr Ala Pro Thr Glu Val Gly Leu His Glu 1760
1765 1770 Met His Ile Lys Tyr Met Gly
Ser His Ile Pro Glu Ser Pro Leu 1775 1780
1785 Gln Phe Tyr Val Asn Tyr Pro Asn Ser Gly Ser Val
Ser Ala Tyr 1790 1795 1800
Gly Pro Gly Leu Val Tyr Gly Val Ala Asn Lys Thr Ala Thr Phe 1805
1810 1815 Thr Ile Val Thr Glu
Asp Ala Gly Glu Gly Gly Leu Asp Leu Ala 1820 1825
1830 Ile Glu Gly Pro Ser Lys Ala Glu Ile Ser
Cys Ile Asp Asn Lys 1835 1840 1845
Asp Gly Thr Cys Thr Val Thr Tyr Leu Pro Thr Leu Pro Gly Asp
1850 1855 1860 Tyr Ser
Ile Leu Val Lys Tyr Asn Asp Lys His Ile Pro Gly Ser 1865
1870 1875 Pro Phe Thr Ala Lys Ile Thr
Asp Asp Ser Arg Arg Cys Ser Gln 1880 1885
1890 Val Lys Leu Gly Ser Ala Ala Asp Phe Leu Leu Asp
Ile Ser Glu 1895 1900 1905
Thr Asp Leu Ser Ser Leu Thr Ala Ser Ile Lys Ala Pro Ser Gly 1910
1915 1920 Arg Asp Glu Pro Cys
Leu Leu Lys Arg Leu Pro Asn Asn His Ile 1925 1930
1935 Gly Ile Ser Phe Ile Pro Arg Glu Val Gly
Glu His Leu Val Ser 1940 1945 1950
Ile Lys Lys Asn Gly Asn His Val Ala Asn Ser Pro Val Ser Ile
1955 1960 1965 Met Val
Val Gln Ser Glu Ile Gly Asp Ala Arg Arg Ala Lys Val 1970
1975 1980 Tyr Gly Arg Gly Leu Ser Glu
Gly Arg Thr Phe Glu Met Ser Asp 1985 1990
1995 Phe Ile Val Asp Thr Arg Asp Ala Gly Tyr Gly Gly
Ile Ser Leu 2000 2005 2010
Ala Val Glu Gly Pro Ser Lys Val Asp Ile Gln Thr Glu Asp Leu 2015
2020 2025 Glu Asp Gly Thr Cys
Lys Val Ser Tyr Phe Pro Thr Val Pro Gly 2030 2035
2040 Val Tyr Ile Val Ser Thr Lys Phe Ala Asp
Glu His Val Pro Gly 2045 2050 2055
Ser Pro Phe Thr Val Lys Ile Ser Gly Glu Gly Arg Val Lys Glu
2060 2065 2070 Ser Ile
Thr Arg Thr Ser Arg Ala Pro Ser Val Ala Thr Val Gly 2075
2080 2085 Ser Ile Cys Asp Leu Asn Leu
Lys Ile Pro Glu Ile Asn Ser Ser 2090 2095
2100 Asp Met Ser Ala His Val Thr Ser Pro Ser Gly Arg
Val Thr Glu 2105 2110 2115
Ala Glu Ile Val Pro Met Gly Lys Asn Ser His Cys Val Arg Phe 2120
2125 2130 Val Pro Gln Glu Met
Gly Val His Thr Val Ser Val Lys Tyr Arg 2135 2140
2145 Gly Gln His Val Thr Gly Ser Pro Phe Gln
Phe Thr Val Gly Pro 2150 2155 2160
Leu Gly Glu Gly Gly Ala His Lys Val Arg Ala Gly Gly Pro Gly
2165 2170 2175 Leu Glu
Arg Gly Glu Ala Gly Val Pro Ala Glu Phe Ser Ile Trp 2180
2185 2190 Thr Arg Glu Ala Gly Ala Gly
Gly Leu Ser Ile Ala Val Glu Gly 2195 2200
2205 Pro Ser Lys Ala Glu Ile Thr Phe Asp Asp His Lys
Asn Gly Ser 2210 2215 2220
Cys Gly Val Ser Tyr Ile Ala Gln Glu Pro Gly Asn Tyr Glu Val 2225
2230 2235 Ser Ile Lys Phe Asn
Asp Glu His Ile Pro Glu Ser Pro Tyr Leu 2240 2245
2250 Val Pro Val Ile Ala Pro Ser Asp Asp Ala
Arg Arg Leu Thr Val 2255 2260 2265
Met Ser Leu Gln Glu Ser Gly Leu Lys Val Asn Gln Pro Ala Ser
2270 2275 2280 Phe Ala
Ile Arg Leu Asn Gly Ala Lys Gly Lys Ile Asp Ala Lys 2285
2290 2295 Val His Ser Pro Ser Gly Ala
Val Glu Glu Cys His Val Ser Glu 2300 2305
2310 Leu Glu Pro Asp Lys Tyr Ala Val Arg Phe Ile Pro
His Glu Asn 2315 2320 2325
Gly Val His Thr Ile Asp Val Lys Phe Asn Gly Ser His Val Val 2330
2335 2340 Gly Ser Pro Phe Lys
Val Arg Val Gly Glu Pro Gly Gln Ala Gly 2345 2350
2355 Asn Pro Ala Leu Val Ser Ala Tyr Gly Thr
Gly Leu Glu Gly Gly 2360 2365 2370
Thr Thr Gly Ile Gln Ser Glu Phe Phe Ile Asn Thr Thr Arg Ala
2375 2380 2385 Gly Pro
Gly Thr Leu Ser Val Thr Ile Glu Gly Pro Ser Lys Val 2390
2395 2400 Lys Met Asp Cys Gln Glu Thr
Pro Glu Gly Tyr Lys Val Met Tyr 2405 2410
2415 Thr Pro Met Ala Pro Gly Asn Tyr Leu Ile Ser Val
Lys Tyr Gly 2420 2425 2430
Gly Pro Asn His Ile Val Gly Ser Pro Phe Lys Ala Lys Val Thr 2435
2440 2445 Gly Gln Arg Leu Val
Ser Pro Gly Ser Ala Asn Glu Thr Ser Ser 2450 2455
2460 Ile Leu Val Glu Ser Val Thr Arg Ser Ser
Thr Glu Thr Cys Tyr 2465 2470 2475
Ser Ala Ile Pro Lys Ala Ser Ser Asp Ala Ser Lys Val Thr Ser
2480 2485 2490 Lys Gly
Ala Gly Leu Ser Lys Ala Phe Val Gly Gln Lys Ser Ser 2495
2500 2505 Phe Leu Val Asp Cys Ser Lys
Ala Gly Ser Asn Met Leu Leu Ile 2510 2515
2520 Gly Val His Gly Pro Thr Thr Pro Cys Glu Glu Val
Ser Met Lys 2525 2530 2535
His Val Gly Asn Gln Gln Tyr Asn Val Thr Tyr Val Val Lys Glu 2540
2545 2550 Arg Gly Asp Tyr Val
Leu Ala Val Lys Trp Gly Glu Glu His Ile 2555 2560
2565 Pro Gly Ser Pro Phe His Val Thr Val Pro
2570 2575 279395DNAHomo sapiens
27gcggccaggg gcgggcggcc gcagagcagc accggccgtg gctccggtag cagcaagttc
60gaaccccgct cccgctccgc ttcggttctc gctccttcgg cccttgggcc tccaaacacc
120agtccccggc agctcgttgc gcattgcgct ctccccgcca ccaggatgcc ggtaaccgag
180aaggatctag ctgaggacgc gccttggaag aagatccagc agaacacgtt cacacgctgg
240tgcaacgagc acctcaagtg cgtgaacaaa cgcatcggca acctgcagac cgacctgagc
300gacgggctgc ggctcatcgc gctgctcgag gtgctcagcc agaagcgcat gtaccgcaag
360taccatcagc ggcccacctt tcgccagatg cagctcgaga atgtgtccgt ggcgctcgag
420ttcctggacc gtgagagcat caagctcgtg tccatcgata gcaaagccat tgtggatggg
480aacctgaagc tcatcttggg tctggtgtgg acgctgatcc tccactactc catctccatg
540cccgtgtggg aggatgaagg ggatgatgat gccaagaagc agacgccaaa gcagaggctg
600ctggggtgga ttcagaacaa gatcccctac ttgcccatca ccaactttaa ccagaactgg
660caagacggca aagccctggg agccctggta gacagctgtg ctccaggtct gtgcccagac
720tgggaatcct gggacccgca gaagcctgtg gataatgcac gagaagccat gcagcaggca
780gatgactggc tgggtgtccc acaggtcatc actcctgaag aaatcattca cccggatgtg
840gacgagcact cagttatgac ttacctgtcc cagttcccca aagccaagct caagccgggg
900gctcctctca aacccaaact caacccgaag aaagccaggg cctatggcag aggaatcgag
960cccactggaa acatggtgaa gcagccagcc aagttcactg tggacaccat cagcgccggg
1020caaggagacg tgatggtgtt tgttgaggac ccagaaggga acaaagagga ggcacaagtg
1080acccctgaca gtgacaagaa caagacatac tctgtggagt atctgcccaa ggtcaccggg
1140ctacacaaag tcacagtcct ctttgcagga cagcacatct ccaagagccc atttgaagtg
1200agtgttgaca aggcccaggg agatgccagt aaagtcactg caaaaggtcc agggttggaa
1260gctgtaggga acatcgccaa taagcccacc tactttgaca tctatacggc aggagctggt
1320gtgggtgaca ttggtgtgga ggtggaagat ccccagggga agaacaccgt ggagttgctc
1380gtggaagaca aaggaaacca ggtgtatcga tgtgtgtaca aacccatgca gcctggccct
1440cacgtggtca agatcttctt tgctggggac actattccta agagtccctt cgttgtgcag
1500gttggggaag cctgcaatcc aaatgcctgc cgggccagtg gccgaggcct acaacccaaa
1560ggcgtccgta tccgggagac cacagatttc aaggttgaca ccaaagctgc aggaagtggg
1620gagctcggtg taaccatgaa gggtcctaag ggtctggagg agctggtgaa gcagaaagac
1680tttctggatg gggtctacgc attcgagtat taccccagca ccccggggag atacagcatt
1740gccatcacat gggggggaca ccacattcca aagagcccct ttgaagttca agttggccct
1800gaagcgggta tgcagaaagt ccgtgcttgg ggccctgggc tccatggtgg gattgtcggg
1860cggtcagcgg acttcgtggt agaatccatt ggctctgaag tggggtctct ggggtttgcc
1920attgaaggcc cctctcaggc aaagattgag tacaacgacc agaatgatgg atcgtgtgat
1980gtcaaatact ggcccaagga gcctggcgaa tatgctgttc acatcatgtg tgacgacgaa
2040gacatcaagg acagcccgta catggccttc atccacccag ccacgggagg ctacaaccct
2100gatctggttc gagcatacgg gccaggtttg gagaaatctg gatgcattgt caacaacctg
2160gccgagttca ctgtggatcc taaggatgct ggaaaagctc ccttaaagat atttgctcag
2220gatggggaag gccaacgcat tgacatccag atgaagaacc ggatggacgg cacatatgca
2280tgctcataca ccccggtgaa ggccatcaag cacaccattg ctgtggtctg gggaggcgtg
2340aacatcccgc acagccccta cagggtcaac atcgggcaag gtagccatcc tcagaaggtc
2400aaagtgtttg ggccaggtgt ggagagaagt ggtctgaagg caaatgaacc tacacacttc
2460acggtggact gtactgaggc tggggaaggt gatgtcagtg ttggcattaa gtgtgatgcc
2520cgggtgttaa gtgaagatga ggaagacgtg gattttgaca ttattcacaa tgccaatgat
2580acgttcacag tcaaatatgt gcctcctgct gctgggcgat acactatcaa agttctcttt
2640gcatctcagg aaatccccgc cagccctttc agagtcaaag ttgacccttc ccacgatgcc
2700agcaaagtga aggcagaagg cccagggctc agcaaagcag gtgtggaaaa tgggaaaccg
2760acccacttca ctgtctacac caagggggct gggaaagccc cgctcaacgt gcagttcaac
2820agccctcttc ctggcgatgc agtgaaggat ttggatatca tcgataatta tgactactct
2880cacacggtta aatatacacc cacccaacag ggcaacatgc aggttctggt gacttacggt
2940ggcgatccca tccctaaaag ccctttcact gtgggtgttg ctgcaccgct ggatctgagc
3000aagataaaac tcaatgggct ggaaaacagg gtggaagttg ggaaggatca ggagttcacc
3060gttgatacca ggggggcagg aggccagggg aagctggacg tgacaatcct cagcccctct
3120cggaaggtcg tgccatgcct agtgacacct gtgacaggcc gggagaacag cacggccaag
3180ttcatccctc gggaggaggg gctgtatgct gtagacgtga cctacgatgg acaccctgtg
3240cccgggagcc cctacacagt ggaggcctcg ctgccaccag atcccagcaa ggtgaaggcc
3300cacggtcccg gcctcgaagg tggtctcgtg ggcaagcctg ccgagttcac catcgatacc
3360aaaggagctg gtactggagg tctgggctta acggtggaag gtccgtgcga ggccaaaatc
3420gagtgctccg acaatggtga tgggacctgc tccgtctctt accttcccac aaaacccggg
3480gagtacttcg tcaacatcct ctttgaagaa gtccacatac ctgggtctcc cttcaaagct
3540gacattgaaa tgccctttga cccctctaaa gtcgtggcat cggggccagg tctcgagcac
3600gggaaggtgg gtgaagctgg cctccttagc gtcgactgct cggaagcggg accgggggcc
3660ctgggcctgg aagctgtctc ggactcggga acaaaagccg aagtcagtat tcagaacaac
3720aaagatggca cctacgcggt gacctacgtg cccctgacgg ccggcatgta cacgttgacc
3780atgaagtatg gtggcgaact cgtgccacac ttccccgccc gggtcaaggt ggagcccgcc
3840gtggacacca gcaggatcaa agtctttgga ccaggaatag aagggaaaga tgtgttccgg
3900gaagctacca ccgactttac agttgactct cggccgctga cccaggttgg gggtgaccac
3960atcaaggccc acattgccaa cccctcaggg gcctccaccg agtgctttgt cacagacaat
4020gcggatggga cctaccaggt ggaatacaca ccctttgaga aaggtctcca tgtagtggag
4080gtgacatatg atgacgtgcc tatcccaaac agtcccttca aggtggctgt cactgaaggc
4140tgccagccat ctagggtgca agcccaagga cctggattga aagaggcctt taccaacaag
4200cccaatgtct tcaccgtggt taccagaggc gcaggaattg gtgggcttgg cataactgtt
4260gagggaccat cagagtcgaa gataaattgc agagacaaca aggatggcag ctgcagtgct
4320gagtacattc ctttcgcacc gggggattac gatgttaata tcacatatgg aggagcccac
4380atccccggca gccccttcag ggttcctgtg aaggatgttg tggaccccag caaggtcaag
4440attgccggcc ccgggctggg ctcaggcgtc cgagcccgtg tcctgcagtc cttcacggtg
4500gacagcagca aggctggcct ggctccgctg gaagtgaggg ttctgggccc acgaggcttg
4560gtggagccag tgaacgtggt ggacaatgga gatggcacac acacagtaac ctacacccca
4620tctcaggagg gaccttacat ggtctcagtt aaatatgctg atgaagagat tcctcgcagt
4680cccttcaagg tcaaggtcct tcccacatat gatgccagca aagtgactgc cagtggcccc
4740ggccttagtt cctatggtgt gcctgccagt ctacctgtgg actttgcaat tgatgcccga
4800gatgccgggg aaggcctgct tgctgttcaa ataacggacc aagaaggaaa acccaaaaga
4860gccattgtcc atgacaataa agatggcacg tatgctgtca cctacatccc cgacaagact
4920gggcgctata tgattggagt cacctacggg ggtgacgaca tcccactttc tccttatcgc
4980atccgagcca cacagacggg tgatgccagc aagtgcctgg ccacgggtcc tggaatcgcc
5040tccactgtga aaactggcga agaagtaggc tttgtggttg atgccaagac tgccgggaag
5100ggtaaagtga cctgcacggt tctgacccca gatggcactg aggccgaggc cgatgtcatt
5160gagaatgaag atggaaccta tgacatcttc tacacagctg ccaagccggg cacatatgtg
5220atctatgtgc gcttcggtgg tgttgatatt cctaacagcc ccttcactgt catggtgacc
5280gaagaggcct atgtcccagt gagtgacatg aacggcctgg gatttaagcc ttttgacctg
5340gtcattccgt ttgctgtcag gaaaggagaa atcactggag aggtccacat gccttctggg
5400aagacagcca cacctgagat tgtggacaac aaggacggca cggtcactgt tagatatgcc
5460cccactgagg tcgggctcca tgagatgcac atcaaataca tgggcagcca catccctgag
5520agcccactcc agttctacgt gaactacccc aacagtggaa gtgtttctgc atacggtcca
5580ggcctcgtgt atggagtggc caacaaaact gccaccttca ccatcgtcac agaggatgca
5640ggagaaggtg gtctggactt ggctattgag ggcccctcaa aagcagaaat cagctgcatt
5700gacaataaag atgggacatg cacagtgacc tacctgccga ctctgccagg cgactacagc
5760attctggtca agtacaatga caagcacatc cctggcagcc ccttcacagc caagatcaca
5820gatgacagca ggcggtgctc ccaggtgaag ttgggctcag ccgctgactt cctgctcgac
5880atcagtgaga ctgacctcag cagcctgacg gccagcatta aggccccatc tggccgagac
5940gagccctgtc tcctgaagag gctgcccaac aaccacattg gcatctcctt catcccccgg
6000gaagtgggcg aacatctggt cagcatcaag aaaaatggca accatgtggc caacagcccc
6060gtgtctatca tggtggtcca gtcggagatt ggtgacgccc gccgagccaa agtctatggc
6120cgcggcctgt cagaaggccg gactttcgag atgtctgact tcatcgtgga cacaagggat
6180gcaggttatg gtggcatatc cttggcggtg gaaggcccca gcaaagtgga catccagacg
6240gaggacctgg aagatggcac ctgcaaagtc tcctacttcc ctaccgtgcc tggggtttat
6300atcgtctcca ccaaattcgc tgacgagcac gtgcctggga gcccatttac cgtgaagatc
6360agtggggagg gaagagtcaa agagagcatc acccgcacca gtcgggcccc gtccgtggcc
6420actgtcggga gcatttgtga cctgaacctg aaaatcccag aaatcaacag cagtgatatg
6480tcggcccacg tcaccagccc ctctggccgt gtgactgagg cagagattgt gcccatgggg
6540aagaactcac actgcgtccg gtttgtgccc caggagatgg gcgtgcacac ggtcagcgtc
6600aagtaccgtg ggcagcacgt caccggcagc cccttccagt tcaccgtggg gccacttggt
6660gaaggaggcg cccacaaggt gcgggcagga ggccctggcc tggagagagg agaagcggga
6720gtcccagctg agttcagcat ttggacccgg gaagcaggcg ctggaggcct ctccatcgct
6780gttgagggcc ccagtaaggc cgagattaca ttcgatgacc ataaaaatgg gtcgtgcggt
6840gtatcttata ttgcccaaga gcctggtaac tacgaggtgt ccatcaagtt caatgatgag
6900cacatcccgg aaagccccta cctggtgccg gtcatcgcac cctccgacga cgcccgccgc
6960ctcactgtta tgagccttca ggaatcggga ttaaaagtta accagccagc atcctttgct
7020ataaggttga atggcgcaaa aggcaagatt gatgcaaagg tgcacagccc ctctggagcc
7080gtggaggagt gccacgtgtc tgagctggag ccagataagt atgctgttcg cttcatccct
7140catgagaatg gtgtccacac catcgatgtc aagttcaatg ggagccacgt ggttggaagc
7200cccttcaaag tgcgcgttgg ggagcctgga caagcgggga accctgccct ggtgtccgcc
7260tatggcacgg gactcgaagg gggcaccaca ggtatccagt cggaattctt tattaacacc
7320acccgagcag gtccagggac attatccgtc accatcgaag gcccatccaa ggttaaaatg
7380gattgccagg aaacacctga agggtacaaa gtcatgtaca cccccatggc tcctggtaac
7440tacctgatca gcgtcaaata cggtgggccc aaccacatcg tgggcagtcc cttcaaggcc
7500aaggtgacag gccagcgtct agttagccct ggctcagcca acgagacctc atccatcctg
7560gtggagtcag tgaccaggtc gtctacagag acctgctata gcgccattcc caaggcatcc
7620tcggacgcca gcaaggtgac ctctaagggg gcagggctct caaaggcctt tgtgggccag
7680aagagttcct tcctggtgga ctgcagcaaa gctggctcca acatgctgct gatcggggtc
7740catgggccca ccaccccctg cgaggaggtc tccatgaagc atgtaggcaa ccagcaatac
7800aacgtcacat acgtcgtcaa ggagaggggc gattatgtgc tggctgtgaa gtggggggag
7860gaacacatcc ctggcagccc ttttcatgtc acagtgcctt aaaacagttt tctcaaatcc
7920tggagagagt tcttgtggtt gcttttgttg cttgtttgta attcatttta tacaaagccc
7980tccagcctgt ttgtggggct gaaaccccat ccctaaaata ttgctgttgt aaaatgcctt
8040cagaaataag tcctagactg gactcttgag ggacatattg gagaatctta agaaatgcaa
8100gcttgttcag ggggctgaga agatcctgag tacactaggt gcaaaccaga actcttggtg
8160gaacagacca gccactgcag cagacagacc aggaacacaa tgagactgac atttcaaaaa
8220aacaaaactg gctagcctga gctgctggtt cactcttcag catttatgaa acaaggctag
8280gggaagatgg gcagagaaaa aggggacacc tagtttggtt gtcatttggc aaaggagatg
8340acttaaaatc cgcttaatct cttccagtgt ccgtgttaat gtatttggct attagatcac
8400tagcactgct ttaccgctcc tcatcgccaa cacccccatg ctctgtggcc ttcttacact
8460tctcagaggg cagagtggca gccgggcacc ctacagaaac tcagagggca gagtggcagc
8520caggcccaca tgtctctcaa gtacctgtcc cctcgctctg gtgattattt cttgcagaat
8580caccacacga gaccatcccg gcagtcatgg ttttgcttta gttttccaag tccgtttcag
8640tcccttcctt ggtctgaaga aattctgcag tggcgagcag tttcccactt gccaaagatc
8700ccttttaacc aacactagcc cttgttttta acacacgctc cagcccttca tcagcctggg
8760cagtcttacc aaaatgttta aagtgatctc agaggggccc atggattaac gccctcatcc
8820caaggtccgt cccatgacat aacactccac acccgcccca gccaacttca tgggtcactt
8880tttctggaaa ataatgatct gtacagacag gacagaatga aactcctgcg ggtctttggc
8940ctgaaagttg ggaatggttg ggggagagaa gggcagcagc ttattggtgg tcttttcacc
9000attggcagaa acagtgagag ctgtgtggtg cagaaatcca gaaatgaggt gtagggaatt
9060ttgcctgcct tcctgcagac ctgagctggc tttggaatga ggttaaagtg tcagggacgt
9120tgcctgagcc caaatgtgta gtgtggtctg ggcaggcaga cctttaggtt ttgctgctta
9180gtcctgagga agtggccact cttgtggcag gtgtagtatc tggggcgagt gttgggggta
9240aaagcccacc ctacagaaag tggaacagcc cggagcctga tgtgaaagga ccacgggtgt
9300tgtaagctgg gacacggaag ccaaactgga atcaaacgcc gactgtaaat tgtatcttat
9360aacttattaa ataaaacatt tgctccgtaa agttg
9395282602PRTHomo sapiens 28Met Pro Val Thr Glu Lys Asp Leu Ala Glu Asp
Ala Pro Trp Lys Lys 1 5 10
15 Ile Gln Gln Asn Thr Phe Thr Arg Trp Cys Asn Glu His Leu Lys Cys
20 25 30 Val Asn
Lys Arg Ile Gly Asn Leu Gln Thr Asp Leu Ser Asp Gly Leu 35
40 45 Arg Leu Ile Ala Leu Leu Glu
Val Leu Ser Gln Lys Arg Met Tyr Arg 50 55
60 Lys Tyr His Gln Arg Pro Thr Phe Arg Gln Met Gln
Leu Glu Asn Val 65 70 75
80 Ser Val Ala Leu Glu Phe Leu Asp Arg Glu Ser Ile Lys Leu Val Ser
85 90 95 Ile Asp Ser
Lys Ala Ile Val Asp Gly Asn Leu Lys Leu Ile Leu Gly 100
105 110 Leu Val Trp Thr Leu Ile Leu His
Tyr Ser Ile Ser Met Pro Val Trp 115 120
125 Glu Asp Glu Gly Asp Asp Asp Ala Lys Lys Gln Thr Pro
Lys Gln Arg 130 135 140
Leu Leu Gly Trp Ile Gln Asn Lys Ile Pro Tyr Leu Pro Ile Thr Asn 145
150 155 160 Phe Asn Gln Asn
Trp Gln Asp Gly Lys Ala Leu Gly Ala Leu Val Asp 165
170 175 Ser Cys Ala Pro Gly Leu Cys Pro Asp
Trp Glu Ser Trp Asp Pro Gln 180 185
190 Lys Pro Val Asp Asn Ala Arg Glu Ala Met Gln Gln Ala Asp
Asp Trp 195 200 205
Leu Gly Val Pro Gln Val Ile Thr Pro Glu Glu Ile Ile His Pro Asp 210
215 220 Val Asp Glu His Ser
Val Met Thr Tyr Leu Ser Gln Phe Pro Lys Ala 225 230
235 240 Lys Leu Lys Pro Gly Ala Pro Leu Lys Pro
Lys Leu Asn Pro Lys Lys 245 250
255 Ala Arg Ala Tyr Gly Arg Gly Ile Glu Pro Thr Gly Asn Met Val
Lys 260 265 270 Gln
Pro Ala Lys Phe Thr Val Asp Thr Ile Ser Ala Gly Gln Gly Asp 275
280 285 Val Met Val Phe Val Glu
Asp Pro Glu Gly Asn Lys Glu Glu Ala Gln 290 295
300 Val Thr Pro Asp Ser Asp Lys Asn Lys Thr Tyr
Ser Val Glu Tyr Leu 305 310 315
320 Pro Lys Val Thr Gly Leu His Lys Val Thr Val Leu Phe Ala Gly Gln
325 330 335 His Ile
Ser Lys Ser Pro Phe Glu Val Ser Val Asp Lys Ala Gln Gly 340
345 350 Asp Ala Ser Lys Val Thr Ala
Lys Gly Pro Gly Leu Glu Ala Val Gly 355 360
365 Asn Ile Ala Asn Lys Pro Thr Tyr Phe Asp Ile Tyr
Thr Ala Gly Ala 370 375 380
Gly Val Gly Asp Ile Gly Val Glu Val Glu Asp Pro Gln Gly Lys Asn 385
390 395 400 Thr Val Glu
Leu Leu Val Glu Asp Lys Gly Asn Gln Val Tyr Arg Cys 405
410 415 Val Tyr Lys Pro Met Gln Pro Gly
Pro His Val Val Lys Ile Phe Phe 420 425
430 Ala Gly Asp Thr Ile Pro Lys Ser Pro Phe Val Val Gln
Val Gly Glu 435 440 445
Ala Cys Asn Pro Asn Ala Cys Arg Ala Ser Gly Arg Gly Leu Gln Pro 450
455 460 Lys Gly Val Arg
Ile Arg Glu Thr Thr Asp Phe Lys Val Asp Thr Lys 465 470
475 480 Ala Ala Gly Ser Gly Glu Leu Gly Val
Thr Met Lys Gly Pro Lys Gly 485 490
495 Leu Glu Glu Leu Val Lys Gln Lys Asp Phe Leu Asp Gly Val
Tyr Ala 500 505 510
Phe Glu Tyr Tyr Pro Ser Thr Pro Gly Arg Tyr Ser Ile Ala Ile Thr
515 520 525 Trp Gly Gly His
His Ile Pro Lys Ser Pro Phe Glu Val Gln Val Gly 530
535 540 Pro Glu Ala Gly Met Gln Lys Val
Arg Ala Trp Gly Pro Gly Leu His 545 550
555 560 Gly Gly Ile Val Gly Arg Ser Ala Asp Phe Val Val
Glu Ser Ile Gly 565 570
575 Ser Glu Val Gly Ser Leu Gly Phe Ala Ile Glu Gly Pro Ser Gln Ala
580 585 590 Lys Ile Glu
Tyr Asn Asp Gln Asn Asp Gly Ser Cys Asp Val Lys Tyr 595
600 605 Trp Pro Lys Glu Pro Gly Glu Tyr
Ala Val His Ile Met Cys Asp Asp 610 615
620 Glu Asp Ile Lys Asp Ser Pro Tyr Met Ala Phe Ile His
Pro Ala Thr 625 630 635
640 Gly Gly Tyr Asn Pro Asp Leu Val Arg Ala Tyr Gly Pro Gly Leu Glu
645 650 655 Lys Ser Gly Cys
Ile Val Asn Asn Leu Ala Glu Phe Thr Val Asp Pro 660
665 670 Lys Asp Ala Gly Lys Ala Pro Leu Lys
Ile Phe Ala Gln Asp Gly Glu 675 680
685 Gly Gln Arg Ile Asp Ile Gln Met Lys Asn Arg Met Asp Gly
Thr Tyr 690 695 700
Ala Cys Ser Tyr Thr Pro Val Lys Ala Ile Lys His Thr Ile Ala Val 705
710 715 720 Val Trp Gly Gly Val
Asn Ile Pro His Ser Pro Tyr Arg Val Asn Ile 725
730 735 Gly Gln Gly Ser His Pro Gln Lys Val Lys
Val Phe Gly Pro Gly Val 740 745
750 Glu Arg Ser Gly Leu Lys Ala Asn Glu Pro Thr His Phe Thr Val
Asp 755 760 765 Cys
Thr Glu Ala Gly Glu Gly Asp Val Ser Val Gly Ile Lys Cys Asp 770
775 780 Ala Arg Val Leu Ser Glu
Asp Glu Glu Asp Val Asp Phe Asp Ile Ile 785 790
795 800 His Asn Ala Asn Asp Thr Phe Thr Val Lys Tyr
Val Pro Pro Ala Ala 805 810
815 Gly Arg Tyr Thr Ile Lys Val Leu Phe Ala Ser Gln Glu Ile Pro Ala
820 825 830 Ser Pro
Phe Arg Val Lys Val Asp Pro Ser His Asp Ala Ser Lys Val 835
840 845 Lys Ala Glu Gly Pro Gly Leu
Ser Lys Ala Gly Val Glu Asn Gly Lys 850 855
860 Pro Thr His Phe Thr Val Tyr Thr Lys Gly Ala Gly
Lys Ala Pro Leu 865 870 875
880 Asn Val Gln Phe Asn Ser Pro Leu Pro Gly Asp Ala Val Lys Asp Leu
885 890 895 Asp Ile Ile
Asp Asn Tyr Asp Tyr Ser His Thr Val Lys Tyr Thr Pro 900
905 910 Thr Gln Gln Gly Asn Met Gln Val
Leu Val Thr Tyr Gly Gly Asp Pro 915 920
925 Ile Pro Lys Ser Pro Phe Thr Val Gly Val Ala Ala Pro
Leu Asp Leu 930 935 940
Ser Lys Ile Lys Leu Asn Gly Leu Glu Asn Arg Val Glu Val Gly Lys 945
950 955 960 Asp Gln Glu Phe
Thr Val Asp Thr Arg Gly Ala Gly Gly Gln Gly Lys 965
970 975 Leu Asp Val Thr Ile Leu Ser Pro Ser
Arg Lys Val Val Pro Cys Leu 980 985
990 Val Thr Pro Val Thr Gly Arg Glu Asn Ser Thr Ala Lys
Phe Ile Pro 995 1000 1005
Arg Glu Glu Gly Leu Tyr Ala Val Asp Val Thr Tyr Asp Gly His
1010 1015 1020 Pro Val Pro
Gly Ser Pro Tyr Thr Val Glu Ala Ser Leu Pro Pro 1025
1030 1035 Asp Pro Ser Lys Val Lys Ala His
Gly Pro Gly Leu Glu Gly Gly 1040 1045
1050 Leu Val Gly Lys Pro Ala Glu Phe Thr Ile Asp Thr Lys
Gly Ala 1055 1060 1065
Gly Thr Gly Gly Leu Gly Leu Thr Val Glu Gly Pro Cys Glu Ala 1070
1075 1080 Lys Ile Glu Cys Ser
Asp Asn Gly Asp Gly Thr Cys Ser Val Ser 1085 1090
1095 Tyr Leu Pro Thr Lys Pro Gly Glu Tyr Phe
Val Asn Ile Leu Phe 1100 1105 1110
Glu Glu Val His Ile Pro Gly Ser Pro Phe Lys Ala Asp Ile Glu
1115 1120 1125 Met Pro
Phe Asp Pro Ser Lys Val Val Ala Ser Gly Pro Gly Leu 1130
1135 1140 Glu His Gly Lys Val Gly Glu
Ala Gly Leu Leu Ser Val Asp Cys 1145 1150
1155 Ser Glu Ala Gly Pro Gly Ala Leu Gly Leu Glu Ala
Val Ser Asp 1160 1165 1170
Ser Gly Thr Lys Ala Glu Val Ser Ile Gln Asn Asn Lys Asp Gly 1175
1180 1185 Thr Tyr Ala Val Thr
Tyr Val Pro Leu Thr Ala Gly Met Tyr Thr 1190 1195
1200 Leu Thr Met Lys Tyr Gly Gly Glu Leu Val
Pro His Phe Pro Ala 1205 1210 1215
Arg Val Lys Val Glu Pro Ala Val Asp Thr Ser Arg Ile Lys Val
1220 1225 1230 Phe Gly
Pro Gly Ile Glu Gly Lys Asp Val Phe Arg Glu Ala Thr 1235
1240 1245 Thr Asp Phe Thr Val Asp Ser
Arg Pro Leu Thr Gln Val Gly Gly 1250 1255
1260 Asp His Ile Lys Ala His Ile Ala Asn Pro Ser Gly
Ala Ser Thr 1265 1270 1275
Glu Cys Phe Val Thr Asp Asn Ala Asp Gly Thr Tyr Gln Val Glu 1280
1285 1290 Tyr Thr Pro Phe Glu
Lys Gly Leu His Val Val Glu Val Thr Tyr 1295 1300
1305 Asp Asp Val Pro Ile Pro Asn Ser Pro Phe
Lys Val Ala Val Thr 1310 1315 1320
Glu Gly Cys Gln Pro Ser Arg Val Gln Ala Gln Gly Pro Gly Leu
1325 1330 1335 Lys Glu
Ala Phe Thr Asn Lys Pro Asn Val Phe Thr Val Val Thr 1340
1345 1350 Arg Gly Ala Gly Ile Gly Gly
Leu Gly Ile Thr Val Glu Gly Pro 1355 1360
1365 Ser Glu Ser Lys Ile Asn Cys Arg Asp Asn Lys Asp
Gly Ser Cys 1370 1375 1380
Ser Ala Glu Tyr Ile Pro Phe Ala Pro Gly Asp Tyr Asp Val Asn 1385
1390 1395 Ile Thr Tyr Gly Gly
Ala His Ile Pro Gly Ser Pro Phe Arg Val 1400 1405
1410 Pro Val Lys Asp Val Val Asp Pro Ser Lys
Val Lys Ile Ala Gly 1415 1420 1425
Pro Gly Leu Gly Ser Gly Val Arg Ala Arg Val Leu Gln Ser Phe
1430 1435 1440 Thr Val
Asp Ser Ser Lys Ala Gly Leu Ala Pro Leu Glu Val Arg 1445
1450 1455 Val Leu Gly Pro Arg Gly Leu
Val Glu Pro Val Asn Val Val Asp 1460 1465
1470 Asn Gly Asp Gly Thr His Thr Val Thr Tyr Thr Pro
Ser Gln Glu 1475 1480 1485
Gly Pro Tyr Met Val Ser Val Lys Tyr Ala Asp Glu Glu Ile Pro 1490
1495 1500 Arg Ser Pro Phe Lys
Val Lys Val Leu Pro Thr Tyr Asp Ala Ser 1505 1510
1515 Lys Val Thr Ala Ser Gly Pro Gly Leu Ser
Ser Tyr Gly Val Pro 1520 1525 1530
Ala Ser Leu Pro Val Asp Phe Ala Ile Asp Ala Arg Asp Ala Gly
1535 1540 1545 Glu Gly
Leu Leu Ala Val Gln Ile Thr Asp Gln Glu Gly Lys Pro 1550
1555 1560 Lys Arg Ala Ile Val His Asp
Asn Lys Asp Gly Thr Tyr Ala Val 1565 1570
1575 Thr Tyr Ile Pro Asp Lys Thr Gly Arg Tyr Met Ile
Gly Val Thr 1580 1585 1590
Tyr Gly Gly Asp Asp Ile Pro Leu Ser Pro Tyr Arg Ile Arg Ala 1595
1600 1605 Thr Gln Thr Gly Asp
Ala Ser Lys Cys Leu Ala Thr Gly Pro Gly 1610 1615
1620 Ile Ala Ser Thr Val Lys Thr Gly Glu Glu
Val Gly Phe Val Val 1625 1630 1635
Asp Ala Lys Thr Ala Gly Lys Gly Lys Val Thr Cys Thr Val Leu
1640 1645 1650 Thr Pro
Asp Gly Thr Glu Ala Glu Ala Asp Val Ile Glu Asn Glu 1655
1660 1665 Asp Gly Thr Tyr Asp Ile Phe
Tyr Thr Ala Ala Lys Pro Gly Thr 1670 1675
1680 Tyr Val Ile Tyr Val Arg Phe Gly Gly Val Asp Ile
Pro Asn Ser 1685 1690 1695
Pro Phe Thr Val Met Ala Thr Asp Gly Glu Val Thr Ala Val Glu 1700
1705 1710 Glu Ala Pro Val Asn
Ala Cys Pro Pro Gly Phe Arg Pro Trp Val 1715 1720
1725 Thr Glu Glu Ala Tyr Val Pro Val Ser Asp
Met Asn Gly Leu Gly 1730 1735 1740
Phe Lys Pro Phe Asp Leu Val Ile Pro Phe Ala Val Arg Lys Gly
1745 1750 1755 Glu Ile
Thr Gly Glu Val His Met Pro Ser Gly Lys Thr Ala Thr 1760
1765 1770 Pro Glu Ile Val Asp Asn Lys
Asp Gly Thr Val Thr Val Arg Tyr 1775 1780
1785 Ala Pro Thr Glu Val Gly Leu His Glu Met His Ile
Lys Tyr Met 1790 1795 1800
Gly Ser His Ile Pro Glu Ser Pro Leu Gln Phe Tyr Val Asn Tyr 1805
1810 1815 Pro Asn Ser Gly Ser
Val Ser Ala Tyr Gly Pro Gly Leu Val Tyr 1820 1825
1830 Gly Val Ala Asn Lys Thr Ala Thr Phe Thr
Ile Val Thr Glu Asp 1835 1840 1845
Ala Gly Glu Gly Gly Leu Asp Leu Ala Ile Glu Gly Pro Ser Lys
1850 1855 1860 Ala Glu
Ile Ser Cys Ile Asp Asn Lys Asp Gly Thr Cys Thr Val 1865
1870 1875 Thr Tyr Leu Pro Thr Leu Pro
Gly Asp Tyr Ser Ile Leu Val Lys 1880 1885
1890 Tyr Asn Asp Lys His Ile Pro Gly Ser Pro Phe Thr
Ala Lys Ile 1895 1900 1905
Thr Asp Asp Ser Arg Arg Cys Ser Gln Val Lys Leu Gly Ser Ala 1910
1915 1920 Ala Asp Phe Leu Leu
Asp Ile Ser Glu Thr Asp Leu Ser Ser Leu 1925 1930
1935 Thr Ala Ser Ile Lys Ala Pro Ser Gly Arg
Asp Glu Pro Cys Leu 1940 1945 1950
Leu Lys Arg Leu Pro Asn Asn His Ile Gly Ile Ser Phe Ile Pro
1955 1960 1965 Arg Glu
Val Gly Glu His Leu Val Ser Ile Lys Lys Asn Gly Asn 1970
1975 1980 His Val Ala Asn Ser Pro Val
Ser Ile Met Val Val Gln Ser Glu 1985 1990
1995 Ile Gly Asp Ala Arg Arg Ala Lys Val Tyr Gly Arg
Gly Leu Ser 2000 2005 2010
Glu Gly Arg Thr Phe Glu Met Ser Asp Phe Ile Val Asp Thr Arg 2015
2020 2025 Asp Ala Gly Tyr Gly
Gly Ile Ser Leu Ala Val Glu Gly Pro Ser 2030 2035
2040 Lys Val Asp Ile Gln Thr Glu Asp Leu Glu
Asp Gly Thr Cys Lys 2045 2050 2055
Val Ser Tyr Phe Pro Thr Val Pro Gly Val Tyr Ile Val Ser Thr
2060 2065 2070 Lys Phe
Ala Asp Glu His Val Pro Gly Ser Pro Phe Thr Val Lys 2075
2080 2085 Ile Ser Gly Glu Gly Arg Val
Lys Glu Ser Ile Thr Arg Thr Ser 2090 2095
2100 Arg Ala Pro Ser Val Ala Thr Val Gly Ser Ile Cys
Asp Leu Asn 2105 2110 2115
Leu Lys Ile Pro Glu Ile Asn Ser Ser Asp Met Ser Ala His Val 2120
2125 2130 Thr Ser Pro Ser Gly
Arg Val Thr Glu Ala Glu Ile Val Pro Met 2135 2140
2145 Gly Lys Asn Ser His Cys Val Arg Phe Val
Pro Gln Glu Met Gly 2150 2155 2160
Val His Thr Val Ser Val Lys Tyr Arg Gly Gln His Val Thr Gly
2165 2170 2175 Ser Pro
Phe Gln Phe Thr Val Gly Pro Leu Gly Glu Gly Gly Ala 2180
2185 2190 His Lys Val Arg Ala Gly Gly
Pro Gly Leu Glu Arg Gly Glu Ala 2195 2200
2205 Gly Val Pro Ala Glu Phe Ser Ile Trp Thr Arg Glu
Ala Gly Ala 2210 2215 2220
Gly Gly Leu Ser Ile Ala Val Glu Gly Pro Ser Lys Ala Glu Ile 2225
2230 2235 Thr Phe Asp Asp His
Lys Asn Gly Ser Cys Gly Val Ser Tyr Ile 2240 2245
2250 Ala Gln Glu Pro Gly Asn Tyr Glu Val Ser
Ile Lys Phe Asn Asp 2255 2260 2265
Glu His Ile Pro Glu Ser Pro Tyr Leu Val Pro Val Ile Ala Pro
2270 2275 2280 Ser Asp
Asp Ala Arg Arg Leu Thr Val Met Ser Leu Gln Glu Ser 2285
2290 2295 Gly Leu Lys Val Asn Gln Pro
Ala Ser Phe Ala Ile Arg Leu Asn 2300 2305
2310 Gly Ala Lys Gly Lys Ile Asp Ala Lys Val His Ser
Pro Ser Gly 2315 2320 2325
Ala Val Glu Glu Cys His Val Ser Glu Leu Glu Pro Asp Lys Tyr 2330
2335 2340 Ala Val Arg Phe Ile
Pro His Glu Asn Gly Val His Thr Ile Asp 2345 2350
2355 Val Lys Phe Asn Gly Ser His Val Val Gly
Ser Pro Phe Lys Val 2360 2365 2370
Arg Val Gly Glu Pro Gly Gln Ala Gly Asn Pro Ala Leu Val Ser
2375 2380 2385 Ala Tyr
Gly Thr Gly Leu Glu Gly Gly Thr Thr Gly Ile Gln Ser 2390
2395 2400 Glu Phe Phe Ile Asn Thr Thr
Arg Ala Gly Pro Gly Thr Leu Ser 2405 2410
2415 Val Thr Ile Glu Gly Pro Ser Lys Val Lys Met Asp
Cys Gln Glu 2420 2425 2430
Thr Pro Glu Gly Tyr Lys Val Met Tyr Thr Pro Met Ala Pro Gly 2435
2440 2445 Asn Tyr Leu Ile Ser
Val Lys Tyr Gly Gly Pro Asn His Ile Val 2450 2455
2460 Gly Ser Pro Phe Lys Ala Lys Val Thr Gly
Gln Arg Leu Val Ser 2465 2470 2475
Pro Gly Ser Ala Asn Glu Thr Ser Ser Ile Leu Val Glu Ser Val
2480 2485 2490 Thr Arg
Ser Ser Thr Glu Thr Cys Tyr Ser Ala Ile Pro Lys Ala 2495
2500 2505 Ser Ser Asp Ala Ser Lys Val
Thr Ser Lys Gly Ala Gly Leu Ser 2510 2515
2520 Lys Ala Phe Val Gly Gln Lys Ser Ser Phe Leu Val
Asp Cys Ser 2525 2530 2535
Lys Ala Gly Ser Asn Met Leu Leu Ile Gly Val His Gly Pro Thr 2540
2545 2550 Thr Pro Cys Glu Glu
Val Ser Met Lys His Val Gly Asn Gln Gln 2555 2560
2565 Tyr Asn Val Thr Tyr Val Val Lys Glu Arg
Gly Asp Tyr Val Leu 2570 2575 2580
Ala Val Lys Trp Gly Glu Glu His Ile Pro Gly Ser Pro Phe His
2585 2590 2595 Val Thr
Val Pro 2600 299467DNAHomo sapiens 29gcggccaggg gcgggcggcc
gcagagcagc accggccgtg gctccggtag cagcaagttc 60gaaccccgct cccgctccgc
ttcggttctc gctccttcgg cccttgggcc tccaaacacc 120agtccccggc agctcgttgc
gcattgcgct ctccccgcca ccaggatgcc ggtaaccgag 180aaggatctag ctgaggacgc
gccttggaag aagatccagc agaacacgtt cacacgctgg 240tgcaacgagc acctcaagtg
cgtgaacaaa cgcatcggca acctgcagac cgacctgagc 300gacgggctgc ggctcatcgc
gctgctcgag gtgctcagcc agaagcgcat gtaccgcaag 360taccatcagc ggcccacctt
tcgccagatg cagctcgaga atgtgtccgt ggcgctcgag 420ttcctggacc gtgagagcat
caagctcgtg tccatcgata gcaaagccat tgtggatggg 480aacctgaagc tcatcttggg
tctggtgtgg acgctgatcc tccactactc catctccatg 540cccgtgtggg aggatgaagg
ggatgatgat gccaagaagc agacgccaaa gcagaggctg 600ctggggtgga ttcagaacaa
gatcccctac ttgcccatca ccaactttaa ccagaactgg 660caagacggca aagccctggg
agccctggta gacagctgtg ctccaggtct gtgcccagac 720tgggaatcct gggacccgca
gaagcctgtg gataatgcac gagaagccat gcagcaggca 780gatgactggc tgggtgtccc
acaggtcatc actcctgaag aaatcattca cccggatgtg 840gacgagcact cagttatgac
ttacctgtcc cagttcccca aagccaagct caagccgggg 900gctcctctca aacccaaact
caacccgaag aaagccaggg cctatggcag aggaatcgag 960cccactggaa acatggtgaa
gcagccagcc aagttcactg tggacaccat cagcgccggg 1020caaggagacg tgatggtgtt
tgttgaggac ccagaaggga acaaagagga ggcacaagtg 1080acccctgaca gtgacaagaa
caagacatac tctgtggagt atctgcccaa ggtcaccggg 1140ctacacaaag tcacagtcct
ctttgcagga cagcacatct ccaagagccc atttgaagtg 1200agtgttgaca aggcccaggg
agatgccagt aaagtcactg caaaaggtcc agggttggaa 1260gctgtaggga acatcgccaa
taagcccacc tactttgaca tctatacggc aggagctggt 1320gtgggtgaca ttggtgtgga
ggtggaagat ccccagggga agaacaccgt ggagttgctc 1380gtggaagaca aaggaaacca
ggtgtatcga tgtgtgtaca aacccatgca gcctggccct 1440cacgtggtca agatcttctt
tgctggggac actattccta agagtccctt cgttgtgcag 1500gttggggaag cctgcaatcc
aaatgcctgc cgggccagtg gccgaggcct acaacccaaa 1560ggcgtccgta tccgggagac
cacagatttc aaggttgaca ccaaagctgc aggaagtggg 1620gagctcggtg taaccatgaa
gggtcctaag ggtctggagg agctggtgaa gcagaaagac 1680tttctggatg gggtctacgc
attcgagtat taccccagca ccccggggag atacagcatt 1740gccatcacat gggggggaca
ccacattcca aagagcccct ttgaagttca agttggccct 1800gaagcgggta tgcagaaagt
ccgtgcttgg ggccctgggc tccatggtgg gattgtcggg 1860cggtcagcgg acttcgtggt
agaatccatt ggctctgaag tggggtctct ggggtttgcc 1920attgaaggcc cctctcaggc
aaagattgag tacaacgacc agaatgatgg atcgtgtgat 1980gtcaaatact ggcccaagga
gcctggcgaa tatgctgttc acatcatgtg tgacgacgaa 2040gacatcaagg acagcccgta
catggccttc atccacccag ccacgggagg ctacaaccct 2100gatctggttc gagcatacgg
gccaggtttg gagaaatctg gatgcattgt caacaacctg 2160gccgagttca ctgtggatcc
taaggatgct ggaaaagctc ccttaaagat atttgctcag 2220gatggggaag gccaacgcat
tgacatccag atgaagaacc ggatggacgg cacatatgca 2280tgctcataca ccccggtgaa
ggccatcaag cacaccattg ctgtggtctg gggaggcgtg 2340aacatcccgc acagccccta
cagggtcaac atcgggcaag gtagccatcc tcagaaggtc 2400aaagtgtttg ggccaggtgt
ggagagaagt ggtctgaagg caaatgaacc tacacacttc 2460acggtggact gtactgaggc
tggggaaggt gatgtcagtg ttggcattaa gtgtgatgcc 2520cgggtgttaa gtgaagatga
ggaagacgtg gattttgaca ttattcacaa tgccaatgat 2580acgttcacag tcaaatatgt
gcctcctgct gctgggcgat acactatcaa agttctcttt 2640gcatctcagg aaatccccgc
cagccctttc agagtcaaag ttgacccttc ccacgatgcc 2700agcaaagtga aggcagaagg
cccagggctc agcaaagcag gtgtggaaaa tgggaaaccg 2760acccacttca ctgtctacac
caagggggct gggaaagccc cgctcaacgt gcagttcaac 2820agccctcttc ctggcgatgc
agtgaaggat ttggatatca tcgataatta tgactactct 2880cacacggtta aatatacacc
cacccaacag ggcaacatgc aggttctggt gacttacggt 2940ggcgatccca tccctaaaag
ccctttcact gtgggtgttg ctgcaccgct ggatctgagc 3000aagataaaac tcaatgggct
ggaaaacagg gtggaagttg ggaaggatca ggagttcacc 3060gttgatacca ggggggcagg
aggccagggg aagctggacg tgacaatcct cagcccctct 3120cggaaggtcg tgccatgcct
agtgacacct gtgacaggcc gggagaacag cacggccaag 3180ttcatccctc gggaggaggg
gctgtatgct gtagacgtga cctacgatgg acaccctgtg 3240cccgggagcc cctacacagt
ggaggcctcg ctgccaccag atcccagcaa ggtgaaggcc 3300cacggtcccg gcctcgaagg
tggtctcgtg ggcaagcctg ccgagttcac catcgatacc 3360aaaggagctg gtactggagg
tctgggctta acggtggaag gtccgtgcga ggccaaaatc 3420gagtgctccg acaatggtga
tgggacctgc tccgtctctt accttcccac aaaacccggg 3480gagtacttcg tcaacatcct
ctttgaagaa gtccacatac ctgggtctcc cttcaaagct 3540gacattgaaa tgccctttga
cccctctaaa gtcgtggcat cggggccagg tctcgagcac 3600gggaaggtgg gtgaagctgg
cctccttagc gtcgactgct cggaagcggg accgggggcc 3660ctgggcctgg aagctgtctc
ggactcggga acaaaagccg aagtcagtat tcagaacaac 3720aaagatggca cctacgcggt
gacctacgtg cccctgacgg ccggcatgta cacgttgacc 3780atgaagtatg gtggcgaact
cgtgccacac ttccccgccc gggtcaaggt ggagcccgcc 3840gtggacacca gcaggatcaa
agtctttgga ccaggaatag aagggaaaga tgtgttccgg 3900gaagctacca ccgactttac
agttgactct cggccgctga cccaggttgg gggtgaccac 3960atcaaggccc acattgccaa
cccctcaggg gcctccaccg agtgctttgt cacagacaat 4020gcggatggga cctaccaggt
ggaatacaca ccctttgaga aaggtctcca tgtagtggag 4080gtgacatatg atgacgtgcc
tatcccaaac agtcccttca aggtggctgt cactgaaggc 4140tgccagccat ctagggtgca
agcccaagga cctggattga aagaggcctt taccaacaag 4200cccaatgtct tcaccgtggt
taccagaggc gcaggaattg gtgggcttgg cataactgtt 4260gagggaccat cagagtcgaa
gataaattgc agagacaaca aggatggcag ctgcagtgct 4320gagtacattc ctttcgcacc
gggggattac gatgttaata tcacatatgg aggagcccac 4380atccccggca gccccttcag
ggttcctgtg aaggatgttg tggaccccag caaggtcaag 4440attgccggcc ccgggctggg
ctcaggcgtc cgagcccgtg tcctgcagtc cttcacggtg 4500gacagcagca aggctggcct
ggctccgctg gaagtgaggg ttctgggccc acgaggcttg 4560gtggagccag tgaacgtggt
ggacaatgga gatggcacac acacagtaac ctacacccca 4620tctcaggagg gaccttacat
ggtctcagtt aaatatgctg atgaagagat tcctcgcagt 4680cccttcaagg tcaaggtcct
tcccacatat gatgccagca aagtgactgc cagtggcccc 4740ggccttagtt cctatggtgt
gcctgccagt ctacctgtgg actttgcaat tgatgcccga 4800gatgccgggg aaggcctgct
tgctgttcaa ataacggacc aagaaggaaa acccaaaaga 4860gccattgtcc atgacaataa
agatggcacg tatgctgtca cctacatccc cgacaagact 4920gggcgctata tgattggagt
cacctacggg ggtgacgaca tcccactttc tccttatcgc 4980atccgagcca cacagacggg
tgatgccagc aagtgcctgg ccacgggtcc tggaatcgcc 5040tccactgtga aaactggcga
agaagtaggc tttgtggttg atgccaagac tgccgggaag 5100ggtaaagtga cctgcacggt
tctgacccca gatggcactg aggccgaggc cgatgtcatt 5160gagaatgaag atggaaccta
tgacatcttc tacacagctg ccaagccggg cacatatgtg 5220atctatgtgc gcttcggtgg
tgttgatatt cctaacagcc ccttcactgt catggccaca 5280gatggggaag tcacagccgt
ggaggaggca ccggtaaatg catgtccccc tggattcagg 5340ccctgggtga ccgaagaggc
ctatgtccca gtgagtgaca tgaacggcct gggatttaag 5400ccttttgacc tggtcattcc
gtttgctgtc aggaaaggag aaatcactgg agaggtccac 5460atgccttctg ggaagacagc
cacacctgag attgtggaca acaaggacgg cacggtcact 5520gttagatatg cccccactga
ggtcgggctc catgagatgc acatcaaata catgggcagc 5580cacatccctg agagcccact
ccagttctac gtgaactacc ccaacagtgg aagtgtttct 5640gcatacggtc caggcctcgt
gtatggagtg gccaacaaaa ctgccacctt caccatcgtc 5700acagaggatg caggagaagg
tggtctggac ttggctattg agggcccctc aaaagcagaa 5760atcagctgca ttgacaataa
agatgggaca tgcacagtga cctacctgcc gactctgcca 5820ggcgactaca gcattctggt
caagtacaat gacaagcaca tccctggcag ccccttcaca 5880gccaagatca cagatgacag
caggcggtgc tcccaggtga agttgggctc agccgctgac 5940ttcctgctcg acatcagtga
gactgacctc agcagcctga cggccagcat taaggcccca 6000tctggccgag acgagccctg
tctcctgaag aggctgccca acaaccacat tggcatctcc 6060ttcatccccc gggaagtggg
cgaacatctg gtcagcatca agaaaaatgg caaccatgtg 6120gccaacagcc ccgtgtctat
catggtggtc cagtcggaga ttggtgacgc ccgccgagcc 6180aaagtctatg gccgcggcct
gtcagaaggc cggactttcg agatgtctga cttcatcgtg 6240gacacaaggg atgcaggtta
tggtggcata tccttggcgg tggaaggccc cagcaaagtg 6300gacatccaga cggaggacct
ggaagatggc acctgcaaag tctcctactt ccctaccgtg 6360cctggggttt atatcgtctc
caccaaattc gctgacgagc acgtgcctgg gagcccattt 6420accgtgaaga tcagtgggga
gggaagagtc aaagagagca tcacccgcac cagtcgggcc 6480ccgtccgtgg ccactgtcgg
gagcatttgt gacctgaacc tgaaaatccc agaaatcaac 6540agcagtgata tgtcggccca
cgtcaccagc ccctctggcc gtgtgactga ggcagagatt 6600gtgcccatgg ggaagaactc
acactgcgtc cggtttgtgc cccaggagat gggcgtgcac 6660acggtcagcg tcaagtaccg
tgggcagcac gtcaccggca gccccttcca gttcaccgtg 6720gggccacttg gtgaaggagg
cgcccacaag gtgcgggcag gaggccctgg cctggagaga 6780ggagaagcgg gagtcccagc
tgagttcagc atttggaccc gggaagcagg cgctggaggc 6840ctctccatcg ctgttgaggg
ccccagtaag gccgagatta cattcgatga ccataaaaat 6900gggtcgtgcg gtgtatctta
tattgcccaa gagcctggta actacgaggt gtccatcaag 6960ttcaatgatg agcacatccc
ggaaagcccc tacctggtgc cggtcatcgc accctccgac 7020gacgcccgcc gcctcactgt
tatgagcctt caggaatcgg gattaaaagt taaccagcca 7080gcatcctttg ctataaggtt
gaatggcgca aaaggcaaga ttgatgcaaa ggtgcacagc 7140ccctctggag ccgtggagga
gtgccacgtg tctgagctgg agccagataa gtatgctgtt 7200cgcttcatcc ctcatgagaa
tggtgtccac accatcgatg tcaagttcaa tgggagccac 7260gtggttggaa gccccttcaa
agtgcgcgtt ggggagcctg gacaagcggg gaaccctgcc 7320ctggtgtccg cctatggcac
gggactcgaa gggggcacca caggtatcca gtcggaattc 7380tttattaaca ccacccgagc
aggtccaggg acattatccg tcaccatcga aggcccatcc 7440aaggttaaaa tggattgcca
ggaaacacct gaagggtaca aagtcatgta cacccccatg 7500gctcctggta actacctgat
cagcgtcaaa tacggtgggc ccaaccacat cgtgggcagt 7560cccttcaagg ccaaggtgac
aggccagcgt ctagttagcc ctggctcagc caacgagacc 7620tcatccatcc tggtggagtc
agtgaccagg tcgtctacag agacctgcta tagcgccatt 7680cccaaggcat cctcggacgc
cagcaaggtg acctctaagg gggcagggct ctcaaaggcc 7740tttgtgggcc agaagagttc
cttcctggtg gactgcagca aagctggctc caacatgctg 7800ctgatcgggg tccatgggcc
caccaccccc tgcgaggagg tctccatgaa gcatgtaggc 7860aaccagcaat acaacgtcac
atacgtcgtc aaggagaggg gcgattatgt gctggctgtg 7920aagtgggggg aggaacacat
ccctggcagc ccttttcatg tcacagtgcc ttaaaacagt 7980tttctcaaat cctggagaga
gttcttgtgg ttgcttttgt tgcttgtttg taattcattt 8040tatacaaagc cctccagcct
gtttgtgggg ctgaaacccc atccctaaaa tattgctgtt 8100gtaaaatgcc ttcagaaata
agtcctagac tggactcttg agggacatat tggagaatct 8160taagaaatgc aagcttgttc
agggggctga gaagatcctg agtacactag gtgcaaacca 8220gaactcttgg tggaacagac
cagccactgc agcagacaga ccaggaacac aatgagactg 8280acatttcaaa aaaacaaaac
tggctagcct gagctgctgg ttcactcttc agcatttatg 8340aaacaaggct aggggaagat
gggcagagaa aaaggggaca cctagtttgg ttgtcatttg 8400gcaaaggaga tgacttaaaa
tccgcttaat ctcttccagt gtccgtgtta atgtatttgg 8460ctattagatc actagcactg
ctttaccgct cctcatcgcc aacaccccca tgctctgtgg 8520ccttcttaca cttctcagag
ggcagagtgg cagccgggca ccctacagaa actcagaggg 8580cagagtggca gccaggccca
catgtctctc aagtacctgt cccctcgctc tggtgattat 8640ttcttgcaga atcaccacac
gagaccatcc cggcagtcat ggttttgctt tagttttcca 8700agtccgtttc agtcccttcc
ttggtctgaa gaaattctgc agtggcgagc agtttcccac 8760ttgccaaaga tcccttttaa
ccaacactag cccttgtttt taacacacgc tccagccctt 8820catcagcctg ggcagtctta
ccaaaatgtt taaagtgatc tcagaggggc ccatggatta 8880acgccctcat cccaaggtcc
gtcccatgac ataacactcc acacccgccc cagccaactt 8940catgggtcac tttttctgga
aaataatgat ctgtacagac aggacagaat gaaactcctg 9000cgggtctttg gcctgaaagt
tgggaatggt tgggggagag aagggcagca gcttattggt 9060ggtcttttca ccattggcag
aaacagtgag agctgtgtgg tgcagaaatc cagaaatgag 9120gtgtagggaa ttttgcctgc
cttcctgcag acctgagctg gctttggaat gaggttaaag 9180tgtcagggac gttgcctgag
cccaaatgtg tagtgtggtc tgggcaggca gacctttagg 9240ttttgctgct tagtcctgag
gaagtggcca ctcttgtggc aggtgtagta tctggggcga 9300gtgttggggg taaaagccca
ccctacagaa agtggaacag cccggagcct gatgtgaaag 9360gaccacgggt gttgtaagct
gggacacgga agccaaactg gaatcaaacg ccgactgtaa 9420attgtatctt ataacttatt
aaataaaaca tttgctccgt aaagttg 946730193PRTHomo sapiens
30Met Val Ala Pro Lys Ser His Thr Asp Asp Trp Ala Pro Gly Pro Phe 1
5 10 15 Ser Ser Lys Pro
Gln Arg Ser Gln Leu Gln Ile Phe Ser Ser Val Leu 20
25 30 Gln Thr Ser Leu Leu Phe Leu Leu Met
Gly Leu Arg Ala Ser Gly Lys 35 40
45 Asp Ser Ala Pro Thr Val Val Ser Gly Ile Leu Gly Gly Ser
Val Thr 50 55 60
Leu Pro Leu Asn Ile Ser Val Asp Thr Glu Ile Glu Asn Val Ile Trp 65
70 75 80 Ile Gly Pro Lys Asn
Ala Leu Ala Phe Ala Arg Pro Lys Glu Asn Val 85
90 95 Thr Ile Met Val Lys Ser Tyr Leu Gly Arg
Leu Asp Ile Thr Lys Trp 100 105
110 Ser Tyr Ser Leu Cys Ile Ser Asn Leu Thr Leu Asn Asp Ala Gly
Ser 115 120 125 Tyr
Lys Ala Gln Ile Asn Gln Arg Asn Phe Glu Val Thr Thr Glu Glu 130
135 140 Glu Phe Thr Leu Phe Val
Tyr Ala Pro Phe Ile Glu Lys Leu Ser Val 145 150
155 160 His Val Ile Glu Gly Asp His Arg Thr Leu Leu
Glu Gly Ser Gly Leu 165 170
175 Glu Ser Ile Ile Ser Thr Leu Ala Glu Pro Arg Val Ser Val Arg Glu
180 185 190 Gly
311525DNAHomo sapiens 31acatacacat acacatgcac acacacactc atatacacat
gcagaagctg tgacacgtgc 60ggaagctgtg gtaagtgcat cctccttcag tctcagttct
gaaaatagat catcatggtg 120gcaccaaaga gtcacacaga tgactgggct cctgggcctt
tctccagtaa gccacagagg 180agtcagctgc aaatattctc ttctgttcta cagacctctc
tcctcttcct gctcatggga 240ctaagagcct ctggaaagga ctcagcccca acagtggtgt
cagggatcct agggggttcc 300gtgactctcc ccctaaacat ctcagtagac acagagattg
agaacgtcat ctggattggt 360cccaaaaatg ctcttgcttt cgcacgtccc aaagaaaatg
taaccattat ggtcaaaagc 420tacctgggcc gactagacat caccaagtgg agttactccc
tgtgcatcag caatctgact 480ctgaatgatg caggatccta caaagcccag ataaaccaaa
ggaattttga agtcaccact 540gaggaggaat tcaccctgtt cgtctatgca ccatttattg
aaaagttgtc cgtccacgtc 600atcgagggtg accaccgcac actcctggag ggcagcggcc
tggagtccat catcagcacc 660ctggctgagc cacgtgtgag cgtgcgggag ggctaggccc
tcgcccccac ctgccactgg 720agaccgctcc gccatcccca cctcaccgcc gcgcagcaga
gctggaaggg tcctgccgat 780gggaccctgc caggcccagt gccactgccc cccgaggctg
ctagacgtgg gcgttaggcg 840tgtcccaccc acccgccgcc tcccatggca cgtcgggaac
accggagccg ccaacttgga 900gactcctggt ctgtgaagag ccgctgacgc ccgcaggaac
cgggctgggc cttgtgtgcc 960agtggggttt gtgcttggtc tttctccgct tggatttgct
tatttattgc attgctggta 1020gagactccca agcctgtcca ccctgcaaag actcctcggg
cagcatgcgg gtcccgcaca 1080ctgcacccat ttcctggatg tcccctgcag gcgcgggagg
ccatccgggc ctgctggctg 1140cggccccctc tcagccaggc ctggctcagc ccactgcgtg
ggaggtcacc ggccactccc 1200cgaggagctg ggatccccgg gatgcaggcc cacagtgcgg
ggctgcaccc atgatgcgga 1260gctggcctcc aaccctgcgg gccgcgccag gcaccaactc
agtgtttgtc agtgtttgtt 1320tttccaagaa atggttcaaa ttgctgctca gatttttaaa
tttactgtag ctgccagtgt 1380acacgtgtgg accccatttt atttttacac caatttggtg
aaaatgctgc tttcctcagc 1440ctccccacaa ttaaactgca catggtctct aaaaaaataa
aaataaataa ataaataaat 1500aaataaaaag tatcttttct cccca
152532641PRTHomo sapiens 32Met Val Ala Pro Lys Ser
His Thr Asp Asp Trp Ala Pro Gly Pro Phe 1 5
10 15 Ser Ser Lys Pro Gln Arg Ser Gln Leu Gln Ile
Phe Ser Ser Val Leu 20 25
30 Gln Thr Ser Leu Leu Phe Leu Leu Met Gly Leu Arg Ala Ser Gly
Lys 35 40 45 Asp
Ser Ala Pro Thr Val Val Ser Gly Ile Leu Gly Gly Ser Val Thr 50
55 60 Leu Pro Leu Asn Ile Ser
Val Asp Thr Glu Ile Glu Asn Val Ile Trp 65 70
75 80 Ile Gly Pro Lys Asn Ala Leu Ala Phe Ala Arg
Pro Lys Glu Asn Val 85 90
95 Thr Ile Met Val Lys Ser Tyr Leu Gly Arg Leu Asp Ile Thr Lys Trp
100 105 110 Ser Tyr
Ser Leu Cys Ile Ser Asn Leu Thr Leu Asn Asp Ala Gly Ser 115
120 125 Tyr Lys Ala Gln Ile Asn Gln
Arg Asn Phe Glu Val Thr Thr Glu Glu 130 135
140 Glu Phe Thr Leu Phe Val Tyr Glu Gln Leu Gln Glu
Pro Gln Val Thr 145 150 155
160 Met Lys Ser Val Lys Val Ser Glu Asn Phe Ser Cys Asn Ile Thr Leu
165 170 175 Met Cys Ser
Val Lys Gly Ala Glu Lys Ser Val Leu Tyr Ser Trp Thr 180
185 190 Pro Arg Glu Pro His Ala Ser Glu
Ser Asn Gly Gly Ser Ile Leu Thr 195 200
205 Val Ser Arg Thr Pro Cys Asp Pro Asp Leu Pro Tyr Ile
Cys Thr Ala 210 215 220
Gln Asn Pro Val Ser Gln Arg Ser Ser Leu Pro Val His Val Gly Gln 225
230 235 240 Phe Cys Thr Asp
Pro Gly Ala Ser Arg Gly Gly Thr Thr Gly Glu Thr 245
250 255 Val Val Gly Val Leu Gly Glu Pro Val
Thr Leu Pro Leu Ala Leu Pro 260 265
270 Ala Cys Arg Asp Thr Glu Lys Val Val Trp Leu Phe Asn Thr
Ser Ile 275 280 285
Ile Ser Lys Glu Arg Glu Glu Ala Ala Thr Ala Asp Pro Leu Ile Lys 290
295 300 Ser Arg Asp Pro Tyr
Lys Asn Arg Val Trp Val Ser Ser Gln Asp Cys 305 310
315 320 Ser Leu Lys Ile Ser Gln Leu Lys Ile Glu
Asp Ala Gly Pro Tyr His 325 330
335 Ala Tyr Val Cys Ser Glu Ala Ser Ser Val Thr Ser Met Thr His
Val 340 345 350 Thr
Leu Leu Ile Tyr Arg Arg Leu Arg Lys Pro Lys Ile Thr Trp Ser 355
360 365 Leu Arg His Ser Glu Asp
Gly Ile Cys Arg Ile Ser Leu Thr Cys Ser 370 375
380 Val Glu Asp Gly Gly Asn Thr Val Met Tyr Thr
Trp Thr Pro Leu Gln 385 390 395
400 Lys Glu Ala Val Val Ser Gln Gly Glu Ser His Leu Asn Val Ser Trp
405 410 415 Arg Ser
Ser Glu Asn His Pro Asn Leu Thr Cys Thr Ala Ser Asn Pro 420
425 430 Val Ser Arg Ser Ser His Gln
Phe Leu Ser Glu Asn Ile Cys Ser Gly 435 440
445 Pro Glu Arg Asn Thr Lys Leu Trp Ile Gly Leu Phe
Leu Met Val Cys 450 455 460
Leu Leu Cys Val Gly Ile Phe Ser Trp Cys Ile Trp Lys Arg Lys Gly 465
470 475 480 Arg Cys Ser
Val Pro Ala Phe Cys Ser Ser Gln Ala Glu Ala Pro Ala 485
490 495 Asp Thr Pro Gly Tyr Glu Lys Leu
Asp Thr Pro Leu Arg Pro Ala Arg 500 505
510 Gln Gln Pro Thr Pro Thr Ser Asp Ser Ser Ser Asp Ser
Asn Leu Thr 515 520 525
Thr Glu Glu Asp Glu Asp Arg Pro Glu Val His Lys Pro Ile Ser Gly 530
535 540 Arg Tyr Glu Val
Phe Asp Gln Val Thr Gln Glu Gly Ala Gly His Asp 545 550
555 560 Pro Ala Pro Glu Gly Gln Ala Asp Tyr
Asp Pro Val Thr Pro Tyr Val 565 570
575 Thr Glu Val Glu Ser Val Val Gly Glu Asn Thr Met Tyr Ala
Gln Val 580 585 590
Phe Asn Leu Gln Gly Lys Thr Pro Val Ser Gln Lys Glu Glu Ser Ser
595 600 605 Ala Thr Ile Tyr
Cys Ser Ile Arg Lys Pro Gln Val Val Pro Pro Pro 610
615 620 Gln Gln Asn Asp Leu Glu Ile Pro
Glu Ser Pro Thr Tyr Glu Asn Phe 625 630
635 640 Thr 332508DNAHomo sapiens 33acatacacat acacatgcac
acacacactc atatacacat gcagaagctg tgacacgtgc 60ggaagctgtg gtaagtgcat
cctccttcag tctcagttct gaaaatagat catcatggtg 120gcaccaaaga gtcacacaga
tgactgggct cctgggcctt tctccagtaa gccacagagg 180agtcagctgc aaatattctc
ttctgttcta cagacctctc tcctcttcct gctcatggga 240ctaagagcct ctggaaagga
ctcagcccca acagtggtgt cagggatcct agggggttcc 300gtgactctcc ccctaaacat
ctcagtagac acagagattg agaacgtcat ctggattggt 360cccaaaaatg ctcttgcttt
cgcacgtccc aaagaaaatg taaccattat ggtcaaaagc 420tacctgggcc gactagacat
caccaagtgg agttactccc tgtgcatcag caatctgact 480ctgaatgatg caggatccta
caaagcccag ataaaccaaa ggaattttga agtcaccact 540gaggaggaat tcaccctgtt
cgtctatgag cagctgcagg agccccaagt caccatgaag 600tctgtgaagg tgtctgagaa
cttctcctgt aacatcactc taatgtgctc cgtgaagggg 660gcagagaaaa gtgttctgta
cagctggacc ccaagggaac cccatgcttc tgagtccaat 720ggaggctcca ttcttaccgt
ctcccgaaca ccatgtgacc cagacctgcc atacatctgc 780acagcccaga accccgtcag
ccagagaagc tccctccctg tccatgttgg gcagttctgt 840acagatccag gagcctccag
aggaggaaca acgggggaga ctgtggtagg ggtcctggga 900gagccagtca ccctgccact
tgcactccca gcctgccggg acacagagaa ggttgtctgg 960ttgtttaaca catccatcat
tagcaaagag agggaagaag cagcaacggc agatccactc 1020attaaatcca gggatcctta
caagaacagg gtgtgggtct ccagccagga ctgctccctg 1080aagatcagcc agctgaagat
agaggacgcc ggcccctacc atgcctacgt gtgctcagag 1140gcctccagcg tcaccagcat
gacacatgtc accctgctca tctaccgcag gctgaggaag 1200cccaaaatca cgtggagcct
caggcacagt gaggatggca tctgcaggat cagcctgacc 1260tgctccgtgg aggacggggg
aaacactgtc atgtacacat ggaccccgct gcagaaggaa 1320gctgttgtgt cccaagggga
atcacacctc aatgtctcat ggagaagcag tgaaaatcac 1380cccaacctca catgcacagc
cagcaaccct gtcagcagga gttcccacca gtttctttct 1440gagaacatct gttcaggacc
tgagagaaac acaaagcttt ggattgggtt gttcctgatg 1500gtttgccttc tgtgcgttgg
gatcttcagc tggtgcattt ggaagcgaaa aggacggtgt 1560tcagtcccag ccttctgttc
cagccaagct gaggccccag cggatacacc aggatatgag 1620aagctggaca ctcccctcag
gcctgccagg caacagccta cacccacctc agacagcagc 1680tctgacagca acctcacaac
tgaggaggat gaggacaggc ctgaggtgca caagcccatc 1740agtggaagat atgaggtatt
tgaccaggtc actcaggagg gcgctggaca tgacccagcc 1800cctgagggcc aagcagacta
tgatcccgtc actccatatg tcacggaagt tgagtctgtg 1860gttggagaga acaccatgta
tgcacaagtg ttcaacttac agggaaagac cccagtttct 1920cagaaggaag agagctcagc
cacaatctac tgctccatac ggaaacctca ggtggtgcca 1980ccaccacaac agaatgatct
tgagattcct gaaagtccta cctatgaaaa tttcacctga 2040aaggaaaagc agctgctgcc
tctctcctgg gaccgtgggg ttggaaagtc agctggacct 2100catggggcct ggggctcaca
gacagaagca cctcagaatt tccttcagtg cctcagagat 2160gcctggatgt ggcccctccc
cctccttctc acccttaagg actcccaaac ccattaatag 2220ttcagacaca ggctccttct
tggagcctat gggcttcaga tgtctttgcc ccatttgtca 2280cctcgcacac ttatagcgtt
tcctcctcga aattctacca agactggtca aatgttgctg 2340aggggcctgg accagctgtc
ctttacacca ccttctcaac actgctgaaa agaacccaag 2400agaattgtca cacatgacac
aagatgtaca taatatcatg ctcactgcag tgttatttaa 2460aataaaaggc aggaaataaa
aaaaaaaaaa aaaaaaaaaa aaaaaaaa 250834565PRTHomo sapiens
34Met Val Ala Pro Lys Ser His Thr Asp Asp Trp Ala Pro Gly Pro Phe 1
5 10 15 Ser Ser Lys Pro
Gln Arg Ser Gln Leu Gln Ile Phe Ser Ser Val Leu 20
25 30 Gln Thr Ser Leu Leu Phe Leu Leu Met
Gly Leu Arg Ala Ser Gly Lys 35 40
45 Asp Ser Ala Pro Thr Val Val Ser Gly Ile Leu Gly Gly Ser
Val Thr 50 55 60
Leu Pro Leu Asn Ile Ser Val Asp Thr Glu Ile Glu Asn Val Ile Trp 65
70 75 80 Ile Gly Pro Lys Asn
Ala Leu Ala Phe Ala Arg Pro Lys Glu Asn Val 85
90 95 Thr Ile Met Val Lys Ser Tyr Leu Gly Arg
Leu Asp Ile Thr Lys Trp 100 105
110 Ser Tyr Ser Leu Cys Ile Ser Asn Leu Thr Leu Asn Asp Ala Gly
Ser 115 120 125 Tyr
Lys Ala Gln Ile Asn Gln Arg Asn Phe Glu Val Thr Thr Glu Glu 130
135 140 Glu Phe Thr Leu Phe Val
Tyr Glu Gln Leu Gln Glu Pro Gln Val Thr 145 150
155 160 Met Lys Ser Val Lys Val Ser Glu Asn Phe Ser
Cys Asn Ile Thr Leu 165 170
175 Met Cys Ser Val Lys Gly Ala Glu Lys Ser Val Leu Tyr Ser Trp Thr
180 185 190 Pro Arg
Glu Pro His Ala Ser Glu Ser Asn Gly Gly Ser Ile Leu Thr 195
200 205 Val Ser Arg Thr Pro Cys Asp
Pro Asp Leu Pro Tyr Ile Cys Thr Ala 210 215
220 Gln Asn Pro Val Ser Gln Arg Ser Ser Leu Pro Val
His Val Gly Gln 225 230 235
240 Phe Cys Thr Asp Pro Gly Ala Ser Arg Gly Gly Thr Thr Gly Glu Thr
245 250 255 Val Val Gly
Val Leu Gly Glu Pro Val Thr Leu Pro Leu Ala Leu Pro 260
265 270 Ala Cys Arg Asp Thr Glu Lys Val
Val Trp Leu Phe Asn Thr Ser Ile 275 280
285 Ile Ser Lys Glu Arg Glu Glu Ala Ala Thr Ala Asp Pro
Leu Ile Lys 290 295 300
Ser Arg Asp Pro Tyr Lys Asn Arg Val Trp Val Ser Ser Gln Asp Cys 305
310 315 320 Ser Leu Lys Ile
Ser Gln Leu Lys Ile Glu Asp Ala Gly Pro Tyr His 325
330 335 Ala Tyr Val Cys Ser Glu Ala Ser Ser
Val Thr Ser Met Thr His Val 340 345
350 Thr Leu Leu Ile Tyr Arg Pro Glu Arg Asn Thr Lys Leu Trp
Ile Gly 355 360 365
Leu Phe Leu Met Val Cys Leu Leu Cys Val Gly Ile Phe Ser Trp Cys 370
375 380 Ile Trp Lys Arg Lys
Gly Arg Cys Ser Val Pro Ala Phe Cys Ser Ser 385 390
395 400 Gln Ala Glu Ala Pro Ala Asp Thr Pro Glu
Pro Thr Ala Gly His Thr 405 410
415 Leu Tyr Ser Val Leu Ser Gln Gly Tyr Glu Lys Leu Asp Thr Pro
Leu 420 425 430 Arg
Pro Ala Arg Gln Gln Pro Thr Pro Thr Ser Asp Ser Ser Ser Asp 435
440 445 Ser Asn Leu Thr Thr Glu
Glu Asp Glu Asp Arg Pro Glu Val His Lys 450 455
460 Pro Ile Ser Gly Arg Tyr Glu Val Phe Asp Gln
Val Thr Gln Glu Gly 465 470 475
480 Ala Gly His Asp Pro Ala Pro Glu Gly Gln Ala Asp Tyr Asp Pro Val
485 490 495 Thr Pro
Tyr Val Thr Glu Val Glu Ser Val Val Gly Glu Asn Thr Met 500
505 510 Tyr Ala Gln Val Phe Asn Leu
Gln Gly Lys Thr Pro Val Ser Gln Lys 515 520
525 Glu Glu Ser Ser Ala Thr Ile Tyr Cys Ser Ile Arg
Lys Pro Gln Val 530 535 540
Val Pro Pro Pro Gln Gln Asn Asp Leu Glu Ile Pro Glu Ser Pro Thr 545
550 555 560 Tyr Glu Asn
Phe Thr 565 352280DNAHomo sapiens 35acatacacat acacatgcac
acacacactc atatacacat gcagaagctg tgacacgtgc 60ggaagctgtg gtaagtgcat
cctccttcag tctcagttct gaaaatagat catcatggtg 120gcaccaaaga gtcacacaga
tgactgggct cctgggcctt tctccagtaa gccacagagg 180agtcagctgc aaatattctc
ttctgttcta cagacctctc tcctcttcct gctcatggga 240ctaagagcct ctggaaagga
ctcagcccca acagtggtgt cagggatcct agggggttcc 300gtgactctcc ccctaaacat
ctcagtagac acagagattg agaacgtcat ctggattggt 360cccaaaaatg ctcttgcttt
cgcacgtccc aaagaaaatg taaccattat ggtcaaaagc 420tacctgggcc gactagacat
caccaagtgg agttactccc tgtgcatcag caatctgact 480ctgaatgatg caggatccta
caaagcccag ataaaccaaa ggaattttga agtcaccact 540gaggaggaat tcaccctgtt
cgtctatgag cagctgcagg agccccaagt caccatgaag 600tctgtgaagg tgtctgagaa
cttctcctgt aacatcactc taatgtgctc cgtgaagggg 660gcagagaaaa gtgttctgta
cagctggacc ccaagggaac cccatgcttc tgagtccaat 720ggaggctcca ttcttaccgt
ctcccgaaca ccatgtgacc cagacctgcc atacatctgc 780acagcccaga accccgtcag
ccagagaagc tccctccctg tccatgttgg gcagttctgt 840acagatccag gagcctccag
aggaggaaca acgggggaga ctgtggtagg ggtcctggga 900gagccagtca ccctgccact
tgcactccca gcctgccggg acacagagaa ggttgtctgg 960ttgtttaaca catccatcat
tagcaaagag agggaagaag cagcaacggc agatccactc 1020attaaatcca gggatcctta
caagaacagg gtgtgggtct ccagccagga ctgctccctg 1080aagatcagcc agctgaagat
agaggacgcc ggcccctacc atgcctacgt gtgctcagag 1140gcctccagcg tcaccagcat
gacacatgtc accctgctca tctaccgacc tgagagaaac 1200acaaagcttt ggattgggtt
gttcctgatg gtttgccttc tgtgcgttgg gatcttcagc 1260tggtgcattt ggaagcgaaa
aggacggtgt tcagtcccag ccttctgttc cagccaagct 1320gaggccccag cggatacacc
agaacccaca gctggccaca cgctatactc tgtgctctcc 1380caaggatatg agaagctgga
cactcccctc aggcctgcca ggcaacagcc tacacccacc 1440tcagacagca gctctgacag
caacctcaca actgaggagg atgaggacag gcctgaggtg 1500cacaagccca tcagtggaag
atatgaggta tttgaccagg tcactcagga gggcgctgga 1560catgacccag cccctgaggg
ccaagcagac tatgatcccg tcactccata tgtcacggaa 1620gttgagtctg tggttggaga
gaacaccatg tatgcacaag tgttcaactt acagggaaag 1680accccagttt ctcagaagga
agagagctca gccacaatct actgctccat acggaaacct 1740caggtggtgc caccaccaca
acagaatgat cttgagattc ctgaaagtcc tacctatgaa 1800aatttcacct gaaaggaaaa
gcagctgctg cctctctcct gggaccgtgg ggttggaaag 1860tcagctggac ctcatggggc
ctggggctca cagacagaag cacctcagaa tttccttcag 1920tgcctcagag atgcctggat
gtggcccctc cccctccttc tcacccttaa ggactcccaa 1980acccattaat agttcagaca
caggctcctt cttggagcct atgggcttca gatgtctttg 2040ccccatttgt cacctcgcac
acttatagcg tttcctcctc gaaattctac caagactggt 2100caaatgttgc tgaggggcct
ggaccagctg tcctttacac caccttctca acactgctga 2160aaagaaccca agagaattgt
cacacatgac acaagatgta cataatatca tgctcactgc 2220agtgttattt aaaataaaag
gcaggaaata aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 228036655PRTHomo sapiens
36Met Val Ala Pro Lys Ser His Thr Asp Asp Trp Ala Pro Gly Pro Phe 1
5 10 15 Ser Ser Lys Pro
Gln Arg Ser Gln Leu Gln Ile Phe Ser Ser Val Leu 20
25 30 Gln Thr Ser Leu Leu Phe Leu Leu Met
Gly Leu Arg Ala Ser Gly Lys 35 40
45 Asp Ser Ala Pro Thr Val Val Ser Gly Ile Leu Gly Gly Ser
Val Thr 50 55 60
Leu Pro Leu Asn Ile Ser Val Asp Thr Glu Ile Glu Asn Val Ile Trp 65
70 75 80 Ile Gly Pro Lys Asn
Ala Leu Ala Phe Ala Arg Pro Lys Glu Asn Val 85
90 95 Thr Ile Met Val Lys Ser Tyr Leu Gly Arg
Leu Asp Ile Thr Lys Trp 100 105
110 Ser Tyr Ser Leu Cys Ile Ser Asn Leu Thr Leu Asn Asp Ala Gly
Ser 115 120 125 Tyr
Lys Ala Gln Ile Asn Gln Arg Asn Phe Glu Val Thr Thr Glu Glu 130
135 140 Glu Phe Thr Leu Phe Val
Tyr Glu Gln Leu Gln Glu Pro Gln Val Thr 145 150
155 160 Met Lys Ser Val Lys Val Ser Glu Asn Phe Ser
Cys Asn Ile Thr Leu 165 170
175 Met Cys Ser Val Lys Gly Ala Glu Lys Ser Val Leu Tyr Ser Trp Thr
180 185 190 Pro Arg
Glu Pro His Ala Ser Glu Ser Asn Gly Gly Ser Ile Leu Thr 195
200 205 Val Ser Arg Thr Pro Cys Asp
Pro Asp Leu Pro Tyr Ile Cys Thr Ala 210 215
220 Gln Asn Pro Val Ser Gln Arg Ser Ser Leu Pro Val
His Val Gly Gln 225 230 235
240 Phe Cys Thr Asp Pro Gly Ala Ser Arg Gly Gly Thr Thr Gly Glu Thr
245 250 255 Val Val Gly
Val Leu Gly Glu Pro Val Thr Leu Pro Leu Ala Leu Pro 260
265 270 Ala Cys Arg Asp Thr Glu Lys Val
Val Trp Leu Phe Asn Thr Ser Ile 275 280
285 Ile Ser Lys Glu Arg Glu Glu Ala Ala Thr Ala Asp Pro
Leu Ile Lys 290 295 300
Ser Arg Asp Pro Tyr Lys Asn Arg Val Trp Val Ser Ser Gln Asp Cys 305
310 315 320 Ser Leu Lys Ile
Ser Gln Leu Lys Ile Glu Asp Ala Gly Pro Tyr His 325
330 335 Ala Tyr Val Cys Ser Glu Ala Ser Ser
Val Thr Ser Met Thr His Val 340 345
350 Thr Leu Leu Ile Tyr Arg Arg Leu Arg Lys Pro Lys Ile Thr
Trp Ser 355 360 365
Leu Arg His Ser Glu Asp Gly Ile Cys Arg Ile Ser Leu Thr Cys Ser 370
375 380 Val Glu Asp Gly Gly
Asn Thr Val Met Tyr Thr Trp Thr Pro Leu Gln 385 390
395 400 Lys Glu Ala Val Val Ser Gln Gly Glu Ser
His Leu Asn Val Ser Trp 405 410
415 Arg Ser Ser Glu Asn His Pro Asn Leu Thr Cys Thr Ala Ser Asn
Pro 420 425 430 Val
Ser Arg Ser Ser His Gln Phe Leu Ser Glu Asn Ile Cys Ser Gly 435
440 445 Pro Glu Arg Asn Thr Lys
Leu Trp Ile Gly Leu Phe Leu Met Val Cys 450 455
460 Leu Leu Cys Val Gly Ile Phe Ser Trp Cys Ile
Trp Lys Arg Lys Gly 465 470 475
480 Arg Cys Ser Val Pro Ala Phe Cys Ser Ser Gln Ala Glu Ala Pro Ala
485 490 495 Asp Thr
Pro Glu Pro Thr Ala Gly His Thr Leu Tyr Ser Val Leu Ser 500
505 510 Gln Gly Tyr Glu Lys Leu Asp
Thr Pro Leu Arg Pro Ala Arg Gln Gln 515 520
525 Pro Thr Pro Thr Ser Asp Ser Ser Ser Asp Ser Asn
Leu Thr Thr Glu 530 535 540
Glu Asp Glu Asp Arg Pro Glu Val His Lys Pro Ile Ser Gly Arg Tyr 545
550 555 560 Glu Val Phe
Asp Gln Val Thr Gln Glu Gly Ala Gly His Asp Pro Ala 565
570 575 Pro Glu Gly Gln Ala Asp Tyr Asp
Pro Val Thr Pro Tyr Val Thr Glu 580 585
590 Val Glu Ser Val Val Gly Glu Asn Thr Met Tyr Ala Gln
Val Phe Asn 595 600 605
Leu Gln Gly Lys Thr Pro Val Ser Gln Lys Glu Glu Ser Ser Ala Thr 610
615 620 Ile Tyr Cys Ser
Ile Arg Lys Pro Gln Val Val Pro Pro Pro Gln Gln 625 630
635 640 Asn Asp Leu Glu Ile Pro Glu Ser Pro
Thr Tyr Glu Asn Phe Thr 645 650
655 372550DNAHomo sapiens 37acatacacat acacatgcac acacacactc
atatacacat gcagaagctg tgacacgtgc 60ggaagctgtg gtaagtgcat cctccttcag
tctcagttct gaaaatagat catcatggtg 120gcaccaaaga gtcacacaga tgactgggct
cctgggcctt tctccagtaa gccacagagg 180agtcagctgc aaatattctc ttctgttcta
cagacctctc tcctcttcct gctcatggga 240ctaagagcct ctggaaagga ctcagcccca
acagtggtgt cagggatcct agggggttcc 300gtgactctcc ccctaaacat ctcagtagac
acagagattg agaacgtcat ctggattggt 360cccaaaaatg ctcttgcttt cgcacgtccc
aaagaaaatg taaccattat ggtcaaaagc 420tacctgggcc gactagacat caccaagtgg
agttactccc tgtgcatcag caatctgact 480ctgaatgatg caggatccta caaagcccag
ataaaccaaa ggaattttga agtcaccact 540gaggaggaat tcaccctgtt cgtctatgag
cagctgcagg agccccaagt caccatgaag 600tctgtgaagg tgtctgagaa cttctcctgt
aacatcactc taatgtgctc cgtgaagggg 660gcagagaaaa gtgttctgta cagctggacc
ccaagggaac cccatgcttc tgagtccaat 720ggaggctcca ttcttaccgt ctcccgaaca
ccatgtgacc cagacctgcc atacatctgc 780acagcccaga accccgtcag ccagagaagc
tccctccctg tccatgttgg gcagttctgt 840acagatccag gagcctccag aggaggaaca
acgggggaga ctgtggtagg ggtcctggga 900gagccagtca ccctgccact tgcactccca
gcctgccggg acacagagaa ggttgtctgg 960ttgtttaaca catccatcat tagcaaagag
agggaagaag cagcaacggc agatccactc 1020attaaatcca gggatcctta caagaacagg
gtgtgggtct ccagccagga ctgctccctg 1080aagatcagcc agctgaagat agaggacgcc
ggcccctacc atgcctacgt gtgctcagag 1140gcctccagcg tcaccagcat gacacatgtc
accctgctca tctaccgcag gctgaggaag 1200cccaaaatca cgtggagcct caggcacagt
gaggatggca tctgcaggat cagcctgacc 1260tgctccgtgg aggacggggg aaacactgtc
atgtacacat ggaccccgct gcagaaggaa 1320gctgttgtgt cccaagggga atcacacctc
aatgtctcat ggagaagcag tgaaaatcac 1380cccaacctca catgcacagc cagcaaccct
gtcagcagga gttcccacca gtttctttct 1440gagaacatct gttcaggacc tgagagaaac
acaaagcttt ggattgggtt gttcctgatg 1500gtttgccttc tgtgcgttgg gatcttcagc
tggtgcattt ggaagcgaaa aggacggtgt 1560tcagtcccag ccttctgttc cagccaagct
gaggccccag cggatacacc agaacccaca 1620gctggccaca cgctatactc tgtgctctcc
caaggatatg agaagctgga cactcccctc 1680aggcctgcca ggcaacagcc tacacccacc
tcagacagca gctctgacag caacctcaca 1740actgaggagg atgaggacag gcctgaggtg
cacaagccca tcagtggaag atatgaggta 1800tttgaccagg tcactcagga gggcgctgga
catgacccag cccctgaggg ccaagcagac 1860tatgatcccg tcactccata tgtcacggaa
gttgagtctg tggttggaga gaacaccatg 1920tatgcacaag tgttcaactt acagggaaag
accccagttt ctcagaagga agagagctca 1980gccacaatct actgctccat acggaaacct
caggtggtgc caccaccaca acagaatgat 2040cttgagattc ctgaaagtcc tacctatgaa
aatttcacct gaaaggaaaa gcagctgctg 2100cctctctcct gggaccgtgg ggttggaaag
tcagctggac ctcatggggc ctggggctca 2160cagacagaag cacctcagaa tttccttcag
tgcctcagag atgcctggat gtggcccctc 2220cccctccttc tcacccttaa ggactcccaa
acccattaat agttcagaca caggctcctt 2280cttggagcct atgggcttca gatgtctttg
ccccatttgt cacctcgcac acttatagcg 2340tttcctcctc gaaattctac caagactggt
caaatgttgc tgaggggcct ggaccagctg 2400tcctttacac caccttctca acactgctga
aaagaaccca agagaattgt cacacatgac 2460acaagatgta cataatatca tgctcactgc
agtgttattt aaaataaaag gcaggaaata 2520aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
255038238PRTHomo sapiens 38Met Trp Val
Pro Val Val Phe Leu Thr Leu Ser Val Thr Trp Ile Gly 1 5
10 15 Ala Ala Pro Leu Ile Leu Ser Arg
Ile Val Gly Gly Trp Glu Cys Glu 20 25
30 Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg
Gly Arg Ala 35 40 45
Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr Ala Ala 50
55 60 His Cys Ile Arg
Asn Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu 65 70
75 80 Phe His Pro Glu Asp Thr Gly Gln Val
Phe Gln Val Ser His Ser Phe 85 90
95 Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn Arg Phe
Leu Arg 100 105 110
Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg Leu Ser Glu
115 120 125 Pro Ala Glu Leu
Thr Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln 130
135 140 Glu Pro Ala Leu Gly Thr Thr Cys
Tyr Ala Ser Gly Trp Gly Ser Ile 145 150
155 160 Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln
Cys Val Asp Leu 165 170
175 His Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln Lys Val
180 185 190 Thr Lys Phe
Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr 195
200 205 Cys Ser Trp Val Ile Leu Ile Thr
Glu Leu Thr Met Pro Ala Leu Pro 210 215
220 Met Val Leu His Gly Ser Leu Val Pro Trp Arg Gly Gly
Val 225 230 235 391906DNAHomo
sapiens 39agccccaagc ttaccacctg cacccggaga gctgtgtcac catgtgggtc
ccggttgtct 60tcctcaccct gtccgtgacg tggattggtg ctgcacccct catcctgtct
cggattgtgg 120gaggctggga gtgcgagaag cattcccaac cctggcaggt gcttgtggcc
tctcgtggca 180gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt cctcacagct
gcccactgca 240tcaggaacaa aagcgtgatc ttgctgggtc ggcacagcct gtttcatcct
gaagacacag 300gccaggtatt tcaggtcagc cacagcttcc cacacccgct ctacgatatg
agcctcctga 360agaatcgatt cctcaggcca ggtgatgact ccagccacga cctcatgctg
ctccgcctgt 420cagagcctgc cgagctcacg gatgctgtga aggtcatgga cctgcccacc
caggagccag 480cactggggac cacctgctac gcctcaggct ggggcagcat tgaaccagag
gagttcttga 540ccccaaagaa acttcagtgt gtggacctcc atgttatttc caatgacgtg
tgtgcgcaag 600ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg acgctggaca
gggggcaaaa 660gcacctgctc gtgggtcatt ctgatcaccg aactgaccat gccagccctg
ccgatggtcc 720tccatggctc cctagtgccc tggagaggag gtgtctagtc agagagtagt
cctggaaggt 780ggcctctgtg aggagccacg gggacagcat cctgcagatg gtcctggccc
ttgtcccacc 840gacctgtcta caaggactgt cctcgtggac cctcccctct gcacaggagc
tggaccctga 900agtcccttcc ccaccggcca ggactggagc ccctacccct ctgttggaat
ccctgcccac 960cttcttctgg aagtcggctc tggagacatt tctctcttct tccaaagctg
ggaactgcta 1020tctgttatct gcctgtccag gtctgaaaga taggattgcc caggcagaaa
ctgggactga 1080cctatctcac tctctccctg cttttaccct tagggtgatt ctgggggccc
acttgtctgt 1140aatggtgtgc ttcaaggtat cacgtcatgg ggcagtgaac catgtgccct
gcccgaaagg 1200ccttccctgt acaccaaggt ggtgcattac cggaagtgga tcaaggacac
catcgtggcc 1260aacccctgag cacccctatc aaccccctat tgtagtaaac ttggaacctt
ggaaatgacc 1320aggccaagac tcaagcctcc ccagttctac tgacctttgt ccttaggtgt
gaggtccagg 1380gttgctagga aaagaaatca gcagacacag gtgtagacca gagtgtttct
taaatggtgt 1440aattttgtcc tctctgtgtc ctggggaata ctggccatgc ctggagacat
atcactcaat 1500ttctctgagg acacagatag gatggggtgt ctgtgttatt tgtggggtac
agagatgaaa 1560gaggggtggg atccacactg agagagtgga gagtgacatg tgctggacac
tgtccatgaa 1620gcactgagca gaagctggag gcacaacgca ccagacactc acagcaagga
tggagctgaa 1680aacataaccc actctgtcct ggaggcactg ggaagcctag agaaggctgt
gagccaagga 1740gggagggtct tcctttggca tgggatgggg atgaagtaag gagagggact
ggaccccctg 1800gaagctgatt cactatgggg ggaggtgtat tgaagtcctc cagacaaccc
tcagatttga 1860tgatttccta gtagaactca cagaaataaa gagctgttat actgtg
190640218PRTHomo sapiens 40Met Trp Val Pro Val Val Phe Leu Thr
Leu Ser Val Thr Trp Ile Gly 1 5 10
15 Ala Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu
Cys Glu 20 25 30
Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala
35 40 45 Val Cys Gly Gly
Val Leu Val His Pro Gln Trp Val Leu Thr Ala Ala 50
55 60 His Cys Ile Arg Lys Pro Gly Asp
Asp Ser Ser His Asp Leu Met Leu 65 70
75 80 Leu Arg Leu Ser Glu Pro Ala Glu Leu Thr Asp Ala
Val Lys Val Met 85 90
95 Asp Leu Pro Thr Gln Glu Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser
100 105 110 Gly Trp Gly
Ser Ile Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu 115
120 125 Gln Cys Val Asp Leu His Val Ile
Ser Asn Asp Val Cys Ala Gln Val 130 135
140 His Pro Gln Lys Val Thr Lys Phe Met Leu Cys Ala Gly
Arg Trp Thr 145 150 155
160 Gly Gly Lys Ser Thr Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Cys
165 170 175 Asn Gly Val Leu
Gln Gly Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala 180
185 190 Leu Pro Glu Arg Pro Ser Leu Tyr Thr
Lys Val Val His Tyr Arg Lys 195 200
205 Trp Ile Lys Asp Thr Ile Val Ala Asn Pro 210
215 411335DNAHomo sapiens 41agccccaagc ttaccacctg
cacccggaga gctgtgtcac catgtgggtc ccggttgtct 60tcctcaccct gtccgtgacg
tggattggtg ctgcacccct catcctgtct cggattgtgg 120gaggctggga gtgcgagaag
cattcccaac cctggcaggt gcttgtggcc tctcgtggca 180gggcagtctg cggcggtgtt
ctggtgcacc cccagtgggt cctcacagct gcccactgca 240tcaggaagcc aggtgatgac
tccagccacg acctcatgct gctccgcctg tcagagcctg 300ccgagctcac ggatgctgtg
aaggtcatgg acctgcccac ccaggagcca gcactgggga 360ccacctgcta cgcctcaggc
tggggcagca ttgaaccaga ggagttcttg accccaaaga 420aacttcagtg tgtggacctc
catgttattt ccaatgacgt gtgtgcgcaa gttcaccctc 480agaaggtgac caagttcatg
ctgtgtgctg gacgctggac agggggcaaa agcacctgct 540cgggtgattc tgggggccca
cttgtctgta atggtgtgct tcaaggtatc acgtcatggg 600gcagtgaacc atgtgccctg
cccgaaaggc cttccctgta caccaaggtg gtgcattacc 660ggaagtggat caaggacacc
atcgtggcca acccctgagc acccctatca accccctatt 720gtagtaaact tggaaccttg
gaaatgacca ggccaagact caagcctccc cagttctact 780gacctttgtc cttaggtgtg
aggtccaggg ttgctaggaa aagaaatcag cagacacagg 840tgtagaccag agtgtttctt
aaatggtgta attttgtcct ctctgtgtcc tggggaatac 900tggccatgcc tggagacata
tcactcaatt tctctgagga cacagatagg atggggtgtc 960tgtgttattt gtggggtaca
gagatgaaag aggggtggga tccacactga gagagtggag 1020agtgacatgt gctggacact
gtccatgaag cactgagcag aagctggagg cacaacgcac 1080cagacactca cagcaaggat
ggagctgaaa acataaccca ctctgtcctg gaggcactgg 1140gaagcctaga gaaggctgtg
agccaaggag ggagggtctt cctttggcat gggatgggga 1200tgaagtaagg agagggactg
gaccccctgg aagctgattc actatggggg gaggtgtatt 1260gaagtcctcc agacaaccct
cagatttgat gatttcctag tagaactcac agaaataaag 1320agctgttata ctgtg
13354269PRTHomo sapiens 42Met
Trp Val Pro Val Val Phe Leu Thr Leu Ser Val Thr Trp Ile Gly 1
5 10 15 Ala Ala Pro Leu Ile Leu
Ser Arg Ile Val Gly Gly Trp Glu Cys Glu 20
25 30 Lys His Ser Gln Pro Trp Gln Val Leu Val
Ala Ser Arg Gly Arg Ala 35 40
45 Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr
Ala Ala 50 55 60
His Cys Ile Arg Lys 65 43555DNAHomo sapiens 43agccccaagc
ttaccacctg cacccggaga gctgtgtcac catgtgggtc ccggttgtct 60tcctcaccct
gtccgtgacg tggattggtg ctgcacccct catcctgtct cggattgtgg 120gaggctggga
gtgcgagaag cattcccaac cctggcaggt gcttgtggcc tctcgtggca 180gggcagtctg
cggcggtgtt ctggtgcacc cccagtgggt cctcacagct gcccactgca 240tcaggaagtg
agtaggggcc tggggtctgg ggagcaggtg tctgtgtccc agaggaataa 300cagctgggca
ttttccccag gataacctct aaggccagcc ttgggactgg gggagagagg 360gaaagttctg
gttcaggtca catggggagg cagggttggg gctggaccac cctccccatg 420gctgcctggg
tctccatctg tgttcctcta tgtctctttg tgtcgctttc attatgtctc 480ttggtaactg
gcttcggttg tgtctctccg tgtgactatt ttgttctctc tctccctctc 540ttctctgtct
tcagt 55544261PRTHomo
sapiens 44Met Trp Val Pro Val Val Phe Leu Thr Leu Ser Val Thr Trp Ile Gly
1 5 10 15 Ala Ala
Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu Cys Glu 20
25 30 Lys His Ser Gln Pro Trp Gln
Val Leu Val Ala Ser Arg Gly Arg Ala 35 40
45 Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val
Leu Thr Ala Ala 50 55 60
His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu 65
70 75 80 Phe His Pro
Glu Asp Thr Gly Gln Val Phe Gln Val Ser His Ser Phe 85
90 95 Pro His Pro Leu Tyr Asp Met Ser
Leu Leu Lys Asn Arg Phe Leu Arg 100 105
110 Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg
Leu Ser Glu 115 120 125
Pro Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln 130
135 140 Glu Pro Ala Leu
Gly Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser Ile 145 150
155 160 Glu Pro Glu Glu Phe Leu Thr Pro Lys
Lys Leu Gln Cys Val Asp Leu 165 170
175 His Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln
Lys Val 180 185 190
Thr Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr
195 200 205 Cys Ser Gly Asp
Ser Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln 210
215 220 Gly Ile Thr Ser Trp Gly Ser Glu
Pro Cys Ala Leu Pro Glu Arg Pro 225 230
235 240 Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp
Ile Lys Asp Thr 245 250
255 Ile Val Ala Asn Pro 260 451464DNAHomo sapiens
45agccccaagc ttaccacctg cacccggaga gctgtgtcac catgtgggtc ccggttgtct
60tcctcaccct gtccgtgacg tggattggtg ctgcacccct catcctgtct cggattgtgg
120gaggctggga gtgcgagaag cattcccaac cctggcaggt gcttgtggcc tctcgtggca
180gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt cctcacagct gcccactgca
240tcaggaacaa aagcgtgatc ttgctgggtc ggcacagcct gtttcatcct gaagacacag
300gccaggtatt tcaggtcagc cacagcttcc cacacccgct ctacgatatg agcctcctga
360agaatcgatt cctcaggcca ggtgatgact ccagccacga cctcatgctg ctccgcctgt
420cagagcctgc cgagctcacg gatgctgtga aggtcatgga cctgcccacc caggagccag
480cactggggac cacctgctac gcctcaggct ggggcagcat tgaaccagag gagttcttga
540ccccaaagaa acttcagtgt gtggacctcc atgttatttc caatgacgtg tgtgcgcaag
600ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg acgctggaca gggggcaaaa
660gcacctgctc gggtgattct gggggcccac ttgtctgtaa tggtgtgctt caaggtatca
720cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc ttccctgtac accaaggtgg
780tgcattaccg gaagtggatc aaggacacca tcgtggccaa cccctgagca cccctatcaa
840ccccctattg tagtaaactt ggaaccttgg aaatgaccag gccaagactc aagcctcccc
900agttctactg acctttgtcc ttaggtgtga ggtccagggt tgctaggaaa agaaatcagc
960agacacaggt gtagaccaga gtgtttctta aatggtgtaa ttttgtcctc tctgtgtcct
1020ggggaatact ggccatgcct ggagacatat cactcaattt ctctgaggac acagatagga
1080tggggtgtct gtgttatttg tggggtacag agatgaaaga ggggtgggat ccacactgag
1140agagtggaga gtgacatgtg ctggacactg tccatgaagc actgagcaga agctggaggc
1200acaacgcacc agacactcac agcaaggatg gagctgaaaa cataacccac tctgtcctgg
1260aggcactggg aagcctagag aaggctgtga gccaaggagg gagggtcttc ctttggcatg
1320ggatggggat gaagtaagga gagggactgg accccctgga agctgattca ctatgggggg
1380aggtgtattg aagtcctcca gacaaccctc agatttgatg atttcctagt agaactcaca
1440gaaataaaga gctgttatac tgtg
1464
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