U.S. patent application number 14/199856 was filed with the patent office on 2014-09-04 for genetic variants on chr 11q and 6q as markers for prostate and colorectal cancer predisposition.
This patent application is currently assigned to deCODE Genetics ehf.. The applicant listed for this patent is deCODE Genetics ehf.. Invention is credited to Julius Gudmundsson, Patrick Sulem, Steinunn Thorlacius.
Application Number | 20140248615 14/199856 |
Document ID | / |
Family ID | 40403974 |
Filed Date | 2014-09-04 |
United States Patent
Application |
20140248615 |
Kind Code |
A1 |
Thorlacius; Steinunn ; et
al. |
September 4, 2014 |
GENETIC VARIANTS ON CHR 11Q AND 6Q AS MARKERS FOR PROSTATE AND
COLORECTAL CANCER PREDISPOSITION
Abstract
It has been discovered that certain polymorphic markers on
chromosome 6 and chromosome 11 are indicative of a susceptibility
to prostate cancer and colon cancer. The invention describes
diagnostic applications for determining a susceptibility to cancer
using such markers, as well as kits for use in such
applications.
Inventors: |
Thorlacius; Steinunn;
(Reykjavik, IS) ; Sulem; Patrick; (Reykjavik,
IS) ; Gudmundsson; Julius; (Reykjavik, IS) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
deCODE Genetics ehf. |
Reykjavik |
|
IS |
|
|
Assignee: |
deCODE Genetics ehf.
Reykjavik
IS
|
Family ID: |
40403974 |
Appl. No.: |
14/199856 |
Filed: |
March 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12315114 |
Nov 26, 2008 |
8697360 |
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14199856 |
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Current U.S.
Class: |
435/6.11 ;
702/19 |
Current CPC
Class: |
G16H 70/60 20180101;
G16H 50/30 20180101; C12Q 1/68 20130101; C12Q 2600/136 20130101;
C12Q 2600/156 20130101; Y10T 436/143333 20150115; C12Q 2600/118
20130101; Y02A 90/10 20180101; C12Q 2600/172 20130101; G16H 10/40
20180101; G16H 50/70 20180101; G16B 20/00 20190201; C12Q 1/6886
20130101; C12Q 2600/106 20130101 |
Class at
Publication: |
435/6.11 ;
702/19 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; G06F 19/18 20060101 G06F019/18; G06F 19/00 20060101
G06F019/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 30, 2007 |
IS |
8696 |
Claims
1. A method for determining a susceptibility to prostate cancer in
a human individual, comprising determining the presence or absence
of at least one allele of at least one polymorphic marker in a
nucleic acid sample obtained from the individual, or in a genotype
dataset from the individual, wherein the at least one polymorphic
marker is selected from rs10896450 and rs10943605, and markers in
linkage disequilibrium therewith, and wherein determination of the
presence of the at least one allele is indicative of a
susceptibility to prostate cancer.
2. The method of claim 1, wherein the at least one polymorphic
marker in linkage disequilibrium with rs10896450 is selected from
the markers set forth in Table 5.
3. The method of claim 1, wherein the at least one polymorphic
marker in linkage disequilibrium with rs10896450 is selected from
the markers set forth in Table 4.
4. The method of claim 3, wherein the at least one polymorphic
marker in linkage disequilibrium with rs10896405 is selected from
rs11228565 and rs7947353.
5. A method for determining a susceptibility to colorectal cancer
in a human individual, comprising determining the presence or
absence of at least one allele of at least one polymorphic marker
in a nucleic acid sample obtained from the individual, or in a
genotype dataset from the individual, wherein the at least one
polymorphic marker is selected from rs10943605 and markers in
linkage disequilibrium therewith, and wherein determination of the
presence of the at least one allele is indicative of a
susceptibility to colorectal cancer.
6. The method of claim 1, wherein the at least one polymorphic
marker in linkage disequilibrium with rs10943605 is selected from
the markers set forth in Table 3.
7. (canceled)
8. The method of claim 1, wherein the susceptibility is increased
susceptibility.
9. The method of claim 8, wherein the presence of the at least one
allele or haplotype is indicative of increased susceptibility with
a relative risk of at least 1.10.
10. (canceled)
11. The method of claim 8, wherein the at least one marker or
haplotype comprises at least one marker selected from the group
consisting of rs10896450 allele G, rs11228565 allele A, rs7947353
allele A and rs10943605 allele G.
12-17. (canceled)
18. The method of claim 1, wherein linkage disequilibrium is
characterized by values r.sup.2 of greater than 0.2 and/or |D'| of
greater than 0.8.
19-40. (canceled)
41. The method of claim 1, further comprising analyzing non-genetic
information to make risk assessment, diagnosis, or prognosis of the
individual.
42. The method of claim 41, wherein the non-genetic information is
selected from age, gender, ethnicity, socioeconomic status,
previous disease diagnosis, medical history of subject, family
history of cancer, biochemical measurements, and clinical
measurements.
43. The method of claim 1, further comprising assessing the
presence or absence of at least one additional genetic risk factor
for prostate cancer or colorectal cancer in the individual.
44. The method of claim 43, wherein the additional genetic risk
factor for prostate cancer is selected from the group consisting of
rs2710646 allele A, rs16901979 allele A, rs1447295 allele A,
rs6983267 allele G, rs10896450 allele G, rs1859962 allele G,
rs4430796 allele A and rs5945572 allele A.
45. The method of claim 43, further comprising calculating overall
risk.
46-67. (canceled)
68. An apparatus for determining a genetic indicator for a cancer
selected from prostate cancer and colorectal cancer in a human
individual, comprising: a computer readable memory; and a routine
stored on the computer readable memory; wherein the routine is
adapted to be executed on a processor to analyze marker and/or
haplotype information for at least one human individual with
respect to at least one polymorphic marker selected from the
markers set forth in Table 3 and Table 4, and markers in linkage
disequilibrium therewith, and generate an output based on the
marker or haplotype information, wherein the output comprises a
risk measure of the at least one marker or haplotype as a genetic
indicator of the cancer for the human individual.
69. The apparatus of claim 68, wherein the routine further
comprises an indicator of the frequency of at least one allele of
at least one polymorphic marker or at least one haplotype in a
plurality of individuals diagnosed with the cancer, and an
indicator of the frequency of at the least one allele of at least
one polymorphic marker or at least one haplotype in a plurality of
reference individuals, and wherein a risk measure is based on a
comparison of the at least one marker and/or haplotype status for
the human individual to the indicator of the frequency of the at
least one marker and/or haplotype information for the plurality of
individuals diagnosed with the cancer.
70. The apparatus of claim 68, wherein the at least one polymorphic
marker is selected from marker rs10896450 and markers in linkage
disequilibrium therewith, as defined by numerical values of r.sup.2
of at least 0.2.
71. The apparatus of claim 68, wherein the risk measure is
characterized by an Odds Ratio (OR) or a Relative Risk (RR).
72. The method of claim 5, wherein the at least one polymorphic
marker in linkage disequilibrium with rs 10943605 is selected from
the markers set forth in Table 3.
Description
RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.119
or 365 to Iceland, Application No. 8696, filed Nov. 30, 2007. The
entire teachings of the above application are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] Cancer, the uncontrolled growth of malignant cells, is a
major health problem of the modern medical era and is one of the
leading causes of death in developed countries. In the United
States, one in four deaths is caused by cancer (Jemal, A. et al.,
CA Cancer J. Clin. 52:23-47 (2002)).
[0003] The incidence of prostate cancer has dramatically increased
over the last decades and prostate cancer is now a leading cause of
death in the United States and Western Europe (Peschel, R. E. and
J. W. Colberg, Lancet 4:233-41 (2003); Nelson, W. G. et al., N
Engl. J. Med. 349(4):366-81 (2003)). Prostate cancer is the most
frequently diagnosed noncutaneous malignancy among men in
industrialized countries, and in the United States, 1 in 8 men will
develop prostate cancer during his life (Simard, J. et al.,
Endocrinology 143(6):2029-40 (2002)). Although environmental
factors, such as dietary factors and lifestyle-related factors,
contribute to the risk of prostate cancer, genetic factors have
also been shown to play an important role. Indeed, a positive
family history is among the strongest epidemiological risk factors
for prostate cancer, and twin studies comparing the concordant
occurrence of prostate cancer in monozygotic twins have
consistently revealed a stronger hereditary component in the risk
of prostate cancer than in any other type of cancer (Nelson, W. G.
et al., N. Engl. J. Med. 349(4):366-81 (2003); Lichtenstein P. et.
al., N. Engl. J. Med. 343(2):78-85 (2000)). In addition, an
increased risk of prostate cancer is seen in 1.sup.st to 5.sup.th
degree relatives of prostate cancer cases in a nation wide study on
the familiality of all cancer cases diagnosed in Iceland from
1955-2003 (Amundadottir et al., PLoS Medicine 1(3):e65 (2004)). The
genetic basis for this disease, emphasized by the increased risk
among relatives, is further supported by studies of prostate cancer
among particular populations: for example, African Americans have
among the highest incidence of prostate cancer and mortality rate
attributable to this disease: they are 1.6 times as likely to
develop prostate cancer and 2.4 times as likely to die from this
disease than European Americans (Ries, L. A. G. et al., NIH Pub.
No. 99-4649 (1999)).
[0004] An average 40% reduction in life expectancy affects males
with prostate cancer. If detected early, prior to metastasis and
local spread beyond the capsule, prostate cancer can be cured
(e.g., using surgery). However, if diagnosed after spread and
metastasis from the prostate, prostate cancer is typically a fatal
disease with low cure rates. While prostate-specific antigen
(PSA)-based screening has aided early diagnosis of prostate cancer,
it is neither highly sensitive nor specific (Punglia et. al., N
Engl J Med. 349(4):335-42 (2003)). This means that a high
percentage of false negative and false positive diagnoses are
associated with the test. The consequences are both many instances
of missed cancers and unnecessary follow-up biopsies for those
without cancer. As many as 65 to 85% of individuals (depending on
age) with prostate cancer have a PSA value less than or equal to
4.0 ng/mL, which has traditionally been used as the upper limit for
a normal PSA level (Punglia et. al., N Engl J Med. 349(4):335-42
(2003); Cookston, M. S., Cancer Control 8(2):133-40 (2001);
Thompson, I. M. et. al., N Engl J Med. 350:2239-46 (2004)). A
significant fraction of those cancers with low PSA levels are
scored as Gleason grade 7 or higher, which is a measure of an
aggressive prostate cancer.
[0005] In addition to the sensitivity problem outlined above, PSA
testing also has difficulty with specificity and predicting
prognosis. PSA levels can be abnormal in those without prostate
cancer. For example, benign prostatic hyperplasia (BPH) is one
common cause of a false-positive PSA test. In addition, a variety
of noncancer conditions may elevate serum PSA levels, including
urinary retention, prostatitis, vigorous prostate massage and
ejaculation.
[0006] Subsequent confirmation of prostate cancer using needle
biopsy in patients with positive PSA levels is difficult if the
tumor is too small to see by ultrasound. Multiple random samples
are typically taken but diagnosis of prostate cancer may be missed
because of the sampling of only small amounts of tissue. Digital
rectal examination (DRE) also misses many cancers because only the
posterior lobe of the prostate is examined. As early cancers are
nonpalpable, cancers detected by DRE may already have spread
outside the prostate (Mistry K. J., Am. Board Fam. Pract.
16(2):95-101 (2003)).
[0007] Thus, there is clearly a great need for improved diagnostic
procedures that would facilitate early-stage prostate cancer
detection and prognosis, as well as aid in preventive and curative
treatments of the disease. In addition, there is a need to develop
tools to better identify those patients who are more likely to have
aggressive forms of prostate cancer from those patients that are
more likely to have more benign forms of prostate cancer that
remain localized within the prostate and do not contribute
significantly to morbidity or mortality. This would help to avoid
invasive and costly procedures for patients not at significant
risk.
[0008] The incidence of prostate cancer has dramatically increased
over the last decades. Prostate cancer is a multifactorial disease
with genetic and environmental components involved in its etiology.
It is characterized by heterogeneous growth patterns that range
from slow growing tumors to very rapid highly metastatic
lesions.
[0009] Although genetic factors are among the strongest
epidemiological risk factors for prostate cancer, the search for
genetic determinants involved in the disease has been challenging.
Studies have revealed that linking candidate genetic markers to
prostate cancer has been more difficult than identifying
susceptibility genes for other cancers, such as breast, ovary and
colorectal cancer. Several reasons have been proposed for this
increased difficulty including: the fact that prostate cancer is
often diagnosed at a late age thereby often making it difficult to
obtain DNA samples from living affected individuals for more than
one generation; the presence within high-risk pedigrees of
phenocopies that are associated with a lack of distinguishing
features between hereditary and sporadic forms; and the genetic
heterogeneity of prostate cancer and the accompanying difficulty of
developing appropriate statistical transmission models for this
complex disease (Simard, J. et al., Endocrinology 143(6):2029-40
(2002)).
[0010] Various genome scans for prostate cancer-susceptibility
genes have been conducted and several prostate cancer
susceptibility loci have been reported. For example, HPC1
(1q24-q25), PCAP (1q42-q43), HCPX (Xq27-q28), CAPB (1p36), HPC20
(20q13), HPC2/ELAC2 (17 .mu.l) and 16q23 have been proposed as
prostate cancer susceptibility loci (Simard, J. et al.,
Endocrinology 143(6):2029-40 (2002); Nwosu, V. et al., Hum. Mol.
Genet. 10(20):2313-18 (2001)). In a genome scan conducted by Smith
et al., the strongest evidence for linkage was at HPC1, although
two-point analysis also revealed a LOD score of .gtoreq.1.5 at
D4S430 and LOD scores .gtoreq.1.0 at several loci, including
markers at Xq27-28 (Ostrander E. A. and J. L. Stanford, Am. J. Hum.
Genet. 67:1367-75 (2000)). In other genome scans, two-point LOD
scores of .gtoreq.1.5 for chromosomes 10q, 12q and 14q using an
autosomal dominant model of inheritance, and chromosomes 1q, 8q,
10q and 16p using a recessive model of inheritance, have been
reported, as well as nominal evidence for linkage to chr 2q, 12p,
15q, 16q and 16p. A genome scan for prostate cancer predisposition
loci using a small set of Utah high risk prostate cancer pedigrees
and a set of 300 polymorphic markers provided evidence for linkage
to a locus on chromosome 17p (Simard, J. et al., Endocrinology
143(6):2029-40 (2002)). Eight new linkage analyses were published
in late 2003, which depicted remarkable heterogeneity. Eleven peaks
with LOD scores higher than 2.0 were reported, none of which
overlapped (see Actane consortium, Schleutker et. al., Wiklund et.
al., Witte et. al., Janer Xu et. al., Lange et. al., Cunningham et
al.; all of which appear in Prostate, vol. 57 (2003)).
[0011] As described above, identification of particular genes
involved in prostate cancer has been challenging. One gene that has
been implicated is RNASEL, which encodes a widely expressed latent
endoribonuclease that participates in an interferon-inducible
RNA-decay pathway believed to degrade viral and cellular RNA, and
has been linked to the HPC locus (Carpten, J. et al., Nat. Genet.
30:181-84 (2002); Casey, G. et al., Nat. Genet. 32(4):581-83
(2002)). Mutations in RNASEL have been associated with increased
susceptibility to prostate cancer. For example, in one family, four
brothers with prostate cancer carried a disabling mutation in
RNASEL, while in another family, four of six brothers with prostate
cancer carried a base substitution affecting the initiator
methionine codon of RNASEL. Other studies have revealed mutant
RNASEL alleles associated with an increased risk of prostate cancer
in Finnish men with familial prostate cancer and an Ashkenazi
Jewish population (Rokman, A. et al., Am J. Hum. Genet.
70:1299-1304 (2002); Rennert, H. et al., Am J. Hum. Genet.
71:981-84 (2002)). In addition, the Ser217Leu genotype has been
proposed to account for approximately 9% of all sporadic cases in
Caucasian Americans younger than 65 years (Stanford, J. L., Cancer
Epidemiol. Biomarkers Prev. 12(9):876-81 (2003)). In contrast to
these positive reports, however, some studies have failed to detect
any association between RNASEL alleles with inactivating mutations
and prostate cancer (Wang, L. et al., Am. J. Hum. Genet. 71:116-23
(2002); Wiklund, F. et al., Clin. Cancer Res. 10(21):7150-56
(2004); Maier, C. et. al., Br. J. Cancer 92(6):1159-64 (2005)).
[0012] The macrophage-scavenger receptor 1 (MSR1) gene, which is
located at 8p22, has also been identified as a candidate prostate
cancer-susceptibility gene (Xu, J. et al., Nat. Genet. 32:321-25
(2002)). A mutant MSR1 allele was detected in approximately 3% of
men with nonhereditary prostate cancer but only 0.4% of unaffected
men. However, not all subsequent reports have confirmed these
initial findings (see, e.g., Lindmark, F. et al., Prostate
59(2):132-40 (2004); Seppala, E. H. et al., Clin. Cancer Res.
9(14):5252-56 (2003); Wang, L. et al., Nat Genet. 35(2):128-29
(2003); Miller, D. C. et al., Cancer Res. 63(13):3486-89 (2003)).
MSR1 encodes subunits of a macrophage-scavenger receptor that is
capable of binding a variety of ligands, including bacterial
lipopolysaccharide and lipoteicholic acid, and oxidized
high-density lipoprotein and low-density lipoprotein in serum
(Nelson, W. G. et al., N. Engl. J. Med. 349(4):366-81 (2003)).
[0013] The ELAC2 gene on Chr17p was the first prostate cancer
susceptibility gene to be cloned in high risk prostate cancer
families from Utah (Tavtigian, S. V., et al., Nat. Genet.
27(2):172-80 (2001)). A frameshift mutation (1641InsG) was found in
one pedigree. Three additional missense changes: Ser217Leu;
Ala541Thr; and Arg781His, were also found to associate with an
increased risk of prostate cancer. The relative risk of prostate
cancer in men carrying both Ser217Leu and Ala541Thr was found to be
2.37 in a cohort not selected on the basis of family history of
prostate cancer (Rebbeck, T. R., et al., Am. J. Hum. Genet.
67(4):1014-19 (2000)). Another study described a new termination
mutation (Glu216X) in one high incidence prostate cancer family
(Wang, L., et al., Cancer Res. 61(17):6494-99 (2001)). Other
reports have not demonstrated strong association with the three
missense mutations, and a recent metaanalysis suggests that the
familial risk associated with these mutations is more moderate than
was indicated in initial reports (Vesprini, D., et al., Am. J. Hum.
Genet. 68(4):912-17 (2001); Shea, P. R., et al., Hum. Genet.
111(4-5):398-400 (2002); Suarez, B. K, et al., Cancer Res.
61(13):4982-84 (2001); Severi, G., et al., J. Natl. Cancer Inst.
95(11):818-24 (2003); Fujiwara, H., et al., J. Hum. Genet.
47(12):641-48 (2002); Camp, N. J., et al., Am. J. Hum. Genet.
71(6):1475-78 (2002)).
[0014] Polymorphic variants of genes involved in androgen action
(e.g., the androgen receptor (AR) gene, the cytochrome P-450c17
(CYP17) gene, and the steroid-5-.alpha.-reductase type II (SRD5A2)
gene), have also been implicated in increased risk of prostate
cancer (Nelson, W. G. et al., N. Engl. J. Med. 349(4):366-81
(2003)). With respect to AR, which encodes the androgen receptor,
several genetic epidemiological studies have shown a correlation
between an increased risk of prostate cancer and the presence of
short androgen-receptor polyglutamine repeats, while other studies
have failed to detect such a correlation. Linkage data has also
implicated an allelic form of CYP17, an enzyme that catalyzes key
reactions in sex-steroid biosynthesis, with prostate cancer (Chang,
B. et al., Int. J. Cancer 95:354-59 (2001)). Allelic variants of
SRD5A2, which encodes the predominant isozyme of
5-.alpha.-reductase in the prostate and functions to convert
testosterone to the more potent dihydrotestosterone, have been
associated with an increased risk of prostate cancer and with a
poor prognosis for men with prostate cancer (Makridakis, N. M. et
al., Lancet 354:975-78 (1999); Nam, R. K. et al., Urology
57:199-204 (2001)).
[0015] In short, despite the effort of many groups around the
world, the genes that account for a substantial fraction of
prostate cancer risk have not been identified. Although twin
studies have implied that genetic factors are likely to be
prominent in prostate cancer, only a handful of genes have been
identified as being associated with an increased risk for prostate
cancer, and these genes account for only a low percentage of cases.
Thus, it is clear that the majority of genetic risk factors for
prostate cancer remain to be found. It is likely that these genetic
risk factors will include a relatively high number of low-to-medium
risk genetic variants. These low-to-medium risk genetic variants
may, however, be responsible for a substantial fraction of prostate
cancer, and their identification, therefore, a great benefit for
public health. Furthermore, none of the published prostate cancer
genes have been reported to predict a greater risk for aggressive
prostate cancer than for less aggressive prostate cancer.
[0016] Extensive genealogical information for a population
containing cancer patients has in a recent study been combined with
powerful gene sharing methods to map a locus on chromosome 8q24.21,
which has been demonstrated to play a major role in cancer. Various
cancer patients and their relatives were genotyped with a
genome-wide marker set including 1100 microsatellite markers, with
an average marker density of 3-4 cM. (Amundadottir L. T., Nature
Genet. 38(6):652-658 (2006)). Association was detected to a single
LD block within the locus between positions 128.414 and 128.506 Mb
(NCBI build 34) in Utah CEPH HapMap samples.
[0017] Colorectal Cancer (CRC) is one of the most commonly
diagnosed cancers and one of the leading causes of cancer mortality
(Parkin D M, et. al. CA Cancer J Clin, 55,:74-108 (2005)). Cancers
of the colon and rectum accounted for about 1 million new cases in
2002 (9.4% of cancer cases world-wide) and it affects men and women
almost equally. The average lifetime risk for an individual in the
US to develop CRC is 6% (Jemal A, et al. CA Cancer J. Clin.,
56:106-30 (2006)). The prognosis is strongly associated with the
stage of the disease at diagnosis; therefore, CRC screening
presents an opportunity for early cancer detection and cancer
prevention.
[0018] Colorectal cancer is a consequence of environmental
exposures acting upon a background of genetically determined
susceptibility. Studies indicate that 30-35% of colorectal cancer
risk could be explained by genetic factors (Lichtenstein P, et. al.
N Engl J Med, 343:78-85 (2000);) Peto J and Mack T M. Nat Genet,
26:411-4 (2000); Risch N. Cancer Epidemiol Biomarkers Prev,
10:733-41 (2001)). The analysis of cancer occurrence in relatives
of cancer patients also lends strong evidence for genetic factors
that increase the risk of cancer.
[0019] At present only a small percentage of the heritable risk of
CRC is identified, usually through the investigation of rare cancer
syndromes. High-penetrance mutations in several genes have been
identified in rare hereditary colorectal cancer syndromes. The most
common of these are the familial adenomatous polyposis (FAP)
syndrome and hereditary non-polyposis colorectal cancer (HNPCC) or
Lynch syndrome (LS). FAP, caused by mutations in the APC gene, is
an autosomal dominant syndrome, characterized by early onset of
multiple adenomatous polyps in the colon that eventually progress
to cancer. LS is caused by mutations in DNA mismatch repair (MMR)
genes and is considered to be the most common hereditary CRC
syndrome, comprising approximately 3-5% of all CRCs (de la
Chapelle, A. Fam Cancer, 4:233-7 (2005)).
[0020] The search for additional highly-penetrant CRC genes has not
been fruitful and accumulating evidence supports the notion that no
single susceptibility gene is likely to explain a large proportion
of highly familial or early onset CRC. This has led to the
currently favored hypothesis that most of the inherited CRC risk is
due to multiple, low genetic risk variants. Each such variant would
be expected to carry a small increase in risk; however, if the
variant is common, it may contribute significantly to the
population attributable risk (PAR).
SUMMARY OF THE INVENTION
[0021] The present invention relates to the use of polymorphic
markers in diagnostic methods, kits and apparatus for determining
susceptibility to prostate cancer and colorectal cancer.
[0022] In one aspect, the present invention relates to a method for
determining a susceptibility to a cancer selected from prostate
cancer and colorectal cancer in a human individual, comprising
determining the presence or absence of at least one allele of at
least one polymorphic marker in a nucleic acid sample obtained from
the individual, or in a genotype dataset from the individual,
wherein the at least one polymorphic marker is selected from
markers selected from the group consisting of markers within LD
Block C11 and LD Block C06, and wherein the presence of the at
least one allele is indicative of a susceptibility to the
cancer.
[0023] In another aspect, the present invention relates to a method
for determining a susceptibility to a cancer selected from prostate
cancer and colorectal cancer in a human individual, comprising
determining the presence or absence of at least one allele of at
least one polymorphic marker in a nucleic acid sample obtained from
the individual, or in a genotype dataset from the individual,
wherein the at least one polymorphic marker is selected from the
group consisting of the markers set forth in Table 5 and Table 6,
and markers in linkage disequilibirium therewith, and wherein the
presence of the at least one allele is indicative of a
susceptibility to the cancer. Determining a susceptibility
comprises in one embodiment a diagnosis of a susceptibility.
Diagnosis may be made by a medical professional, or other
professional that provides information about disease risk.
Alternatively, diagnosis of a susceptibility is provided by a
genotype provider, or by an individual or organization that
interprets genotype data for an individual or groups of
individuals.
[0024] The genotype dataset comprises in one embodiment information
about marker identity and the allelic status of the individual for
at least one allele of a marker, i.e. information about the
identity of at least one allele of the marker in the individual.
The genotype dataset may comprise allelic information (information
about allelic status) about one or more marker, including two or
more markers, three or more markers, five or more markers, ten or
more markers, one hundred or more markers, an so on. In some
embodiments, the genotype dataset comprises genotype information
from a whole-genome assessment of the individual, that may include
hundreds of thousands of markers, or even one million or more
markers spanning the entire genome of the individual.
[0025] Another aspect relates to a method of determining a
susceptibility to a cancer selected from prostate cancer and
colorectal cancer in a human individual, comprising determining
whether at least one at-risk allele in at least one polymorphic
marker is present in a genotype dataset derived from the
individual, wherein the at least one polymorphic marker is selected
from the group consisting of the markers set forth in Tables 5 and
6, and markers in linkage disequilibrium therewith, and wherein
determination of the presence of the at least one at-risk allele is
indicative of increased susceptibility to cancer.
[0026] Another aspect of the invention relates to a method of
determining a susceptibility to prostate cancer, the method
comprising: obtaining nucleic acid sequence data about a human
individual identifying at least one allele of at least one
polymorphic marker, wherein different alleles of the at least one
polymorphic marker are associated with different susceptibilities
to prostate cancer in humans, and determining a susceptibility to
prostate cancer from the nucleic acid sequence data, wherein the at
least one polymorphic marker is selected from the group consisting
of rs10896450, and markers in linkage disequilibirium
therewith.
[0027] In general, polymorphic genetic markers lead to alternate
sequences at the nucleic acid level. If the nucleic acid marker
changes the codon of a polypeptide encoded by the nucleic acid,
then the marker will also result in alternate sequence at the amino
acid level of the encoded polypeptide (polypeptide markers).
Determination of the identity of particular alleles at polymorphic
markers in a nucleic acid or particular alleles at polypeptide
markers comprises whether particular alleles are present at a
certain position in the sequence. Sequence data identifying a
particular allele at a marker comprises sufficient sequence to
detect the particular allele. For single nucleotide polymorphisms
(SNPs) or amino acid polymorphisms described herein, sequence data
can comprise sequence at a single position, i.e. the identity of a
nucleotide or amino acid at a single position within a sequence.
The sequence data can optionally include information about sequence
flanking the polymorphic site, which in the case of SNPs spans a
single nucleotide.
[0028] In certain embodiments, it may be useful to determine the
nucleic acid sequence for at least two polymorphic markers. In
other embodiments, the nucleic acid sequence for at least three, at
least four or at least five or more polymorphic markers is
determined. Haplotype information can be derived from an analysis
of two or more polymorphic markers. Thus, in certain embodiments, a
further step is performed, whereby haplotype information is derived
based on sequence data for at least two polymorphic markers.
[0029] The invention also provides a method of determining a
susceptibility to a cancer selected from prostate cancer and
colorectal cancer in a human individual, the method comprising
obtaining nucleic acid sequence data about a human individual
identifying both alleles of at least two polymorphic markers
selected from the markers listed in Table 3 and Table 4, and
markers in linkage disequilibrium therewith, determine the identity
of at least one haplotype based on the sequence data, and determine
a susceptibility to the cancer from the haplotype data.
[0030] In certain embodiments, determination of a susceptibility
comprises comparing the nucleic acid sequence data to a database
containing correlation data between the at least one polymorphic
marker and susceptibility to cancer. In some embodiments, the
database comprises at least one risk measure of susceptibility to
cancer for the at least one marker. The sequence database can for
example be provided as a look-up table that contains data that
indicates the susceptibility of cancer for any one, or a plurality
of, particular polymorphisms. The database may also contain data
that indicates the susceptibility for a particular haplotype that
comprises at least two polymorphic markers.
[0031] Obtaining nucleic acid sequence data can in certain
embodiments comprise obtaining a biological sample from the human
individual and analyzing sequence of the at least one polymorphic
marker in nucleic acid in the sample. Analyzing sequence can
comprise determining the presence or absence of at least one allele
of the at least one polymorphic marker. Determination of the
presence of a particular susceptibility allele (e.g., an at-risk
allele) is indicative of susceptibility to cancer in the human
individual. Determination of the absence of a particular
susceptibility allele is indicative that the particular
susceptibility due to the at least one polymorphism is not present
in the individual.
[0032] In some embodiments, obtaining nucleic acid sequence data
comprises obtaining nucleic acid sequence information from a
preexisting record. The preexisting record can for example be a
computer file or database containing sequence data, such as
genotype data, for the human individual, for at least one
polymorphic marker.
[0033] Susceptibility determined by the diagnostic methods of the
invention can be reported to a particular entity. In some
embodiments, the at least one entity is selected from the group
consisting of the individual, a guardian of the individual, a
genetic service provider, a physician, a medical organization, and
a medical insurer.
[0034] In certain embodiments, genetic markers associated with risk
of prostate cancer and/or colorectal cancer as described herein are
indicative of different response rates to particular treatment
modalities for the cancer. Thus, in certain embodiments, the
presence of the marker or haplotype is indicative of a different
response rate of the subject to a particular treatment
modality.
[0035] Another aspect of the invention relates to a method of
identification of a marker for use in assessing susceptibility to
prostate cancer, the method comprising
[0036] identifying at least one polymorphic marker within LD Block
C06 or LD Block C11, or at least one polymorphic marker in linkage
disequilibrium therewith;
[0037] determining the genotype status of a sample of individuals
diagnosed with, or having a susceptibility to, prostate cancer;
and
[0038] determining the genotype status of a sample of control
individuals;
[0039] wherein a significant difference in frequency of at least
one allele in at least one polymorphism in individuals diagnosed
with, or having a susceptibility to, prostate cancer, as compared
with the frequency of the at least one allele in the control sample
is indicative of the at least one polymorphism being useful for
assessing susceptibility to prostate cancer.
[0040] The invention also relates, in another aspect, to a method
of identification of a marker for use in assessing susceptibility
to colorectal cancer, the method comprising
[0041] identifying at least one polymorphic marker within The LD
Block C11 genomic region, or at least one polymorphic marker in
linkage disequilibrium therewith;
[0042] determining the genotype status of a sample of individuals
diagnosed with, or having a susceptibility to, colorectal cancer;
and
[0043] determining the genotype status of a sample of control
individuals;
[0044] wherein a significant difference in frequency of at least
one allele in at least one polymorphism in individuals diagnosed
with, or having a susceptibility to, colorectal cancer, as compared
with the frequency of the at least one allele in the control sample
is indicative of the at least one polymorphism being useful for
assessing susceptibility to colorectal cancer. In one embodiment,
an increase in frequency of the at least one allele in the at least
one polymorphism in individuals diagnosed with, or having a
susceptibility to, the cancer, as compared with the frequency of
the at least one allele in the control sample is indicative of the
at least one polymorphism being useful for assessing increased
susceptibility to the cancer. In another embodiment, a decrease in
frequency of the at least one allele in the at least one
polymorphism in individuals diagnosed with, or having a
susceptibility to, the cancer, as compared with the frequency of
the at least one allele in the control sample is indicative of the
at least one polymorphism being useful for assessing decreased
susceptibility to, or protection against, the cancer.
[0045] The invention, in another aspect, also relates to a method
of genotyping a nucleic acid sample obtained from a human
individual at risk for, or diagnosed with, a cancer selected from
prostate cancer and colorectal cancer, comprising determining the
presence or absence of at least one allele of at least one
polymorphic marker in the sample, wherein the at least one marker
is selected from the markers set forth in Table 3 and Table 4, and
markers in linkage disequilibrium therewith, and wherein the
presence of the at least one allele is indicative of a
susceptibility to the cancer. In one embodiment, genotyping
comprises amplifying a segment of a nucleic acid that comprises the
at least one polymorphic marker by Polymerase Chain Reaction (PCR),
using a nucleotide primer pair flanking the at least one
polymorphic marker. In another embodiment, genotyping is performed
using a process selected from allele-specific probe hybridization,
allele-specific primer extension, allele-specific amplification,
nucleic acid sequencing, 5'-exonuclease digestion, molecular beacon
assay, oligonucleotide ligation assay, size analysis, and
single-stranded conformation analysis. In one preferred embodiment,
the process comprises allele-specific probe hybridization. In
another preferred embodiment, the process comprises DNA sequencing.
In yet another preferred embodiment, genotyping comprises the steps
of
[0046] contacting copies of the nucleic acid with a detection
oligonucleotide probe and an enhancer oligonucleotide probe under
conditions for specific hybridization of the oligonucleotide probe
with the nucleic acid;
[0047] wherein
[0048] the detection oligonucleotide probe is from 5-100
nucleotides in length and specifically hybridizes to a first
segment of the nucleic acid whose nucleotide sequence is given by
SEQ ID NO:2 that comprises at least one polymorphic site;
[0049] the detection oligonucleotide probe comprises a detectable
label at its 3' terminus and a quenching moiety at its 5'
terminus;
[0050] the enhancer oligonucleotide is from 5-100 nucleotides in
length and is complementary to a second segment of the nucleotide
sequence that is 5' relative to the oligonucleotide probe, such
that the enhancer oligonucleotide is located 3' relative to the
detection oligonucleotide probe when both oligonucleotides are
hybridized to the nucleic acid; and
[0051] a single base gap exists between the first segment and the
second segment, such that when the oligonucleotide probe and the
enhancer oligonucleotide probe are both hybridized to the nucleic
acid, a single base gap exists between the oligonucleotides;
[0052] treating the nucleic acid with an endonuclease that will
cleave the detectable label from the 3' terminus of the detection
probe to release free detectable label when the detection probe is
hybridized to the nucleic acid; and
[0053] measuring free detectable label, wherein the presence of the
free detectable label indicates that the detection probe
specifically hybridizes to the first segment of the nucleic acid,
and indicates the sequence of the polymorphic site as the
complement of the detection probe. The copies of the nucleic acid
are preferably provided by amplification by Polymerase Chain
Reaction (PCR).
[0054] Another aspect relates to a method of assessing an
individual for probability of response to a therapeutic agent for
preventing and/or ameliorating symptoms associated with cancer,
comprising: determining the presence or absence of at least one
allele of at least one polymorphic marker in a nucleic acid sample
obtained from the individual, wherein the at least one polymorphic
marker is selected from the group consisting of the polymorphic
markers set forth in Table 3 and Table 4, and markers in linkage
disequilibrium therewith, wherein the presence of the at least one
allele of the at least one marker is indicative of a probability of
a positive response to a cancer therapeutic agent.
[0055] Another aspect relates to a method of predicting prognosis
of an individual diagnosed with a cancer selected from prostate
cancer and colorectal cancer, the method comprising determining the
presence or absence of at least one allele of at least one
polymorphic marker in a nucleic acid sample obtained from the
individual, wherein the at least one polymorphic marker is selected
from the group consisting of the polymorphic markers listed in
Table 3 and Table 4, and markers in linkage disequilibrium
therewith, wherein the presence of the at least one allele is
indicative of a worse prognosis of the cancer in the
individual.
[0056] Yet another aspect relates to a method of monitoring
progress of a treatment of an individual undergoing treatment for a
cancer selected from prostate cancer and colorectal cancer, the
method comprising determining the presence or absence of at least
one allele of at least one polymorphic marker in a nucleic acid
sample obtained from the individual, wherein the at least one
polymorphic marker is selected from the group consisting of the
polymorphic markers listed in Table 3 and Table 4, and markers in
linkage disequilibrium therewith, wherein the presence of the at
least one allele is indicative of the treatment outcome of the
individual.
[0057] The invention in another aspect relates to a kit for
assessing susceptibility to a cancer selected from prostate cancer
and colorectal cancer in a human individual, the kit comprising
reagents for selectively detecting at least one allele of at least
one polymorphic marker in the genome of the individual, wherein the
polymorphic marker is selected from the group consisting of the
polymorphic markers set forth in Table 5 and Table 6, and markers
in linkage disequilibrium therewith, and a collection of data
comprising correlation data between the polymorphic markers
assessed by the kit and susceptibility to prostate cancer and/or
colorectal cancer. In one embodiment, the reagents comprise at
least one contiguous oligonucleotide that hybridizes to a fragment
of the genome of the individual comprising the at least one
polymorphic marker, a buffer and a detectable label. In another
embodiment, the reagents comprise at least one pair of
oligonucleotides that hybridize to opposite strands of a genomic
nucleic acid segment obtained from the subject, wherein each
oligonucleotide primer pair is designed to selectively amplify a
fragment of the genome of the individual that includes one
polymorphic marker, and wherein the fragment is at least 30 base
pairs in size. In yet another embodiment, the at least one
oligonucleotide is completely complementary to the genome of the
individual. In one embodiment, the oligonucleotide is about 18 to
about 50 nucleotides in length. In another embodiment, the
oligonucleotide is 20-30 nucleotides in length.
[0058] In one preferred embodiment, the kit comprises:
[0059] a detection oligonucleotide probe that is from 5-100
nucleotides in length;
[0060] an enhancer oligonucleotide probe that is from 5-100
nucleotides in length; and
[0061] an endonuclease enzyme;
[0062] wherein the detection oligonucleotide probe specifically
hybridizes to a first segment of the nucleic acid whose nucleotide
sequence is given by SEQ ID NO: 201 that comprises at least one
polymorphic site; and
[0063] wherein the detection oligonucleotide probe comprises a
detectable label at its 3' terminus and a quenching moiety at its
5' terminus;
[0064] wherein the enhancer oligonucleotide is from 5-100
nucleotides in length and is complementary to a second segment of
the nucleotide sequence that is 5' relative to the oligonucleotide
probe, such that the enhancer oligonucleotide is located 3'
relative to the detection oligonucleotide probe when both
oligonucleotides are hybridized to the nucleic acid;
[0065] wherein a single base gap exists between the first segment
and the second segment, such that when the oligonucleotide probe
and the enhancer oligonucleotide probe are both hybridized to the
nucleic acid, a single base gap exists between the
oligonucleotides; and
[0066] wherein treating the nucleic acid with the endonuclease will
cleave the detectable label from the 3' terminus of the detection
probe to release free detectable label when the detection probe is
hybridized to the nucleic acid.
[0067] Another aspect of the invention relates to the use of an
oligonucleotide probe in the manufacture of a diagnostic reagent
for diagnosing and/or assessing susceptibility to a cancer selected
from prostate cancer and colorectal cancer in a human individual,
wherein the probe hybridizes to a segment of a nucleic acid within
LD Block C06 or LD Block C11 that comprises at least one
polymorphic site, wherein the fragment is 15-500 nucleotides in
length.
[0068] The invention also provides computer-implemented aspects. In
one such aspect, the invention provides a computer-readable medium
having computer executable instructions for determining
susceptibility to a cancer selected from prostate cancer and
colorectal cancer in an individual, the computer readable medium
comprising: data representing at least one polymorphic marker; and
a routine stored on the computer readable medium and adapted to be
executed by a processor to determine susceptibility to the cancer
in an individual based on the allelic status of at least one allele
of said at least one polymorphic marker in the individual.
[0069] In one embodiment, said data representing at least one
polymorphic marker comprises at least one parameter indicative of
the susceptibility to the cancer linked to said at least one
polymorphic marker. In another embodiment, said data representing
at least one polymorphic marker comprises data indicative of the
allelic status of at least one allele of said at least one allelic
marker in said individual. In another embodiment, said routine is
adapted to receive input data indicative of the allelic status for
at least one allele of said at least one allelic marker in said
individual. In a preferred embodiment, the at least one marker is
selected from rs10896450 and rs10943605, and markers in linkage
disequilibrium therewith. In another preferred embodiment, the at
least one polymorphic marker is selected from the markers set forth
in Table 3 and Table 4.
[0070] The invention further provides an apparatus for determining
a genetic indicator for a cancer selected from prostate cancer and
colorectal cancer in a human individual, comprising:
[0071] a processor,
[0072] a computer readable memory having computer executable
instructions adapted to be executed on the processor to analyze
marker and/or haplotype information for at least one human
individual with respect to a cancer selected from prostate cancer
and colorectal cancer, and
[0073] generate an output based on the marker or haplotype
information, wherein the output comprises a risk measure of the at
least one marker or haplotype as a genetic indicator of the cancer
for the human individual.
[0074] In one embodiment, the computer readable memory comprises
data indicative of the frequency of at least one allele of at least
one polymorphic marker or at least one haplotype in a plurality of
individuals diagnosed with prostate cancer and/or colorectal
cancer, and data indicative of the frequency of at the least one
allele of at least one polymorphic marker or at least one haplotype
in a plurality of reference individuals, and wherein a risk measure
is based on a comparison of the at least one marker and/or
haplotype status for the human individual to the data indicative of
the frequency of the at least one marker and/or haplotype
information for the plurality of individuals diagnosed with the
cancer. In one embodiment, the computer readable memory further
comprises data indicative of a risk of developing prostate cancer
and/or colorectal cancer associated with at least one allele of at
least one polymorphic marker or at least one haplotype, and wherein
a risk measure for the human individual is based on a comparison of
the at least one marker and/or haplotype status for the human
individual to the risk associated with the at least one allele of
the at least one polymorphic marker or the at least one haplotype.
In another embodiment, the computer readable memory further
comprises data indicative of the frequency of at least one allele
of at least one polymorphic marker or at least one haplotype in a
plurality of individuals diagnosed with a cancer selected from
prostate cancer and colorectal cancer, and data indicative of the
frequency of at the least one allele of at least one polymorphic
marker or at least one haplotype in a plurality of reference
individuals, and wherein risk of developing the cancer is based on
a comparison of the frequency of the at least one allele or
haplotype in individuals diagnosed with the cancer, and reference
individuals. In a preferred embodiment, the at least one marker is
selected from rs10943605 and rs10896450, and markers in linkage
disequilibrium therewith. In another preferred embodiment, the at
least one polymorphic marker is selected from the markers set forth
in Table 3 and Table 4.
[0075] Different embodiments of the various aspects of the
invention relate to specific use of the polymorphic variants
described herein to be associated with prostate cancer and
colorectal cancer, or variants (polymorphic markers) in linkage
disequilibrium therewith. In one embodiment of the invention, the
at least one marker is selected from the markers within LD Block
C06 and/or LD Block C11, as defined herein, and markers in linkage
disequilibrium therewith. In one such embodiment, the at least one
marker is selected from markers within LD Block C06 and/or LD Block
C11. In one embodiment, the at least one polymorphic marker is
selected from the markers set forth in Table 5 and Table 6. In
another embodiment, the at least one polymorphic marker comprises
at least one marker selected from the group of markers set forth in
Table 3 and Table 4, and markers in linkage disequilibrium
therewith. One embodiment relates to at least one marker selected
from the group consisting of marker rs10896450, marker rs11228565,
marker rs7947353 and marker rs10943605, and markers in linkage
disequilibrium therewith. One embodiment relates to marker
rs10896450, and markers in linkage disequilibrium therewith. One
embodiment relates to marker rs11228565, and markers in linkage
disequilibrium therewith. One embodiment relates to marker
rs10943605, and markers in linkage disequilibrium therewith. One
embodiment relates to marker rs10896450. Another embodiment relates
to marker rs11228565. Another embodiment relates to marker
rs10943605. In certain embodiments, the cancer assessed by the
invention is prostate cancer. In certain other embodiments, the
cancer is colorectal cancer. In one such embodiment, the at least
one polymorphic marker is selected from the group of markers set
forth in Table 3. In another embodiment, the marker is rs10943605,
and markers in linkage disequilibrium therewith.
[0076] Some embodiments of the invention, further comprise
assessing the frequency of at least one haplotype in the
individual.
[0077] The methods of the invention comprise, in some embodiments,
an additional step of assessing at least one biomarker in a sample
from the individual. The sample can be a blood sample or a cancer
biopsy sample, or any other biological sample derived from an
individual that is suitable for assessing the presence or absence,
or for quantitative determination, of at least one biomarker. The
biomarker is preferably a biological molecule that represents
directly or indirectly the disease state in question, i.e. prostate
cancer or colorectal cancer. An exemplary biomarker is PSA. Other
embodiments of the methods of the invention further comprise
analyzing non-genetic information to make risk assessment,
diagnosis, or prognosis of the individual. The non-genetic
information is in some embodiments selected from age, gender,
ethnicity, socioeconomic status, previous disease diagnosis,
medical history of subject, family history of cancer, biochemical
measurements, and clinical measurements.
[0078] Other genetic risk factors for cancer, e.g., prostate cancer
and/or colorectal cancer, can be assessed in combination with the
markers of the present invention found to be predictive of these
cancers, for providing overall risk assessment of prostate cancer
and/or colorectal cancer. Thus, in one embodiment, the methods of
the invention relate to further steps comprising assessing the
presence of absence of at least one additional genetic risk factor
for prostate cancer or colorectal cancer in the individual. In
certain embodiments, the additional genetic risk factor is not
associated, defined by values of r.sup.2 of at least 0.2 and/or
values of |D'| of at least 0.8, to markers set forth in Tables 3
and 4, in particular marker rs10896450, marker rs11228565, marker
rs7947353 and marker rs10943605. Such additional risk factor are in
certain embodiments risk factors for a particular type of cancer,
i.e. cancer at a particular site (e.g., prostate cancer and/or
colorectal cancer). In certain other embodiments, such additional
risk factors are susceptibility variants for multiple forms of
cancer.
[0079] Thus, in certain embodiments, a further step is included,
comprising determining whether at least one at-risk allele of at
least one at-risk variant for a cancer selected from prostate
cancer and colorectal cancer not in linkage disequilibrium with any
one of the markers rs10896450, rs11228565, rs7947353 and rs10943605
are present in a sample comprising genomic DNA from a human
individual or a genotype dataset derived from a human individual.
In other words, genetic markers in other locations in the genome
can be useful in combination with the markers of the present
invention, so as to determine overall risk of the cancer based on
multiple genetic variants. In one embodiment, the at least one
at-risk variant for cancer is not in linkage disequilibrium with
marker rs10896450. Selection of markers that are not in linkage
disequilibrium (not in LD) can be based on a suitable measure for
linkage disequilibrium, as described further herein. In certain
embodiments, markers that are not in linkage disequilibrium have
values for the LD measure r.sup.2 correlating the markers of less
than 0.2. In certain other embodiments, markers that are not in LD
have values for r.sup.2 correlating the markers of less than 0.15,
including less than 0.10, less than 0.05, less than 0.02 and less
than 0.01. Other suitable numerical values for establishing that
markers are not in LD are contemplated, including values bridging
any of the above-mentioned values.
[0080] The risk factors are in one embodiment selected from
rs1447295, rs4430796, rs1859962, rs5945572, rs6983267, rs16901979
and rs10505483, and markers in linkage disequilibrium therewith. In
another embodiment, the additional genetic risk factor is selected
from the group consisting of rs2710646 allele A, rs16901979 allele
A, rs1447295 allele A, rs6983267 allele G, rs10896450 allele G,
rs1859962 allele G, rs4430796 allele A and rs5945572 allele A. In
other embodiments, the additional genetic risk factor is selected
from markers in linkage disequilibrium with any of the markers
rs2710646, rs16901979, rs1447295, rs6983267, rs10896450, rs1859962,
rs4430796 and rs5945572. An overall risk for prostate cancer and/or
colon cancer is in one embodiment calculated based on the genotype
status of the individual.
[0081] In certain embodiments, the susceptibility is increased
susceptibility. Increased susceptibility is in certain embodiments
accompanied by an odds ratio (OR) or relative risk (RR) of at least
1.10. In other embodiments, the odds ratio or relative risk is at
least 1.15. In other embodiments, the relative risk or odds ratio
is at least 1.20. In one embodiment, the at least one marker or
haplotype comprises marker rs10896450 allele G, marker rs7947353
allele A and marker rs10943605 allele G.
[0082] In certain other embodiments, the susceptibility is
decreased susceptibility. The decreased susceptibility is in some
embodiments accompanied by a relative risk or odds ratio of less
than 0.9.
[0083] Certain embodiments of the invention relate to aggressive
forms of prostate cancer. In some embodiments, the prostate cancer
is an aggressive prostate cancer as defined by a combined Gleason
score of 7(4+3)-10. In other embodiments, the prostate cancer is a
less aggressive prostate cancer as defined by a combined Gleason
score of 2-7(3+4).
[0084] In certain embodiments of the invention, the individual is
of a specific ancestry. One embodiment relates to the ancestry
being Caucasian ancestry. In other embodiments, the ancestry is
African ancestry or African American ancestry. In another
embodiment, the ancestry is European ancestry. The ancestry is in
some embodiment self-reported. In other embodiments, the ancestry
is determined by detecting at least one allele of at least one
polymorphic marker in a sample from the individual, wherein the
presence or absence of the allele is indicative of the ancestry of
the individual.
[0085] In certain embodiments of the invention, linkage
disequilibrium is determined using the linkage disequilibrium
measures r.sup.2 and |D'|, which give a quantitative measure of the
extent of linkage disequilibrium (LD) between two genetic element
(e.g., polymorphic markers). Certain numerical values of these
measures for particular markers are indicative of the markers being
in linkage disequilibrium, as described further herein. The higher
the numerical value for the LD measures r.sup.2 and |D'|, the
stronger the LD between the genetic elements is, as further
described herein. In one embodiment of the invention, linkage
disequilibrium between marker (i.e., LD values indicative of the
markers being in linkage disequilibrium) is defined as
r.sup.2>0.1. In another embodiment, linkage disequilibrium is
defined as r.sup.2>0.2. Other embodiments can include other
definitions of linkage disequilibrium, such as r.sup.2>0.25,
r.sup.2>0.3, r.sup.2>0.35, r.sup.2>0.4, r.sup.2>0.45,
r.sup.2>0.5, r.sup.2>0.55, r.sup.2>0.6, r.sup.2>0.65,
r.sup.2>0.7, r.sup.2>0.75, r.sup.2>0.8, r.sup.2>0.85,
r.sup.2>0.9, r.sup.2>0.95, r.sup.2>0.96, r.sup.2>0.97,
r.sup.2>0.98, or r.sup.2>0.99. Linkage disequilibrium can in
certain embodiments also be defined as |D'|>0.2, or as
|D'|>0.3, |D'|>0.4, |D'|>0.5, |D'|>0.6, |D'|>0.7,
|D'|>0.8, |D'|>0.9, |D'|>0.95, |D'|>0.98 or
|D'|>0.99. In certain embodiments, linkage disequilibrium is
defined as fulfilling two criteria of r.sup.2 and |D'|, such as
r.sup.2>0.2 and/or |D'|>0.8. Other combinations of values for
r.sup.2 and |D'| are also possible and within scope of the present
invention, including but not limited to the values for these
parameters set forth in the above.
[0086] It should be understood that all combinations of features
described herein are contemplated, even if the combination of
feature is not specifically found in the same sentence or paragraph
herein. This includes, but is not limited to, the use of all
markers disclosed herein, alone or in combination, for analysis
individually or in haplotypes, in all aspects of the invention as
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0087] The foregoing and other objects, features and advantages of
the invention will be apparent from the following more particular
description of preferred embodiments of the invention.
[0088] The FIGURE provides a diagram illustrating a
computer-implemented system utilizing risk variants as described
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0089] The present invention discloses polymorphic variants and
haplotypes that have been found to be associated with prostate and
colorectal cancer. Such markers and haplotypes are useful for
diagnostic purposes, as described in further detail herein.
DEFINITIONS
[0090] Unless otherwise indicated, nucleic acid sequences are
written left to right in a 5' to 3' orientation. Numeric ranges
recited within the specification are inclusive of the numbers
defining the range and include each integer or any non-integer
fraction within the defined range. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by the ordinary person skilled in the art to
which the invention pertains.
[0091] The following terms shall, in the present context, have the
meaning as indicated:
[0092] A "polymorphic marker", sometimes referred to as a "marker",
as described herein, refers to a genomic polymorphic site. Each
polymorphic marker has at least two sequence variations
characteristic of particular alleles at the polymorphic site. Thus,
genetic association to a polymorphic marker implies that there is
association to at least one specific allele of that particular
polymorphic marker. The marker can comprise any allele of any
variant type found in the genome, including SNPs, mini- or
microsatellites, translocations and copy number variations
(insertions, deletions, duplications). Polymorphic markers can be
of any measurable frequency in the population. For mapping of
disease genes, polymorphic markers with population frequency higher
than 5-10% are in general most useful. However, polymorphic markers
may also have lower population frequencies, such as 1-5% frequency,
or even lower frequency, in particular copy number variations
(CNVs). The term shall, in the present context, be taken to include
polymorphic markers with any population frequency.
[0093] An "allele" refers to the nucleotide sequence of a given
locus (position) on a chromosome. A polymorphic marker allele thus
refers to the composition (i.e., sequence) of the marker on a
chromosome. Genomic DNA from an individual contains two alleles for
any given polymorphic marker, representative of each copy of the
marker on each chromosome. Sequence codes for nucleotides used
herein are: A=1, C=2, G=3, T=4. For microsatellite alleles, the
CEPH sample (Centre d'Etudes du Polymorphisme Humain, genomics
repository, CEPH sample 1347-02) is used as a reference, the
shorter allele of each microsatellite in this sample is set as 0
and all other alleles in other samples are numbered in relation to
this reference. Thus, e.g., allele 1 is 1 bp longer than the
shorter allele in the CEPH sample, allele 2 is 2 bp longer than the
shorter allele in the CEPH sample, allele 3 is 3 bp longer than the
lower allele in the CEPH sample, etc., and allele -1 is 1 bp
shorter than the shorter allele in the CEPH sample, allele -2 is 2
bp shorter than the shorter allele in the CEPH sample, etc.
[0094] Sequence conucleotide ambiguity as described herein is as
proposed by IUPAC-IUB. These codes are compatible with the codes
used by the EMBL, GenBank, and PIR databases.
TABLE-US-00001 IUB code Meaning A Adenosine C Cytidine G Guanine T
Thymidine R G or A Y T or C K G or T M A or C S G or C W A or T B
C, G or T D A, G or T H A, C or T V A, C or G N A, C, G or T (Any
base)
[0095] A nucleotide position at which more than one sequence is
possible in a population (either a natural population or a
synthetic population, e.g., a library of synthetic molecules) is
referred to herein as a "polymorphic site".
[0096] A "Single Nucleotide Polymorphism" or "SNP" is a DNA
sequence variation occurring when a single nucleotide at a specific
location in the genome differs between members of a species or
between paired chromosomes in an individual. Most SNP polymorphisms
have two alleles. Each individual is in this instance either
homozygous for one allele of the polymorphism (i.e. both
chromosomal copies of the individual have the same nucleotide at
the SNP location), or the individual is heterozygous (i.e. the two
sister chromosomes of the individual contain different
nucleotides). The SNP nomenclature as reported herein refers to the
official Reference SNP (rs) ID identification tag as assigned to
each unique SNP by the National Center for Biotechnological
Information (NCBI).
[0097] A "variant", as described herein, refers to a segment of DNA
that differs from the reference DNA. A "marker" or a "polymorphic
marker", as defined herein, is a variant. Alleles that differ from
the reference are referred to as "variant" alleles.
[0098] A "microsatellite" is a polymorphic marker that has multiple
small repeats of bases that are 2-8 nucleotides in length (such as
CA repeats) at a particular site, in which the number of repeat
lengths varies in the general population.
[0099] An "indel" is a common form of polymorphism comprising a
small insertion or deletion that is typically only a few
nucleotides long.
[0100] A "haplotype," as described herein, refers to a segment of
genomic DNA within one strand of DNA that is characterized by a
specific combination of alleles arranged along the segment. For
diploid organisms such as humans, a haplotype comprises one member
of the pair of alleles for each polymorphic marker or locus along
the segment. In a certain embodiment, the haplotype can comprise
two or more alleles, three or more alleles, four or more alleles,
or five or more alleles. Haplotypes are described herein in the
context of the marker name and the allele of the marker in that
haplotype, e.g., "3 rs10896450" refers to the 3 allele of marker
rs10896450 being in the haplotype, and is equivalent to "rs10896450
allele 3". Furthermore, allelic codes in haplotypes are as for
individual markers, i.e. 1=A, 2=C, 3=G and 4=T.
[0101] The term "susceptibility", as described herein, encompasses
both increased susceptibility and decreased susceptibility. Thus,
particular polymorphic markers and/or haplotypes of the invention
may be characteristic of increased susceptibility (i.e., increased
risk) of prostate cancer, as characterized by a relative risk (RR)
or odds ratio (OR) of greater than one for the particular allele or
haplotype. Alternatively, the markers and/or haplotypes of the
invention are characteristic of decreased susceptibility (i.e.,
decreased risk) of prostate cancer, as characterized by a relative
risk of less than one.
[0102] The term "and/or" shall in the present context be understood
to indicate that either or both of the items connected by it are
involved. In other words, the term herein shall be taken to mean
"one or the other or both".
[0103] The term "look-up table", as described herein, is a table
that correlates one form of data to another form, or one or more
forms of data to a predicted outcome to which the data is relevant,
such as phenotype or trait. For example, a look-up table can
comprise a correlation between allelic data for at least one
polymorphic marker and a particular trait or phenotype, such as a
particular disease diagnosis, that an individual who comprises the
particular allelic data is likely to display, or is more likely to
display than individuals who do not comprise the particular allelic
data. Look-up tables can be multidimensional, i.e. they can contain
information about multiple alleles for single markers
simultaneously, or the can contain information about multiple
markers, and they may also comprise other factors, such as
particulars about diseases diagnoses, racial information,
biomarkers, biochemical measurements, therapeutic methods or drugs,
etc.
[0104] A "computer-readable medium", is an information storage
medium that can be accessed by a computer using a commercially
available or custom-made interface. Exemplary compute-readable
media include memory (e.g., RAM, ROM, flash memory, etc.), optical
storage media (e.g., CD-ROM), magnetic storage media (e.g.,
computer hard drives, floppy disks, etc.), punch cards, or other
commercially available media. Information may be transferred
between a system of interest and a medium, between computers, or
between computers and the computer-readable medium for storage or
access of stored information. Such transmission can be electrical,
or by other available methods, such as IR links, wireless
connections, etc.
[0105] A "nucleic acid sample", as described herein, refer to a
sample obtained from an individual that contains nucleic acid (DNA
or RNA). In certain embodiments, i.e. the detection of specific
polymorphic markers and/or haplotypes, the nucleic acid sample
comprises genomic DNA. Such a nucleic acid sample can be obtained
from any source that contains genomic DNA, including as a blood
sample, sample of amniotic fluid, sample of cerebrospinal fluid, or
tissue sample from skin, muscle, buccal or conjunctival mucosa,
placenta, gastrointestinal tract or other organs.
[0106] The term "prostate cancer therapeutic agent" and "colorectal
cancer therapeutic agent", as described herein, refers to an agent
that can be used to ameliorate or prevent symptoms associated with
prostate cancer and colorectal cancer, respectively.
[0107] The term "prostate cancer-associated nucleic acid" and
"colorectal cancer-associated nucleic acid", as described herein,
refers to a nucleic acid that has been found to be associated to
prostate and/or colorectal cancer. This includes, but is not
limited to, the markers and haplotypes described herein and markers
and haplotypes in strong linkage disequilibrium (LD) therewith. In
one embodiment, a prostate and/or colon cancer-associated nucleic
acid refers to an LD-block found to be associated with prostate
and/or colorectal cancer through at least one polymorphic marker
located within the LD block C06 or associated with the LD block
C11.
[0108] "Aggressive prostate cancer", as described herein, refers to
prostate cancer with combined Gleason grades of 7 or higher OR
stage T3 or higher OR node positive OR metastasis positive disease
OR death because of prostate cancer. Note that it is sufficient to
have one of these criteria to be determined aggressive prostate
cancer. These clinical parameters are well known surrogates for
increased aggressiveness of the disease.
[0109] The term "LD block 06", as described herein, refers to the
Linkage Disequilibrium (LD) block on Chromosome 6 between positions
79,300,773 and 79,917,888 of NCBI (National Center for
Biotechnology Information) Build 36, spanning the region flanked by
the SNP markers rs611737 and rs9294130.
[0110] The term "LD block C11", as described herein, refers to the
Linkage Disequilibrium (LD) block on Chromosome 11 between
positions 68,709,630 and 68,782,375 of NCBI (National Center for
Biotechnology Information) Build 36, spanning the region flanked by
the SNP markers rs7128814 and rs3884627. The LD block C11 has the
sequence as set forth in SEQ ID NO:201 herein, based on NCBI Build
36 of the human genome sequence assembly.
[0111] A genome-wide search for variants associated with prostate
and/or colorectal cancer has identified two genomic regions
associated with these cancers. Markers rs10896450 and rs7947353 on
Chr 11q13.3, within a region herein called LD Block C11, were
identified as contributing to risk of prostate cancer (see Table
1). The two markers are fully correlated (D'=1 and r.sup.2=1; see
footnote of Table 1) and do therefore essentially represent the
same association signal. The G allele of SNP marker rs10896450
confers increased risk of prostate cancer, with an odds ratio (OR)
of 1.17 in the Icelandic samples (P=6.6.times.10.sup.-5). The
initial discovery in an Icelandic prostate cancer cohort was
validated by analysis of marker rs7947353, which is perfectly
correlated (i.e., a perfect surrogate marker) to rs10896450, in
prostate cancer cohorts from the Netherlands, Spain and US
(Chicago, Ill.). The results for these additional cohorts are
comparable to the results for the Icelandic discovery cohort,
showing that the initial observation represents a true association
signal. Overall, the association is significant with a p-value of
1.43.times.10.sup.-6.
[0112] A follow-up analysis revealed that marker rs11228565,
located within LD Block C11, shows that this marker associated very
significantly with prostate cancer, with an OR of 1.23 for all
cohorts and an overall P-value of 6.7.times.10.sup.-12 (Table
7).
[0113] A second region on Chromosome 6 (LD Block C06) was
identified as a prostate cancer susceptibility region, as shown in
Table 2a. The association of the G allele of the rs10943605 SNP
marker observed in the Icelandic cohort was replicated in Dutch and
Spanish cohort, both which gave increased risk conferred by the G
allele, although only the replication in the Dutch cohort is
statistically significant. Surprisingly, the G allele of the
rs10943605 SNP marker was also found to be associated with
increased risk of developing colorectal cancer, with an OR of 1.14
in the Icelandic colorectal cancer samples (P=4.8.times.10.sup.-3)
(Table 2b).
[0114] Accordingly, the present invention provides methods for
determining a susceptibility to prostate cancer and colorectal
cancer, by assessing for the presence or absence of particular
alleles of polymorphic markers within the LD Block C06 and/or LD
Block C11 genomic segments that are indicative of risk of prostate
cancer and colorectal cancer. Determination of the presence of such
marker alleles is indicative of risk of prostate cancer and/or
colorectal cancer in the individual.
[0115] Assessment for Markers and Haplotypes
[0116] The genomic sequence within populations is not identical
when individuals are compared. Rather, the genome exhibits sequence
variability between individuals at many locations in the genome.
Such variations in sequence are commonly referred to as
polymorphisms, and there are many such sites within each genome For
example, the human genome exhibits sequence variations which occur
on average every 500 base pairs. The most common sequence variant
consists of base variations at a single base position in the
genome, and such sequence variants, or polymorphisms, are commonly
called Single Nucleotide Polymorphisms ("SNPs"). These SNPs are
believed to have occurred in a single mutational event, and
therefore there are usually two possible alleles possible at each
SNP site; the original allele and the mutated allele. Due to
natural genetic drift and possibly also selective pressure, the
original mutation has resulted in a polymorphism characterized by a
particular frequency of its alleles in any given population. Many
other types of sequence variants are found in the human genome,
including mini- and microsatellites, and insertions, deletions and
inversions (also called copy number variations (CNVs)). A
polymorphic microsatellite has multiple small repeats of bases
(such as CA repeats, TG on the complimentary strand) at a
particular site in which the number of repeat lengths varies in the
general population. In general terms, each version of the sequence
with respect to the polymorphic site represents a specific allele
of the polymorphic site. These sequence variants can all be
referred to as polymorphisms, occurring at specific polymorphic
sites characteristic of the sequence variant in question. In
general terms, polymorphisms can comprise any number of specific
alleles. Thus in one embodiment of the invention, the polymorphism
is characterized by the presence of two or more alleles in any
given population. In another embodiment, the polymorphism is
characterized by the presence of three or more alleles. In other
embodiments, the polymorphism is characterized by four or more
alleles, five or more alleles, six or more alleles, seven or more
alleles, nine or more alleles, or ten or more alleles. All such
polymorphisms can be utilized in the methods and kits of the
present invention, and are thus within the scope of the
invention.
[0117] Due to their abundance, SNPs account for a majority of
sequence variation in the human genome. Over 6 million SNPs have
been validated to date
(ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi). However, CNVs are
receiving increased attention. These large-scale polymorphisms
(typically 1 kb or larger) account for polymorphic variation
affecting a substantial proportion of the assembled human genome;
known CNVs cover over 15% of the human genome sequence (Estivill,
X., Armengol; L., PloS Genetics 3:1787-99 (2007). A
http://projects.tcag.ca/variation/). Most of these polymorphisms
are however very rare, and on average affect only a fraction of the
genomic sequence of each individual. CNVs are known to affect gene
expression, phenotypic variation and adaptation by disrupting gene
dosage, and are also known to cause disease (microdeletion and
microduplication disorders) and confer risk of common complex
diseases, including HIV-1 infection and glomerulonephritis (Redon,
R., et al. Nature 23:444-454 (2006)). It is thus possible that
either previously described or unknown CNVs represent causative
variants in linkage disequilibrium with the markers described
herein to be associated with prostate and colorectal cancer.
Methods for detecting CNVs include comparative genomic
hybridization (CGH) and genotyping, including use of genotyping
arrays, as described by Carter (Nature Genetics 39:S16-S21 (2007)).
The Database of Genomic Variants
(http://projects.tcag.ca/variation/) contains updated information
about the location, type and size of described CNVs. The database
currently contains data for over 15,000 CNVs.
[0118] In some instances, reference is made to different alleles at
a polymorphic site without choosing a reference allele.
Alternatively, a reference sequence can be referred to for a
particular polymorphic site. The reference allele is sometimes
referred to as the "wild-type" allele and it usually is chosen as
either the first sequenced allele or as the allele from a
"non-affected" individual (e.g., an individual that does not
display a trait or disease phenotype).
[0119] Alleles for SNP markers as referred to herein refer to the
bases A, C, G or T as they occur at the polymorphic site in the SNP
assay employed. The allele codes for SNPs used herein are as
follows: 1=A, 2=C, 3=G, 4=T. The person skilled in the art will
however realise that by assaying or reading the opposite DNA
strand, the complementary allele can in each case be measured.
Thus, for a polymorphic site (polymorphic marker) characterized by
an A/G polymorphism, the assay employed may be designed to
specifically detect the presence of one or both of the two bases
possible, e.g. A and G. Alternatively, by designing an assay that
is designed to detect the complimentary strand on the DNA template,
the presence of the complementary bases T and C can be measured.
Quantitatively (for example, in terms of risk estimates), identical
results would be obtained from measurement of either DNA strand (+
strand or - strand).
[0120] Typically, a reference sequence is referred to for a
particular sequence. Alleles that differ from the reference are
sometimes referred to as "variant" alleles. A variant sequence, as
used herein, refers to a sequence that differs from the reference
sequence but is otherwise substantially similar. Alleles at the
polymorphic genetic markers described herein are variants.
Additional variants can include changes that affect a polypeptide.
Sequence differences, when compared to a reference nucleotide
sequence, can include the insertion or deletion of a single
nucleotide, or of more than one nucleotide, resulting in a frame
shift; the change of at least one nucleotide, resulting in a change
in the encoded amino acid; the change of at least one nucleotide,
resulting in the generation of a premature stop codon; the deletion
of several nucleotides, resulting in a deletion of one or more
amino acids encoded by the nucleotides; the insertion of one or
several nucleotides, such as by unequal recombination or gene
conversion, resulting in an interruption of the coding sequence of
a reading frame; duplication of all or a part of a sequence;
transposition; or a rearrangement of a nucleotide sequence. Such
sequence changes can alter the polypeptide encoded by the nucleic
acid. For example, if the change in the nucleic acid sequence
causes a frame shift, the frame shift can result in a change in the
encoded amino acids, and/or can result in the generation of a
premature stop codon, causing generation of a truncated
polypeptide. Alternatively, a polymorphism associated with a
disease or trait can be a synonymous change in one or more
nucleotides (i.e., a change that does not result in a change in the
amino acid sequence). Such a polymorphism can, for example, alter
splice sites, affect the stability or transport of mRNA, or
otherwise affect the transcription or translation of an encoded
polypeptide. It can also alter DNA to increase the possibility that
structural changes, such as amplifications or deletions, occur at
the somatic level. The polypeptide encoded by the reference
nucleotide sequence is the "reference" polypeptide with a
particular reference amino acid sequence, and polypeptides encoded
by variant alleles are referred to as "variant" polypeptides with
variant amino acid sequences.
[0121] A haplotype refers to a segment of DNA that is characterized
by a specific combination of alleles arranged along the segment.
For diploid organisms such as humans, a haplotype comprises one
member of the pair of alleles for each polymorphic marker or locus.
In a certain embodiment, the haplotype can comprise two or more
alleles, three or more alleles, four or more alleles, or five or
more alleles, each allele corresponding to a specific polymorphic
marker along the segment. Haplotypes can comprise a combination of
various polymorphic markers, e.g., SNPs and microsatellites, having
particular alleles at the polymorphic sites. The haplotypes thus
comprise a combination of alleles at various genetic markers.
[0122] Detecting specific polymorphic markers and/or haplotypes can
be accomplished by methods known in the art for detecting sequences
at polymorphic sites. For example, standard techniques for
genotyping for the presence of SNPs and/or microsatellite markers
can be used, such as fluorescence-based techniques (Chen, X. et
al., Genome Res. 9(5): 492-98 (1999); Kutyavin et al., Nucleic Acid
Res. 34:e128 (2006)), utilizing PCR, LCR, Nested PCR and other
techniques for nucleic acid amplification. Specific methodologies
available for SNP genotyping include, but are not limited to,
TaqMan genotyping assays and SNPlex platforms (Applied Biosystems),
mass spectrometry (e.g., MassARRAY system from Sequenom),
minisequencing methods, real-time PCR, Bio-Plex system (BioRad),
CEQ and SNPstream systems (Beckman), Molecular Inversion Probe
array technology (e.g., Affymetrix GeneChip), and BeadArray
Technologies (e.g., Illumina GoldenGate and Infinium assays). By
these or other methods available to the person skilled in the art,
one or more alleles at polymorphic markers, including
microsatellites, SNPs or other types of polymorphic markers, can be
identified.
[0123] In the present context, and individual who is at an
increased susceptibility (i.e., increased risk) for a disease, is
an individual in whom at least one specific allele at one or more
polymorphic marker or haplotype conferring increased susceptibility
(increased risk) for the disease is identified (i.e., at-risk
marker alleles or haplotypes). The at-risk marker or haplotype is
one that confers an increased risk (increased susceptibility) of
the disease. In one embodiment, significance associated with a
marker or haplotype is measured by a relative risk (RR). In another
embodiment, significance associated with a marker or haplotye is
measured by an odds ratio (OR). In a further embodiment, the
significance is measured by a percentage. In one embodiment, a
significant increased risk is measured as a risk (relative risk
and/or odds ratio) of at least 1.2, including but not limited to:
at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least
1.6, at least 1.7, 1.8, at least 1.9, at least 2.0, at least 2.5,
at least 3.0, at least 4.0, and at least 5.0. In a particular
embodiment, a risk (relative risk and/or odds ratio) of at least
1.2 is significant. In another particular embodiment, a risk of at
least 1.3 is significant. In yet another embodiment, a risk of at
least 1.4 is significant. In a further embodiment, a relative risk
of at least 1.5 is significant. In another further embodiment, a
significant increase in risk is at least 1.7 is significant.
However, other cutoffs are also contemplated, e.g., at least 1.15,
1.25, 1.35, and so on, and such cutoffs are also within scope of
the present invention. In other embodiments, a significant increase
in risk is at least about 20%, including but not limited to about
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 100%, 150%, 200%, 300%, and 500%. In one particular
embodiment, a significant increase in risk is at least 20%. In
other embodiments, a significant increase in risk is at least 30%,
at least 40%, at least 50%, at least 60%, at least 70%, at least
80%, at least 90% and at least 100%. Other cutoffs or ranges as
deemed suitable by the person skilled in the art to characterize
the invention are however also contemplated, and those are also
within scope of the present invention. In certain embodiments, a
significant increase in risk is characterized by a p-value, such as
a p-value of less than 0.05, less than 0.01, less than 0.001, less
than 0.0001, less than 0.00001, less than 0.000001, less than
0.0000001, less than 0.00000001, or less than 0.000000001.
[0124] An at-risk polymorphic marker or haplotype of the present
invention is one where at least one allele of at least one marker
or haplotype is more frequently present in an individual at risk
for the disease or trait (affected), compared to the frequency of
its presence in a comparison group (control), and wherein the
presence of the marker or haplotype is indicative of susceptibility
to the disease or trait. The control group may in one embodiment be
a population sample, i.e. a random sample from the general
population. In another embodiment, the control group is represented
by a group of individuals who are disease-free. Such disease-free
control may in one embodiment be characterized by the absence of
one or more specific disease-associated symptoms. In another
embodiment, the disease-free control group is characterized by the
absence of one or more disease-specific risk factors. Such risk
factors are in one embodiment at least one environmental risk
factor. Representative environmental factors are natural products,
minerals or other chemicals which are known to affect, or
contemplated to affect, the risk of developing the specific disease
or trait. Other environmental risk factors are risk factors related
to lifestyle, including but not limited to food and drink habits,
geographical location of main habitat, and occupational risk
factors. In another embodiment, the risk factors are at least one
genetic risk factor.
[0125] As an example of a simple test for correlation would be a
Fisher-exact test on a two by two table. Given a cohort of
chromosomes, the two by two table is constructed out of the number
of chromosomes that include both of the markers or haplotypes, one
of the markers or haplotypes but not the other and neither of the
markers or haplotypes.
[0126] In other embodiments of the invention, an individual who is
at a decreased susceptibility (i.e., at a decreased risk) for a
disease or trait is an individual in whom at least one specific
allele at one or more polymorphic marker or haplotype conferring
decreased susceptibility for the disease or trait is identified.
The marker alleles and/or haplotypes conferring decreased risk are
also said to be protective. In one aspect, the protective marker or
haplotype is one that confers a significant decreased risk (or
susceptibility) of the disease or trait. In one embodiment,
significant decreased risk is measured as a relative risk of less
than 0.9, including but not limited to less than 0.9, less than
0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4,
less than 0.3, less than 0.2 and less than 0.1. In one particular
embodiment, significant decreased risk is less than 0.7. In another
embodiment, significant decreased risk is less than 0.5. In yet
another embodiment, significant decreased risk is less than 0.3. In
another embodiment, the decrease in risk (or susceptibility) is at
least 20%, including but not limited to at least 25%, at least 30%,
at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95% and at least
98%. In one particular embodiment, a significant decrease in risk
is at least about 30%. In another embodiment, a significant
decrease in risk is at least about 50%. In another embodiment, the
decrease in risk is at least about 70%. Other cutoffs or ranges as
deemed suitable by the person skilled in the art to characterize
the invention are however also contemplated, and those are also
within scope of the present invention.
[0127] The person skilled in the art will appreciate that for
markers with two alleles present in the population being studied
(such as SNPs), and wherein one allele is found in increased
frequency in a group of individuals with a trait or disease in the
population, compared with controls, the other allele of the marker
will be found in decreased frequency in the group of individuals
with the trait or disease, compared with controls. In such a case,
one allele of the marker (the one found in increased frequency in
individuals with the trait or disease) will be the at-risk allele,
while the other allele will be a protective allele.
[0128] A genetic variant associated with a disease or a trait can
be used alone to predict the risk of the disease for a given
genotype. For a biallelic marker, such as a SNP, there are 3
possible genotypes: homozygote for the at risk variant,
heterozygote, and non carrier of the at risk variant. Risk
associated with variants at multiple loci can be used to estimate
overall risk. For multiple SNP variants, there are k possible
genotypes k=3.sup.n.times.2.sup.p; where n is the number autosomal
loci and p the number of gonosomal (sex chromosomal) loci. Overall
risk assessment calculations for a plurality of risk variants
usually assume that the relative risks of different genetic
variants multiply, i.e. the overall risk (e.g., RR or OR)
associated with a particular genotype combination is the product of
the risk values for the genotype at each locus. If the risk
presented is the relative risk for a person, or a specific genotype
for a person, compared to a reference population with matched
gender and ethnicity, then the combined risk--is the product of the
locus specific risk values--and which also corresponds to an
overall risk estimate compared with the population. If the risk for
a person is based on a comparison to non-carriers of the at risk
allele, then the combined risk corresponds to an estimate that
compares the person with a given combination of genotypes at all
loci to a group of individuals who do not carry risk variants at
any of those loci. The group of non-carriers of any at risk variant
has the lowest estimated risk and has a combined risk, compared
with itself (i.e., non-carriers) of 1.0, but has an overall risk,
compare with the population, of less than 1.0. It should be noted
that the group of non-carriers can potentially be very small,
especially for large number of loci, and in that case, its
relevance is correspondingly small.
[0129] The multiplicative model is a parsimonious model that
usually fits the data of complex traits reasonably well. Deviations
from multiplicity have been rarely described in the context of
common variants for common diseases, and if reported are usually
only suggestive since very large sample sizes are usually required
to be able to demonstrate statistical interactions between
loci.
[0130] By way of an example, let us consider variants in eight
regions (loci) that have been described to associate with prostate
cancer (Gudmundsson, J., et al., Nat Genet 39:631-7 (2007),
Gudmundsson, J., et al., Nat Genet 39:977-83 (2007); Yeager, M., et
al, Nat Genet 39:645-49 (2007), Amundadottir, L., et al., Nat Genet
38:652-8 (2006); Haiman, C. A., et al., Nat Genet 39:638-44
(2007)). Seven of these loci are on autosomes, and the remaining
locus is on chromosome X. The total number of theoretical genotypic
combinations is then 3.sup.7.times.2.sup.1=4374. Some of those
genotypic classes are very rare, but are still possible, and should
be considered for overall risk assessment. It is likely that the
multiplicative model applied in the case of multiple genetic
variant will also be valid in conjugation with non-genetic risk
variants assuming that the genetic variant does not clearly
correlate with the "environmental" factor. In other words, genetic
and non-genetic at-risk variants can be assessed under the
multiplicative model to estimate combined risk, assuming that the
non-genetic and genetic risk factors do not interact.
[0131] Accordingly, in certain embodiments, therefore, the markers
shown herein to be predictive of risk of prostate cancer in humans
can be used in combination with any one, or a combination of,
rs2710646 allele A, rs16901979 allele A, rs1447295 allele A,
rs6983267 allele G, rs10896450 allele G, rs1859962 allele G,
rs4430796 allele A and rs5945572 allele A. In a preferred
embodiment, the at-risk markers for prostate cancer as described
herein are assessed together with rs2710646 allele A, rs 16901979
allele A, rs1447295 allele A, rs6983267 allele G, rs10896450 allele
G, rs1859962 allele G, rs4430796 allele A and rs5945572 allele A to
determine overall risk of prostate cancer in an individual.
[0132] The skilled person will realize that the markers presented
herein may also be assessed in combination with any other genetic
risk factors for prostate cancer and/or colorectal cancer, so as to
determine overall risk of the cancer in an individual.
[0133] Linkage Disequilibrium
[0134] The natural phenomenon of recombination, which occurs on
average once for each chromosomal pair during each meiotic event,
represents one way in which nature provides variations in sequence
(and biological function by consequence). It has been discovered
that recombination does not occur randombly in the genome; rather,
there are large variations in the frequency of recombination rates,
resulting in small regions of high recombination frequency (also
called recombination hotspots) and larger regions of low
recombination frequency, which are commonly referred to as Linkage
Disequilibrium (LD) blocks (Myers, S. et al., Biochem Soc Trans
34:526-530 (2006); Jeffreys, A. J., et al., Nature Genet.
29:217-222 (2001); May, C. A., et al., Nature Genet. 31:272-275
(2002)).
[0135] Linkage Disequilibrium (LD) refers to a non-random
assortment of two genetic elements. For example, if a particular
genetic element (e.g., an allele of a polymorphic marker, or a
haplotype) occurs in a population at a frequency of 0.50 (50%) and
another element occurs at a frequency of 0.50 (50%), then the
predicted occurrance of a person's having both elements is 0.25
(25%), assuming a random distribution of the elements. However, if
it is discovered that the two elements occur together at a
frequency higher than 0.25, then the elements are said to be in
linkage disequilibrium, since they tend to be inherited together at
a higher rate than what their independent frequencies of occurrence
(e.g., allele or haplotype frequencies) would predict. Roughly
speaking, LD is generally correlated with the frequency of
recombination events between the two elements. Allele or haplotype
frequencies can be determined in a population by genotyping
individuals in a population and determining the frequency of the
occurence of each allele or haplotype in the population. For
populations of diploids, e.g., human populations, individuals will
typically have two alleles for each genetic element (e.g., a
marker, haplotype or gene).
[0136] Many different measures have been proposed for assessing the
strength of linkage disequilibrium (LD; reviewed in Devlin, B.
& Risch, N., Genomics 29:311-22 (1995))). Most capture the
strength of association between pairs of biallelic sites. Two
important pairwise measures of LD are r.sup.2 (sometimes denoted
.DELTA..sup.2) and |D'| (Lewontin, R., Genetics 49:49-67 (1964);
Hill, W. G. & Robertson, A. Theor. Appl. Genet. 22:226-231
(1968)). Both measures range from 0 (no disequilibrium) to 1
(`complete` disequilibrium), but their interpretation is slightly
different. |D'| is defined in such a way that it is equal to 1 if
just two or three of the possible haplotypes are present, and it is
<1 if all four possible haplotypes are present. Therefore, a
value of |D'| that is <1 indicates that historical recombination
may have occurred between two sites (recurrent mutation can also
cause |D'| to be <1, but for single nucleotide polymorphisms
(SNPs) this is usually regarded as being less likely than
recombination). The measure r.sup.2 represents the statistical
correlation between two sites, and takes the value of 1 if only two
haplotypes are present.
[0137] The r.sup.2 measure is arguably the most relevant measure
for association mapping, because there is a simple inverse
relationship between r.sup.2 and the sample size required to detect
association between susceptibility loci and SNPs. These measures
are defined for pairs of sites, but for some applications a
determination of how strong LD is across an entire region that
contains many polymorphic sites might be desirable (e.g., testing
whether the strength of LD differs significantly among loci or
across populations, or whether there is more or less LD in a region
than predicted under a particular model). Measuring LD across a
region is not straightforward, but one approach is to use the
measure r, which was developed in population genetics. Roughly
speaking, r measures how much recombination would be required under
a particular population model to generate the LD that is seen in
the data. This type of method can potentially also provide a
statistically rigorous approach to the problem of determining
whether LD data provide evidence for the presence of recombination
hotspots. For the methods described herein, a significant r.sup.2
value can be at least 0.1 such as at least 0.1, 0.15, 0.2, 0.25,
0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85,
0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99 or 1.0.
In one preferred embodiment, the significant r.sup.2 value can be
at least 0.2. Alternatively, linkage disequilibrium as described
herein, refers to linkage disequilibrium characterized by values of
|D'| of at least 0.2, such as 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.85,
0.9, 0.95, 0.96, 0.97, 0.98, 0.99. Thus, linkage disequilibrium
represents a correlation between alleles of distinct markers. It is
measured by correlation coefficient or |D'| (r.sup.2 up to 1.0 and
|D'| up to 1.0). In certain embodiments, linkage disequilibrium is
defined in terms of values for both the r.sup.2 and |D'| measures.
In one such embodiment, a significant linkage disequilibrium is
defined as r.sup.2>0.2 and/or |D'|>0.8. In another
embodiment, a significant linkage disequilibrium is defined as
r.sup.2>0.2 and/or |D'|>0.9. Other combinations and
permutations of values of r.sup.2 and |D'| for determining linkage
disequilibrium are also possible, and within the scope of the
invention. Linkage disequilibrium can be determined in a single
human population, as defined herein, or it can be determined in a
collection of samples comprising individuals from more than one
human population. In one embodiment of the invention, LD is
determined in a sample from one or more of the HapMap populations
(caucasian, african, japanese, chinese), as defined
(http://www.hapmap.org). In one such embodiment, LD is determined
in the CEU population of the HapMap samples. In another embodiment,
LD is determined in the YRI population. In yet another embodiment,
LD is determined in samples from the Icelandic population.
[0138] If all polymorphisms in the genome were identical at the
population level, then every single one of them would need to be
investigated in association studies. However, due to linkage
disequilibrium between polymorphisms, tightly linked polymorphisms
are strongly correlated, which reduces the number of polymorphisms
that need to be investigated in an association study to observe a
significant association. Another consequence of LD is that many
polymorphisms may give an association signal due to the fact that
these polymorphisms are strongly correlated.
[0139] Genomic LD maps have been generated across the genome, and
such LD maps have been proposed to serve as framework for mapping
disease-genes (Risch, N. & Merkiangas, K, Science 273:1516-1517
(1996); Maniatis, N., et al., Proc Natl Acad Sci USA 99:2228-2233
(2002); Reich, D E et al, Nature 411:199-204 (2001)).
[0140] It is now established that many portions of the human genome
can be broken into series of discrete haplotype blocks containing a
few common haplotypes; for these blocks, linkage disequilibrium
data provides little evidence indicating recombination (see, e.g.,
Wall., J. D. and Pritchard, J. K., Nature Reviews Genetics
4:587-597 (2003); Daly, M. et al., Nature Genet. 29:229-232 (2001);
Gabriel, S. B. et al., Science 296:2225-2229 (2002); Patil, N. et
al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature
418:544-548 (2002); Phillips, M. S. et al., Nature Genet.
33:382-387 (2003)).
[0141] There are two main methods for defining these haplotype
blocks: blocks can be defined as regions of DNA that have limited
haplotype diversity (see, e.g., Daly, M. et al., Nature Genet.
29:229-232 (2001); Patil, N. et al., Science 294:1719-1723 (2001);
Dawson, E. et al., Nature 418:544-548 (2002); Zhang, K. et al.,
Proc. Natl. Acad. Sci. USA 99:7335-7339 (2002)), or as regions
between transition zones having extensive historical recombination,
identified using linkage disequilibrium (see, e.g., Gabriel, S. B.
et al., Science 296:2225-2229 (2002); Phillips, M. S. et al.,
Nature Genet. 33:382-387 (2003); Wang, N. et al., Am. J. Hum.
Genet. 71:1227-1234 (2002); Stumpf, M. P., and Goldstein, D. B.,
Curr. Biol. 13:1-8 (2003)). More recently, a fine-scale map of
recombination rates and corresponding hotspots across the human
genome has been generated (Myers, S., et al., Science 310:321-32324
(2005); Myers, S. et al., Biochem Soc Trans 34:526530 (2006)). The
map reveals the enormous variation in recombination across the
genome, with recombination rates as high as 10-60 cM/Mb in
hotspots, while closer to 0 in intervening regions, which thus
represent regions of limited haplotype diversity and high LD. The
map can therefore be used to define haplotype blocks/LD blocks as
regions flanked by recombination hotspots. As used herein, the
terms "haplotype block" or "LD block" includes blocks defined by
any of the above described characteristics, or other alternative
methods used by the person skilled in the art to define such
regions.
[0142] Haplotype blocks can be used to map associations between
phenotype and haplotype status, using single markers or haplotypes
comprising a plurality of markers. The main haplotypes can be
identified in each haplotype block, and then a set of "tagging"
SNPs or markers (the smallest set of SNPs or markers needed to
distinguish among the haplotypes) can then be identified. These
tagging SNPs or markers can then be used in assessment of samples
from groups of individuals, in order to identify association
between phenotype and haplotype. If desired, neighboring haplotype
blocks can be assessed concurrently, as there may also exist
linkage disequilibrium among the haplotype blocks.
[0143] It has thus become apparent that for any given observed
association to a polymorphic marker in the genome, it is likely
that additional markers in the genome also show association. This
is a natural consequence of the uneven distribution of LD across
the genome, as observed by the large variation in recombination
rates. The markers used to detect association thus in a sense
represent "tags" for a genomic region (i.e., a haplotype block or
LD block) that is associating with a given disease or trait, and as
such are useful for use in the methods and kits of the present
invention. One or more causative (functional) variants or mutations
may reside within the region found to be associating to the disease
or trait. The functional variant may be another SNP, a tandem
repeat polymorphism (such as a minisatellite or a microsatellite),
a transposable element, or a copy number variation, such as an
inversion, deletion or insertion. Such variants in LD with the
variants described herein may confer a higher relative risk (RR) or
odds ratio (OR) than observed for the tagging markers used to
detect the association. The present invention thus refers to the
markers used for detecting association to the disease, as described
herein, as well as markers in linkage disequilibrium with the
markers. Thus, in certain embodiments of the invention, markers
that are in LD with the markers and/or haplotypes of the invention,
as described herein, may be used as surrogate markers. The
surrogate markers have in one embodiment relative risk (RR) and/or
odds ratio (OR) values smaller than for the markers or haplotypes
initially found to be associating with the disease, as described
herein. In other embodiments, the surrogate markers have RR or OR
values greater than those initially determined for the markers
initially found to be associating with the disease, as described
herein. An example of such an embodiment would be a rare, or
relatively rare (such as <10% allelic population frequency)
variant in LD with a more common variant (>10% population
frequency) initially found to be associating with the disease, such
as the variants described herein. Identifying and using such
markers for detecting the association discovered by the inventors
as described herein can be performed by routine methods well known
to the person skilled in the art, and are therefore within the
scope of the present invention.
[0144] Determination of Haplotype Frequency
[0145] The frequencies of haplotypes in patient and control groups
can be estimated using an expectation-maximization algorithm
(Dempster A. et al., J. R. Stat. Soc. B, 39:1-38 (1977)). An
implementation of this algorithm that can handle missing genotypes
and uncertainty with the phase can be used. Under the null
hypothesis, the patients and the controls are assumed to have
identical frequencies. Using a likelihood approach, an alternative
hypothesis is tested, where a candidate at-risk-haplotype, which
can include the markers described herein, is allowed to have a
higher frequency in patients than controls, while the ratios of the
frequencies of other haplotypes are assumed to be the same in both
groups. Likelihoods are maximized separately under both hypotheses
and a corresponding 1-df likelihood ratio statistic is used to
evaluate the statistical significance.
[0146] To look for at-risk and protective markers and haplotypes
within a linkage region, for example, association of all possible
combinations of genotyped markers is studied, provided those
markers span a practical region. The combined patient and control
groups can be randomly divided into two sets, equal in size to the
original group of patients and controls. The marker and haplotype
analysis is then repeated and the most significant p-value
registered is determined. This randomization scheme can be
repeated, for example, over 100 times to construct an empirical
distribution of p-values. In a preferred embodiment, a p-value of
<0.05 is indicative of a significant marker and/or haplotype
association.
[0147] Haplotype Analysis
[0148] One general approach to haplotype analysis involves using
likelihood-based inference applied to NEsted MOdels (Gretarsdottir
S., et al., Nat. Genet. 35:131-38 (2003)). The method is
implemented in the program NEMO, which allows for many polymorphic
markers, SNPs and microsatellites. The method and software are
specifically designed for case-control studies where the purpose is
to identify haplotype groups that confer different risks. It is
also a tool for studying LD structures. In NEMO, maximum likelihood
estimates, likelihood ratios and p-values are calculated directly,
with the aid of the EM algorithm, for the observed data treating it
as a missing-data problem.
[0149] Even though likelihood ratio tests based on likelihoods
computed directly for the observed data, which have captured the
information loss due to uncertainty in phase and missing genotypes,
can be relied on to give valid p-values, it would still be of
interest to know how much information had been lost due to the
information being incomplete. The information measure for haplotype
analysis is described in Nicolae and Kong (Technical Report 537,
Department of Statistics, University of Statistics, University of
Chicago; Biometrics, 60(2):368-75 (2004)) as a natural extension of
information measures defined for linkage analysis, and is
implemented in NEMO.
[0150] For single marker association to a disease, the Fisher exact
test can be used to calculate two-sided p-values for each
individual allele. Usually, all p-values are presented unadjusted
for multiple comparisons unless specifically indicated. The
presented frequencies (for microsatellites, SNPs and haplotypes)
are allelic frequencies as opposed to carrier frequencies. To
minimize any bias due to the relatedness of patients who were
recruited as families, first and second-degree relatives can be
eliminated from the patient list. Furthermore, the test can be
repeated for association correcting for any remaining relatedness
among the patients, by extending a variance adjustment procedure
described in Risch, N. & Teng, J. (Genome Res., 8:1273-1288
(1998)), DNA pooling (ibid) for sibships so that it can be applied
to general familial relationships, and present both adjusted and
unadjusted p-values for comparison. The differences are in general
very small as expected. To assess the significance of single-marker
association corrected for multiple testing we can carry out a
randomization test using the same genotype data. Cohorts of
patients and controls can be randomized and the association
analysis redone multiple times (e.g., up to 500,000 times) and the
p-value is the fraction of replications that produced a p-value for
some marker allele that is lower than or equal to the p-value we
observed using the original patient and control cohorts.
[0151] For both single-marker and haplotype analyses, relative risk
(RR) and the population attributable risk (PAR) can be calculated
assuming a multiplicative model (haplotype relative risk model)
(Terwilliger, J. D. & Ott, J., Hum. Hered. 42:337-46 (1992) and
Falk, C. T. & Rubinstein, P, Ann. Hum. Genet. 51 (Pt 3):227-33
(1987)), i.e., that the risks of the two alleles/haplotypes a
person carries multiply. For example, if RR is the risk of A
relative to a, then the risk of a person homozygote AA will be RR
times that of a heterozygote Aa and RR.sup.2 times that of a
homozygote aa. The multiplicative model has a nice property that
simplifies analysis and computations--haplotypes are independent,
i.e., in Hardy-Weinberg equilibrium, within the affected population
as well as within the control population. As a consequence,
haplotype counts of the affecteds and controls each have
multinomial distributions, but with different haplotype frequencies
under the alternative hypothesis. Specifically, for two haplotypes,
h.sub.i and h.sub.j,
risk(h.sub.i)/risk(h.sub.j)=(f.sub.i/p.sub.i)/(f.sub.j/p.sub.j),
where f and p denote, respectively, frequencies in the affected
population and in the control population. While there is some power
loss if the true model is not multiplicative, the loss tends to be
mild except for extreme cases. Most importantly, p-values are
always valid since they are computed with respect to null
hypothesis.
[0152] An association signal detected in one association study may
be replicated in a second cohort, ideally from a different
population (e.g., different region of same country, or a different
country) of the same or different ethnicity. The advantage of
replication studies is that the number of tests performed in the
replication study is usually quite small, and hence the less
stringent the statistical measure that needs to be applied. For
example, for a genome-wide search for susceptibility variants for a
particular disease or trait using 300,000 SNPs, a correction for
the 300,000 tests performed (one for each SNP) can be performed.
Since many SNPs on the arrays typically used are correlated (i.e.,
in LD), they are not independent. Thus, the correction is
conservative. Nevertheless, applying this correction factor
requires an observed P-value of less than
0.05/300,000=1.7.times.10.sup.-7 for the signal to be considered
significant applying this conservative test on results from a
single study cohort. Obviously, signals found in a genome-wide
association study with P-values less than this conservative
threshold are a measure of a true genetic effect, and replication
in additional cohorts is not necessarily from a statistical point
of view. Importantly, however, signals with P-values that are
greater than this threshold may also be due to a true genetic
effect. Thus, since the correction factor depends on the number of
statistical tests performed, if one signal (one SNP) from an
initial study is replicated in a second case-control cohort, the
appropriate statistical test for significance is that for a single
statistical test, i.e., P-value less than 0.05. Replication studies
in one or even several additional case-control cohorts have the
added advantage of providing assessment of the association signal
in additional populations, thus simultaneously confirming the
initial finding and providing an assessment of the overall
significance of the genetic variant(s) being tested in human
populations in general.
[0153] The results from several case-control cohorts can also be
combined to provide an overall assessment of the underlying effect.
The methodology commonly used to combine results from multiple
genetic association studies is the Mantel-Haenszel model (Mantel
and Haenszel, J Natl Cancer Inst 22:719-48 (1959)). The model is
designed to deal with the situation where association results from
different populations, with each possibly having a different
population frequency of the genetic variant, are combined. The
model combines the results assuming that the effect of the variant
on the risk of the disease, a measured by the OR or RR, is the same
in all populations, while the frequency of the variant may differ
between the populations. Combining the results from several
populations has the added advantage that the overall power to
detect a real underlying association signal is increased, due to
the increased statistical power provided by the combined cohorts.
Furthermore, any deficiencies in individual studies, for example
due to unequal matching of cases and controls or population
stratification will tend to balance out when results from multiple
cohorts are combined, again providing a better estimate of the true
underlying genetic effect.
[0154] Risk Assessment and Diagnostics
[0155] Within any given population, there is an absolute risk of
developing a disease or trait, defined as the chance of a person
developing the specific disease or trait over a specified
time-period. For example, a woman's lifetime absolute risk of
breast cancer is one in nine. That is to say, one woman in every
nine will develop breast cancer at some point in their lives. Risk
is typically measured by looking at very large numbers of people,
rather than at a particular individual. Risk is often presented in
terms of Absolute Risk (AR) and Relative Risk (RR). Relative Risk
is used to compare risks associating with two variants or the risks
of two different groups of people. For example, it can be used to
compare a group of people with a certain genotype with another
group having a different genotype. For a disease, a relative risk
of 2 means that one group has twice the chance of developing a
disease as the other group. The risk presented is usually the
relative risk for a person, or a specific genotype of a person,
compared to the population with matched gender and ethnicity. Risks
of two individuals of the same gender and ethnicity could be
compared in a simple manner. For example, if, compared to the
population, the first individual has relative risk 1.5 and the
second has relative risk 0.5, then the risk of the first individual
compared to the second individual is 1.5/0.5=3.
[0156] As described herein, certain polymorphic markers and
haplotypes comprising such markers are found to be useful for risk
assessment of prostate cancer and colorectal cancer. Risk
assessment can involve the use of the markers for diagnosing a
susceptibility to prostate cancer and/or colorectal cancer.
Particular alleles of polymorphic markers are found more frequently
in individuals with prostate cancer and/or colorectal cancer, than
in individuals without diagnosis of prostate cancer and/or
colorectal cancer. Therefore, these marker alleles have predictive
value for detecting prostate cancer and/or colorectal cancer, or a
susceptibility to prostate cancer and/or colorectal cancer, in an
individual. Tagging markers in linkage disequilibrium with the
at-risk variants (or protective variants) described herein can be
used as surrogates for these markers (and/or haplotypes). Such
surrogate markers can be located within a particular haplotype
block or LD block, e.g. LD Block C11 or LD Block C06. Such
surrogate markers can also sometimes be located outside the
physical boundaries of such a haplotype block or LD block, either
in close vicinity of the LD block/haplotype block, but possibly
also located in a more distant genomic location.
[0157] Long-distance LD can for example arise if particular genomic
regions (e.g., genes) are in a functional relationship. For
example, if two genes encode proteins that play a role in a shared
metabolic pathway, then particular variants in one gene may have a
direct impact on observed variants for the other gene. Let us
consider the case where a variant in one gene leads to increased
expression of the gene product. To counteract this effect and
preserve overall flux of the particular pathway, this variant may
have led to selection of one (or more) variants at a second gene
that confers decreased expression levels of that gene. These two
genes may be located in different genomic locations, possibly on
different chromosomes, but variants within the genes are in
apparent LD, not because of their shared physical location within a
region of high LD, but rather due to evolutionary forces. Such LD
is also contemplated and within scope of the present invention. The
skilled person will appreciate that many other scenarios of
functional gene-gene interaction are possible, and the particular
example discussed here represents only one such possible
scenario.
[0158] Markers with values of r.sup.2 equal to 1 are perfect
surrogates for the at-risk variants, i.e. genotypes for one marker
perfectly predicts genotypes for the other. Markers with smaller
values of r.sup.2 than 1 can also be surrogates for the at-risk
variant, or alternatively represent variants with relative risk
values as high as or possibly even higher than the at-risk variant.
The at-risk variant identified may not be the functional variant
itself, but is in this instance in linkage disequilibrium with the
true functional variant. The functional variant may for example be
a tandem repeat, such as a minisatellite or a microsatellite, a
transposable element (e.g., an Alu element), or a structural
alteration, such as a deletion, insertion or inversion (sometimes
also called copy number variations, or CNVs). The present invention
encompasses the assessment of such surrogate markers for the
markers as disclosed herein. Such markers are annotated, mapped and
listed in public databases, as well known to the skilled person, or
can alternatively be readily identified by sequencing the region or
a part of the region identified by the markers of the present
invention in a group of individuals, and identify polymorphisms in
the resulting group of sequences. As a consequence, the person
skilled in the art can readily and without undue experimentation
genotype surrogate markers in linkage disequilibrium with the
markers and/or haplotypes as described herein. The tagging or
surrogate markers in LD with the at-risk variants detected, also
have predictive value for detecting association to prostate cancer
and/or colorectal cancer, or a susceptibility to prostate cancer
and/or colorectal cancer, in an individual. These tagging or
surrogate markers that are in LD with the markers of the present
invention can also include other markers that distinguish among
haplotypes, as these similarly have predictive value for detecting
susceptibility to prostate cancer and/or colorectal cancer.
[0159] The present invention can in certain embodiments be
practiced by assessing a sample comprising genomic DNA from an
individual for the presence of variants described herein to be
associated with cancer. Such assessment typically steps that detect
the presence or absence of at least one allele of at least one
polymorphic marker, using methods well known to the skilled person
and further described herein, and based on the outcome of such
assessment, determine whether the individual from whom the sample
is derived is at increased or decreased risk (increased or
decreased susceptibility) of cancer. Detecting particular alleles
of polymorphic markers can in certain embodiments be done by
obtaining nucleic acid sequence data for a particular human
individual, that identifies at least one allele of at least one
polymorphic marker. Different alleles of the at least one marker
are associated with different susceptibility to the disease in
humans. Obtaining nucleic acid sequence data can comprise nucleic
acid sequence at a single nucleotide position, which is sufficient
to identify alleles at polymorphic markers, such as SNPs and
microsatellites. The nucleic acid sequence data can also comprise
sequence at any other number of nucleotide positions, in particular
for genetic markers that comprise multiple nucleotide positions,
and can be anywhere from two to hundreds of thousands, possibly
even millions, of nucleotides (in particular, in the case of copy
number variations (CNVs)).
[0160] In certain embodiments, the invention can be practiced
utilizing a dataset comprising information about the genotype
status of at least one polymorphic marker associated with prostate
and/or colorectal cancer (or markers in linkage disequilibrium with
at least one marker associated with these diseases). In other
words, a dataset containing information about such genetic status,
for example in the form of genotype counts at a certain polymorphic
marker, or a plurality of markers (e.g., an indication of the
presence or absence of certain at-risk alleles), or actual
genotypes for one or more markers, can be queried for the presence
or absence of certain at-risk alleles at certain polymorphic
markers shown by the present inventors to be associated with risk
of prostate cancer and colorectal cancer. A positive result for a
variant (e.g., marker allele) associated with the cancer is
indicative of the individual from which the dataset is derived is
at increased susceptibility (increased risk) of the cancer.
[0161] In certain embodiments of the invention, a polymorphic
marker is correlated to the cancer by referencing genotype data for
the polymorphic marker to a look-up table that comprises
correlations between at least one allele of the polymorphism and
the cancer. In some embodiments, the table comprises a correlation
for one polymorphism. In other embodiments, the table comprises a
correlation for a plurality of polymorphisms. In both scenarios, by
referencing to a look-up table that gives an indication of a
correlation between a marker and the cancer, a risk for the cancer,
or a susceptibility to the cancer, can be identified in the
individual from whom the sample is derived. In some embodiments,
the correlation is reported as a statistical measure. The
statistical measure may be reported as a risk measure, such as a
relative risk (RR), an absolute risk (AR) or an odds ratio
(OR).
[0162] The markers of the invention, e.g., the markers presented in
Tables 1-6, may be useful for risk assessment and diagnostic
purposes for prostate cancer and/or colorectal cancer, either alone
or in combination. Thus, even in cases where the increase in risk
by individual markers is relatively modest, i.e. on the order of
10-30%, the association may have significant implications. Thus,
relatively common variants may have significant contribution to the
overall risk (Population Attributable Risk is high), or combination
of markers can be used to define groups of individual who, based on
the combined risk of the markers, is at significant combined risk
of developing the disease.
[0163] Thus, in one embodiment of the invention, a plurality of
variants (genetic markers, biomarkers and/or haplotypes) is used
for overall risk assessment. These variants are in one embodiment
selected from the variants as disclosed herein. Other embodiments
include the use of the variants of the present invention in
combination with other variants known to be useful for diagnosing a
susceptibility to prostate cancer and/or colorectal cancer. In such
embodiments, the genotype status of a plurality of markers and/or
haplotypes is determined in an individual, and the status of the
individual compared with the population frequency of the associated
variants, or the frequency of the variants in clinically healthy
subjects, such as age-matched and sex-matched subjects. Methods
known in the art, such as multivariate analyses or joint risk
analyses, may subsequently be used to determine the overall risk
conferred based on the genotype status at the multiple loci.
Assessment of risk based on such analysis may subsequently be used
in the methods and kits of the invention, as described herein.
[0164] In certain embodiments of risk assessment of prostate
cancer, the variants described herein to be associated with
prostate cancer risk are assessed in combination with at least one
marker selected from the group consisting of rs2710646, rs
16901979, rs1447295, rs6983267, rs10896450, rs1859962, rs4430796
and rs5945572. Any combination of these markers, or surrogate
markers in linkage disequilibrium therewith, with any of the
variants described herein for risk assessment of prostate cancer is
contemplated.
[0165] As described in the above, the haplotype block structure of
the human genome has the effect that a large number of variants
(markers and/or haplotypes) in linkage disequilibrium with the
variant originally associated with a disease or trait may be used
as surrogate markers for assessing association to the disease or
trait. The number of such surrogate markers will depend on factors
such as the historical recombination rate in the region, the
mutational frequency in the region (i.e., the number of polymorphic
sites or markers in the region), and the extent of LD (size of the
LD block) in the region. These markers are usually located within
the physical boundaries of the LD block or haplotype block in
question as defined using the methods described herein (e.g., LD
block C11 and/or LD block C06), or by other methods known to the
person skilled in the art. However, sometimes marker and haplotype
association is found to extend beyond the physical boundaries of
the haplotype block as defined. Such markers and/or haplotypes may
in those cases be also used as surrogate markers and/or haplotypes
for the markers and/or haplotypes physically residing within the
haplotype block as defined. As a consequence, markers and
haplotypes in LD (typically characterized by r.sup.2 greater than
0.1, such as r.sup.2 greater than 0.2, including r.sup.2 greater
than 0.3, also including r.sup.2 greater than 0.4) with the markers
and haplotypes of the present invention are also within the scope
of the invention, even if they are physically located beyond the
boundaries of the haplotype block as defined. This includes markers
that are described herein (e.g., Tables 1-6, e.g. Tables 3-4), but
may also include other markers that are in strong LD (e.g.,
characterized by r.sup.2 greater than 0.1 or 0.2 and/or
|D'|>0.8) with one or more of the markers listed in Tables
1-6.
[0166] For the SNP markers described herein, the opposite allele to
the allele found to be in excess in patients (at-risk allele) is
found in decreased frequency in prostate cancer and/or colorectal
cancer. These markers and haplotypes in LD and/or comprising such
markers, are thus protective for prostate cancer and/or colorectal
cancer, i.e. they confer a decreased risk or susceptibility of
individuals carrying these markers and/or haplotypes developing
prostate cancer and/or colorectal cancer.
[0167] Certain variants of the present invention, including certain
haplotypes comprise, in some cases, a combination of various
genetic markers, e.g., SNPs and microsatellites. Detecting
haplotypes can be accomplished by methods known in the art and/or
described herein for detecting sequences at polymorphic sites.
Furthermore, correlation between certain haplotypes or sets of
markers and disease phenotype can be verified using standard
techniques. A representative example of a simple test for
correlation would be a Fisher-exact test on a two by two table.
[0168] In specific embodiments, a marker allele or haplotype found
to be associated with prostate cancer and/or colorectal cancer,
(e.g., marker alleles as listed in Tables 1-6) is one in which the
marker allele or haplotype is more frequently present in an
individual at risk for prostate cancer and/or colorectal cancer
(affected), compared to the frequency of its presence in a healthy
individual (control), wherein the presence of the marker allele or
haplotype is indicative of prostate cancer and/or colorectal cancer
or a susceptibility to prostate cancer and/or colorectal cancer. In
other embodiments, at-risk markers in linkage disequilibrium with
one or more markers found to be associated with prostate cancer
and/or colorectal cancer (e.g., marker alleles as listed in Tables
1-6) are tagging markers that are more frequently present in an
individual at risk for prostate cancer and/or colorectal cancer
(affected), compared to the frequency of their presence in a
healthy individual (control), wherein the presence of the tagging
markers is indicative of increased susceptibility to prostate
cancer and/or colorectal cancer. In a further embodiment, at-risk
markers alleles (i.e. conferring increased susceptibility) in
linkage disequilibrium with one or more markers found to be
associated with prostate cancer and/or colorectal cancer (e.g.,
marker alleles as listed in Table 1-6), are markers comprising one
or more allele that is more frequently present in an individual at
risk for prostate cancer and/or colorectal cancer, compared to the
frequency of their presence in a healthy individual (control),
wherein the presence of the markers is indicative of increased
susceptibility to.
[0169] Study Population
[0170] In a general sense, the methods and kits of the invention
can be utilized from samples containing genomic DNA from any
source, i.e. any individual. In preferred embodiments, the
individual is a human individual. The individual can be an adult,
child, or fetus. The present invention also provides for assessing
markers and/or haplotypes in individuals who are members of a
target population. Such a target population is in one embodiment a
population or group of individuals at risk of developing the
disease, based on other genetic factors, biomarkers, biophysical
parameters (e.g., weight, BMD, blood pressure), or general health
and/or lifestyle parameters (e.g., history of prostate and/or
colorectal cancer or other cancers, previous diagnosis of prostate
and/or colorectal cancer, family history of prostate cancer and/or
colorectal cancer).
[0171] The invention provides for embodiments that include
individuals from specific age subgroups, such as those over the age
of 40, over age of 45, or over age of 50, 55, 60, 65, 70, 75, 80,
or 85. Other embodiments of the invention pertain to other age
groups, such as individuals aged less than 85, such as less than
age 80, less than age 75, or less than age 70, 65, 60, 55, 50, 45,
40, 35, or age 30. Other embodiments relate to individuals with age
at onset of the disease in any of the age ranges described in the
above. It is also contemplated that a range of ages may be relevant
in certain embodiments, such as age at onset at more than age 45
but less than age 60. Other age ranges are however also
contemplated, including all age ranges bracketed by the age values
listed in the above. The invention furthermore relates to
individuals of either gender, males or females.
[0172] The Icelandic population is a Caucasian population of
Northern European ancestry. A large number of studies reporting
results of genetic linkage and association in the Icelandic
population have been published in the last few years. Many of those
studies show replication of variants, originally identified in the
Icelandic population as being associating with a particular
disease, in other populations (Styrkarsdottir, U., et al. N Engl J
Med Apr. 29 2008 (Epub ahead of print); Thorgeirsson, T., et al.
Nature 452:638-42 (2008); Gudmundsson, J., et al. Nat Genet.
40:281-3 (2008); Stacey, S, N., et al., Nat Genet. 39:865-69
(2007); Helgadottir, A., et al., Science 316:1491-93 (2007);
Steinthorsdottir, V., et al., Nat Genet. 39:770-75 (2007);
Gudmundsson, J., et al., Nat Genet. 39:631-37 (2007); Frayling, T
M, Nature Reviews Genet 8:657-662 (2007); Amundadottir, L. T., et
al., Nat Genet. 38:652-58 (2006); Grant, S. F., et al., Nat Genet.
38:320-23 (2006)). Thus, genetic findings in the Icelandic
population have in general been replicated in other populations,
including populations from Africa and Asia.
[0173] It is thus believed that the markers of the present
invention found to be associated with risk of prostate cancer and
colorectal cancer to show similar association in other human
populations. Particular embodiments comprising individual human
populations are thus also contemplated and within the scope of the
invention. Such embodiments relate to human subjects that are from
one or more human population including, but not limited to,
Caucasian populations, European populations, American populations,
Eurasian populations, Asian populations, Central/South Asian
populations, East Asian populations, Middle Eastern populations,
African populations, Hispanic populations, and Oceanian
populations. European populations include, but are not limited to,
Swedish, Norwegian, Finnish, Russian, Danish, Icelandic, Irish,
Kelt, English, Scottish, Dutch, Belgian, French, German, Spanish,
Portugues, Italian, Polish, Bulgarian, Slavic, Serbian, Bosnian,
Chech, Greek and Turkish populations. The invention furthermore in
other embodiments can be practiced in specific human populations
that include Bantu, Mandenk, Yoruba, San, Mbuti Pygmy, Orcadian,
Adygel, Russian, Sardinian, Tuscan, Mozabite, Bedouin, Druze,
Palestinian, Balochi, Brahui, Makrani, Sindhi, Pathan, Burusho,
Hazara, Uygur, Kalash, Han, Dai, Daur, Hezhen, Lahu, Miao, Orogen,
She, Tujia, Tu, Xibo, Yi, Mongolan, Naxi, Cambodian, Japanese,
Yakut, Melanesian, Papuan, Karitianan, Surui, Colmbian, Maya and
Pima.
[0174] In one preferred embodiment, the invention relates to
populations that include black African ancestry such as populations
comprising persons of African descent or lineage. Black African
ancestry may be determined by self reporting as African-Americans,
Afro-Americans, Black Americans, being a member of the black race
or being a member of the negro race. For example, African Americans
or Black Americans are those persons living in North America and
having origins in any of the black racial groups of Africa. In
another example, self-reported persons of black African ancestry
may have at least one parent of black African ancestry or at least
one grandparent of black African ancestry.
[0175] The racial contribution in individual subjects may also be
determined by genetic analysis. Genetic analysis of ancestry may be
carried out using unlinked microsatellite markers such as those set
out in Smith et al. (Am J Hum Genet 74, 1001-13 (2004)).
[0176] In certain embodiments, the invention relates to markers
and/or haplotypes identified in specific populations, as described
in the above. The person skilled in the art will appreciate that
measures of linkage disequilibrium (LD) may give different results
when applied to different populations. This is due to different
population history of different human populations as well as
differential selective pressures that may have led to differences
in LD in specific genomic regions. It is also well known to the
person skilled in the art that certain markers, e.g. SNP markers,
have different population frequency in different populations, or
are polymorphic in one population but not in another. The person
skilled in the art will however apply the methods available and as
thought herein to practice the present invention in any given human
population. This may include assessment of polymorphic markers in
the LD region of the present invention, so as to identify those
markers that give strongest association within the specific
population. Thus, the at-risk variants of the present invention may
reside on different haplotype background and in different
frequencies in various human populations. However, utilizing
methods known in the art and the markers of the present invention,
the invention can be practiced in any given human population.
[0177] Utility of Genetic Testing
[0178] The person skilled in the art will appreciate and understand
that the variants described herein in general do not, by
themselves, provide an absolute identification of individuals who
will develop a particular disease. The variants described herein do
however indicate increased and/or decreased likelihood that
individuals carrying the at-risk or protective variants of the
invention will develop symptoms associated with prostate cancer
and/or colorectal cancer. This information is however extremely
valuable in itself, as outlined in more detail in the below, as it
can be used to, for example, initiate preventive measures at an
early stage, perform regular physical and/or mental exams to
monitor the progress and/or appearance of symptoms, or to schedule
exams at a regular interval to identify the condition in question,
so as to be able to apply treatment at an early stage.
[0179] The knowledge of a genetic variant that confers a risk of
developing cancer offers the opportunity to apply a genetic-test to
distinguish between individuals with increased risk of developing
the cancer (i.e. carriers of the at-risk variant) and those with
decreased risk of developing the cancer (i.e. carriers of the
protective variant, or non-carriers of the at-risk variant). The
core values of genetic testing, for individuals belonging to both
of the above mentioned groups, are the possibilities of being able
to diagnose the cancer at an early stage and provide information to
the clinician about prognosis/aggressiveness of the disease in
order to be able to apply the most appropriate treatment. For
example, the application of a genetic test for cancer (e.g.,
colorectal cancer or prostate cancer (including aggressive or high
Gleason grade prostate cancer, less aggressive or low Gleason grade
prostate cancer)) can provide an opportunity for the detection of
the cancer at an earlier stage which may lead to the application of
therapeutic measures at an earlier stage, and thus can minimize the
deleterious effects of the symptoms and serious health consequences
conferred by cancer. Some advantages of genetic tests for prostate
cancer include:
[0180] 1. To Aid Early Detection
[0181] The application of a genetic test for prostate cancer can
provide an opportunity for the detection of the disease at an
earlier stage which leads to higher cure rates, if found locally,
and increases survival rates by minimizing regional and distant
spread of the tumor. For prostate cancer, a genetic test will most
likely increase the sensitivity and specificity of the already
generally applied Prostate Specific Antigen (PSA) test and Digital
Rectal Examination (DRE). This can lead to lower rates of false
positives (thus minimize unnecessary procedures such as needle
biopsies) and false negatives (thus increasing detection of occult
disease and minimizing morbidity and mortality due to PCA).
[0182] 2. To Determine Aggressiveness
[0183] Genetic testing can provide information about pre-diagnostic
prognostic indicators and enable the identification of individuals
at high or low risk for aggressive tumor types that can lead to
modification in screening strategies. For example, an individual
determined to be a carrier of a high risk allele for the
development of aggressive prostate cancer will likely undergo more
frequent PSA testing, examination and have a lower threshold for
needle biopsy in the presence of an abnormal PSA value.
[0184] Furthermore, identifying individuals that are carriers of
high or low risk alleles for aggressive tumor types will lead to
modification in treatment strategies. For example, if prostate
cancer is diagnosed in an individual that is a carrier of an allele
that confers increased risk of developing an aggressive form of
prostate cancer, then the clinician would likely advise a more
aggressive treatment strategy such as a prostatectomy instead of a
less aggressive treatment strategy.
[0185] As is known in the art, Prostate Specific Antigen (PSA) is a
protein that is secreted by the epithelial cells of the prostate
gland, including cancer cells. An elevated level in the blood
indicates an abnormal condition of the prostate, either benign or
malignant. PSA is used to detect potential problems in the prostate
gland and to follow the progress of prostate cancer therapy. PSA
levels above 4 ng/ml are indicative of the presence of prostate
cancer (although as known in the art and described herein, the test
is neither very specific nor sensitive).
[0186] In one embodiment, the method of the invention is performed
in combination with (either prior to, concurrently or after) a PSA
assay. In a particular embodiment, the presence of an at-risk
marker or haplotype, in conjunction with the subject having a PSA
level greater than 4 ng/ml, is indicative of a more aggressive
prostate cancer and/or a worse prognosis. As described herein,
particular markers and haplotypes are associated with high Gleason
(i.e., more aggressive) prostate cancer. In another embodiment, the
presence of a marker or haplotype, in a patient who has a normal
PSA level (e.g., less than 4 ng/ml), is indicative of a high
Gleason (i.e., more aggressive) prostate cancer and/or a worse
prognosis. A "worse prognosis" or "bad prognosis" occurs when it is
more likely that the cancer will grow beyond the boundaries of the
prostate gland, metastasize, escape therapy and/or kill the
host.
[0187] In one embodiment, the presence of a marker or haplotype is
indicative of a predisposition to a somatic rearrangement (e.g.,
one or more of an amplification, a translocation, an insertion
and/or deletion) in a tumor or its precursor. The somatic
rearrangement itself may subsequently lead to a more aggressive
form of prostate cancer (e.g., a higher histologic grade, as
reflected by a higher Gleason score or higher stage at diagnosis,
an increased progression of prostate cancer (e.g., to a higher
stage), a worse outcome (e.g., in terms of morbidity, complications
or death)). As is known in the art, the Gleason grade is a widely
used method for classifying prostate cancer tissue for the degree
of loss of the normal glandular architecture (size, shape and
differentiation of glands). A grade from 1-5 is assigned
successively to each of the two most predominant tissue patterns
present in the examined tissue sample and are added together to
produce the total or combined Gleason grade (scale of 2-10). High
numbers indicate poor differentiation and therefore more aggressive
cancer.
[0188] Aggressive prostate cancer is cancer that grows beyond the
prostate, metastasizes and eventually kills the patient. As
described herein, one surrogate measure of aggressiveness is a high
combined Gleason grade. The higher the grade on a scale of 2-10 the
more likely it is that a patient has aggressive disease.
[0189] The present invention furthermore relates to risk assessment
for prostate cancer and colorectal cancer, including diagnosing
whether an individual is at risk for developing prostate cancer
and/or colorectal cancer. The polymorphic markers of the present
invention can be used alone or in combination, as well as in
combination with other factors, including other genetic risk
factors or biomarkers, for risk assessment of an individual for
prostate cancer and/or colorectal cancer. Certain factors known to
affect the predisposition of an individual towards developing risk
of developing common disease, including prostate cancer and/or
colorectal cancer are known to the person skilled in the art and
can be utilized in such assessment. These include, but are not
limited to, age, gender, smoking status, family history of cancer,
previously diagnosed cancer, colonic adenomas, chronic inflammatory
bowel disease and diet. Methods known in the art can be used for
such assessment, including multivariate analyses or logistic
regression.
[0190] Methods
[0191] Methods for risk assessment of and risk management of
prostate cancer and/or colorectal cancer are described herein and
are encompassed by the invention. The invention also encompasses
methods of assessing an individual for probability of response to a
therapeutic agent for prostate cancer and/or colorectal cancer, as
well as methods for predicting the effectiveness of a therapeutic
agent for prostate cancer and/or colorectal cancer. Kits for
assaying a sample from a subject to detect susceptibility to
prostate cancer and/or colorectal cancer are also encompassed by
the invention.
[0192] Diagnostic and Screening Methods
[0193] In certain embodiments, the present invention pertains to
methods of diagnosing, or aiding in the diagnosis of, prostate
cancer and/or colorectal cancer or a susceptibility to prostate
cancer and/or colorectal cancer, by detecting particular alleles at
genetic markers that appear more frequently in prostate cancer
and/or colorectal cancer subjects or subjects who are susceptible
to prostate cancer and/or colorectal cancer. In a particular
embodiment, the invention is a method of diagnosing a
susceptibility to prostate cancer and/or colorectal cancer by
detecting at least one allele of at least one polymorphic marker
(e.g., the markers described herein). The present invention
describes methods whereby detection of particular alleles of
particular markers or haplotypes is indicative of a susceptibility
to prostate cancer and/or colorectal cancer. Such prognostic or
predictive assays can also be used to determine prophylactic
treatment of a subject prior to the onset of symptoms of prostate
cancer and/or colorectal cancer.
[0194] The present invention pertains in some embodiments to
methods of clinical applications of diagnosis, e.g., diagnosis
performed by a medical professional. In other embodiments, the
invention pertains to methods of diagnosis performed by a layman.
The layman can be the customer of a genotyping service. The layman
may also be a genotype service provider, who performs genotype
analysis on a DNA sample from an individual, in order to provide
service related to genetic risk factors for particular traits or
diseases, based on the genotype status of the individual (i.e., the
customer). Recent technological advances in genotyping
technologies, including high-throughput genotyping of SNP markers,
such as Molecular Inversion Probe array technology (e.g.,
Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina
GoldenGate and Infinium assays) have made it possible for
individuals to have their own genome assessed for up to one million
SNPs simultaneously, at relatively little cost. The resulting
genotype information, made available to the customer can be
compared to information from the public literature about disease or
trait risk associated with various SNPs. The diagnostic application
of disease-associated alleles as described herein, can thus be
performed either by the individual, through analysis of his/her
genotype data, or by a health professional based on results of a
clinical test. In other words, the diagnosis or assessment of a
susceptibility based on genetic risk can be made by health
professionals, genetic counselors or by the layman, based on
information about his/her genotype and publications on various risk
factors. In the present context, the term "diagnosing", and
"diagnose a susceptibility", is meant to refer to any available
diagnostic method, including those mentioned above.
[0195] In certain embodiments, a sample containing genomic DNA from
an individual is collected. Such sample can for example be a buccal
swab, a saliva sample, a blood sample, or other suitable samples
containing genomic DNA, as described further herein. The genomic
DNA is then analyzed using any common technique available to the
skilled person, such as high-throughput array technologies. Results
from such genotyping are stored in a convenient data storage unit,
such as a data carrier, including computer databases, data storage
disks, or by other convenient data storage means. In certain
embodiments, the computer database is an object database, a
relational database or a post-relational database. The genotype
data is subsequently analyzed for the presence of certain variants
known to be susceptibility variants for a particular human
conditions, such as the genetic variants described herein. Genotype
data can be retrieved from the data storage unit using any
convenient data query method. Calculating risk conferred by a
particular genotype for the individual can be based on comparing
the genotype of the individual to previously determined risk
(expressed as a relative risk (RR) or and odds ratio (OR), for
example) for the genotype, for example for an heterozygous carrier
of an at-risk variant for a particular disease or trait (such as
prostate cancer and colorectal cancer). The calculated risk for the
individual can be the relative risk for a person, or for a specific
genotype of a person, compared to the average population with
matched gender and ethnicity. The average population risk can be
expressed as a weighted average of the risks of different
genotypes, using results from a reference population, and the
appropriate calculations to calculate the risk of a genotype group
relative to the population can then be performed. Alternatively,
the risk for an individual is based on a comparison of particular
genotypes, for example heterozygous carriers of an at-risk allele
of a marker compared with non-carriers of the at-risk allele. Using
the population average may in certain embodiments be more
convenient, since it provides a measure which is easy to interpret
for the user, i.e. a measure that gives the risk for the
individual, based on his/her genotype, compared with the average in
the population. The calculated risk estimated can be made available
to the customer via a website, preferably a secure website.
[0196] In certain embodiments, a service provider will include in
the provided service all of the steps of isolating genomic DNA from
a sample provided by the customer, performing genotyping of the
isolated DNA, calculating genetic risk based on the genotype data,
and report the risk to the customer. In some other embodiments, the
service provider will include in the service the interpretation of
genotype data for the individual, i.e., risk estimates for
particular genetic variants based on the genotype data for the
individual. In some other embodiments, the service provider may
include service that includes genotyping service and interpretation
of the genotype data, starting from a sample of isolated DNA from
the individual (the customer).
[0197] Custom sequencing service can also be used to assess
genotype status of individuals. Targeted sequencing or whole genome
sequencing technologies can be used to determine the identity of
nucleotides at certain polymorphic sites. Determination of such
identity defines the allelic status of the individual at the site,
i.e. provides genotype information. Such sequencing services can
thus also be utilized to realize the present invention. As
whole-genome sequencing technologies become economically feasible
on a large scale, utilization of genotype information based on such
technologies may become preferable. Certain embodiments of the
invention encompass genotyping performed by such sequencing
technologies.
[0198] In addition, in certain other embodiments, the present
invention pertains to methods of diagnosing, or aiding in the
diagnosis of, a decreased susceptibility to prostate cancer and/or
colorectal cancer, by detecting particular genetic marker alleles
or haplotypes that appear less frequently in prostate cancer and/or
colorectal cancer patients than in individual not diagnosed with
prostate cancer and/or colorectal cancer or in the general
population.
[0199] Overall risk for multiple risk variants can be performed
using standard methodology. For example, assuming a multiplicative
model, i.e. assuming that the risk of individual risk variants
multiply to establish the overall effect, allows for a
straightforward calculation of the overall risk for multiple
markers.
[0200] As described and exemplified herein, particular marker
alleles or haplotypes (e.g. the markers and haplotypes as listed in
Tables 1-6) are associated with prostate cancer and colorectal
cancer. In one embodiment, the marker allele or haplotype is one
that confers a significant risk or susceptibility to prostate
cancer and/or colorectal cancer. In another embodiment, the
invention relates to a method of determining or diagnosing a
susceptibility to prostate cancer and/or colorectal cancer in a
human individual, the method comprising determining the presence or
absence of at least one allele of at least one polymorphic marker
in a nucleic acid sample obtained from the individual, wherein the
at least one polymorphic marker is selected from the group
consisting of the polymorphic markers listed in Table 5 and 6, and
markers in linkage disequilibrium (e.g., defined as r.sup.2>0.2)
therewith. In another embodiment, the invention pertains to methods
of diagnosing or determining a susceptibility to prostate cancer
and/or colorectal cancer in a human individual, by screening for at
least one marker allele as listed in Table 3 and Table 4 or markers
in linkage disequilibrium therewith. In another embodiment, the
invention relates to methods of diagnosing or determining a
susceptibility to colorectal cancer in a human individual, by
screening for at least one marker as listed in Table 4. In another
embodiment, the marker allele or haplotype is more frequently
present in a subject having, or who is susceptible to, prostate
cancer and/or colorectal cancer (affected), as compared to the
frequency of its presence in a healthy subject (control, such as
population controls). In certain embodiments, the significance of
association of the at least one marker allele or haplotype is
characterized by a p value <0.05. In other embodiments, the
significance of association is characterized by smaller p-values,
such as <0.01, <0.001, <0.0001, <0.00001, <0.000001,
<0.0000001, <0.00000001 or <0.000000001.
[0201] In these embodiments, the presence of the at least one
marker allele or haplotype is indicative of a susceptibility to
prostate cancer and/or colorectal cancer. These diagnostic methods
involve detecting the presence or absence of at least one marker
allele or haplotype that is associated with prostate cancer and/or
colorectal cancer. The haplotypes described herein include
combinations of alleles at various genetic markers (e.g., SNPs,
microsatellites). The detection of the particular genetic marker
alleles that make up the particular haplotypes can be performed by
a variety of methods described herein and/or known in the art. For
example, genetic markers can be detected at the nucleic acid level
(e.g., by direct nucleotide sequencing or by other means known to
the skilled in the art) or at the amino acid level if the genetic
marker affects the coding sequence of a protein encoded by a cancer
(prostate cancer or colorectal cancer)-associated nucleic acid
(e.g., by protein sequencing or by immunoassays using antibodies
that recognize such a protein). The marker alleles or haplotypes of
the present invention correspond to fragments of a genomic DNA
sequence associated with prostate cancer and/or colorectal cancer.
Such fragments encompass the DNA sequence of the polymorphic marker
or haplotype in question, but may also include DNA segments in
strong LD (linkage disequilibrium) with the marker or haplotype. In
one embodiment, such segments comprises segments in LD with the
marker or haplotype as determined by a value of r.sup.2 greater
than 0.1 and/or |D'|>0.8).
[0202] In one embodiment, diagnosis of a susceptibility to prostate
cancer and/or colorectal cancer can be accomplished using
hybridization methods, such as Southern analysis, Northern
analysis, and/or in situ hybridizations (see Current Protocols in
Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons,
including all supplements). The presence of a specific marker
allele can be indicated by sequence-specific hybridization of a
nucleic acid probe specific for the particular allele. The presence
of more than specific marker allele or a specific haplotype can be
indicated by using several sequence-specific nucleic acid probes,
each being specific for a particular allele. In one embodiment, a
haplotype can be indicated by a single nucleic acid probe that is
specific for the specific haplotype (i.e., hybridizes specifically
to a DNA strand comprising the specific marker alleles
characteristic of the haplotype). A sequence-specific probe can be
directed to hybridize to genomic DNA, RNA, or cDNA. A "nucleic acid
probe", as used herein, can be a DNA probe or an RNA probe that
hybridizes to a complementary sequence. One of skill in the art
would know how to design such a probe so that sequence specific
hybridization will occur only if a particular allele is present in
a genomic sequence from a test sample.
[0203] To diagnose a susceptibility to prostate cancer and/or
colorectal cancer, a hybridization sample is formed by contacting
the test sample containing a prostate cancer and/or colorectal
cancer-associated nucleic acid, such as a genomic DNA sample, with
at least one nucleic acid probe. A non-limiting example of a probe
for detecting mRNA or genomic DNA is a labeled nucleic acid probe
that is capable of hybridizing to mRNA or genomic DNA sequences
described herein. The nucleic acid probe can be, for example, a
full-length nucleic acid molecule, or a portion thereof, such as an
oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides
in length that is sufficient to specifically hybridize under
stringent conditions to appropriate mRNA or genomic DNA. For
example, the nucleic acid probe can comprise all or a portion of
the nucleotide sequence of LD Block C06 or LD Block C11, as
described herein, optionally comprising at least one allele of a
marker described herein, or the probe can be the complementary
sequence of such a sequence. In a particular embodiment, the
nucleic acid probe is a portion of the nucleotide sequence of LD
Block C06 or LD Block C11, as described herein, optionally
comprising at least one allele of a marker described herein, or at
least one allele of one polymorphic marker or haplotype comprising
at least one polymorphic marker described herein, or the probe can
be the complementary sequence of such a sequence. Other suitable
probes for use in the diagnostic assays of the invention are
described herein. Hybridization can be performed by methods well
known to the person skilled in the art (see, e.g., Current
Protocols in Molecular Biology, Ausubel, F. et al., eds., John
Wiley & Sons, including all supplements). In one embodiment,
hybridization refers to specific hybridization, i.e., hybridization
with no mismatches (exact hybridization). In one embodiment, the
hybridization conditions for specific hybridization are high
stringency.
[0204] Specific hybridization, if present, is detected using
standard methods. If specific hybridization occurs between the
nucleic acid probe and the nucleic acid in the test sample, then
the sample contains the allele that is complementary to the
nucleotide that is present in the nucleic acid probe. The process
can be repeated for any markers of the present invention, or
markers that make up a haplotype of the present invention, or
multiple probes can be used concurrently to detect more than one,
marker alleles at a time. It is also possible to design a single
probe containing more than one marker alleles of a particular
haplotype (e.g., a probe containing alleles complementary to 2, 3,
4, 5 or all of the markers that make up a particular haplotype).
Detection of the particular markers of the haplotype in the sample
is indicative that the source of the sample has the particular
haplotype (e.g., a haplotype) and therefore is susceptible to
prostate cancer and/or colorectal cancer.
[0205] In one preferred embodiment, a method utilizing a detection
oligonucleotide probe comprising a fluorescent moiety or group at
its 3' terminus and a quencher at its 5' terminus, and an enhancer
oligonucleotide, is employed, as described by Kutyavin et al.
(Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be
Gig Harbor Green or Yakima Yellow, or other suitable fluorescent
moieties. The detection probe is designed to hybridize to a short
nucleotide sequence that includes the SNP polymorphism to be
detected. Preferably, the SNP is anywhere from the terminal residue
to -6 residues from the 3' end of the detection probe. The enhancer
is a short oligonucleotide probe which hybridizes to the DNA
template 3' relative to the detection probe. The probes are
designed such that a single nucleotide gap exists between the
detection probe and the enhancer nucleotide probe when both are
bound to the template. The gap creates a synthetic abasic site that
is recognized by an endonuclease, such as Endonuclease IV. The
enzyme cleaves the dye off the fully complementary detection probe,
but cannot cleave a detection probe containing a mismatch. Thus, by
measuring the fluorescence of the released fluorescent moiety,
assessment of the presence of a particular allele defined by
nucleotide sequence of the detection probe can be performed.
[0206] The detection probe can be of any suitable size, although
preferably the probe is relatively short. In one embodiment, the
probe is from 5-100 nucleotides in length. In another embodiment,
the probe is from 10-50 nucleotides in length, and in another
embodiment, the probe is from 12-30 nucleotides in length. Other
lengths of the probe are possible and within scope of the skill of
the average person skilled in the art.
[0207] In a preferred embodiment, the DNA template containing the
SNP polymorphism is amplified by Polymerase Chain Reaction (PCR)
prior to detection. In such an embodiment, the amplified DNA serves
as the template for the detection probe and the enhancer probe.
[0208] Certain embodiments of the detection probe, the enhancer
probe, and/or the primers used for amplification of the template by
PCR include the use of modified bases, including modified A and
modified G. The use of modified bases can be useful for adjusting
the melting temperature of the nucleotide molecule (probe and/or
primer) to the template DNA, for example for increasing the melting
temperature in regions containing a low percentage of G or C bases,
in which modified A with the capability of forming three hydrogen
bonds to its complementary T can be used, or for decreasing the
melting temperature in regions containing a high percentage of G or
C bases, for example by using modified G bases that form only two
hydrogen bonds to their complementary C base in a double stranded
DNA molecule. In a preferred embodiment, modified bases are used in
the design of the detection nucleotide probe. Any modified base
known to the skilled person can be selected in these methods, and
the selection of suitable bases is well within the scope of the
skilled person based on the teachings herein and known bases
available from commercial sources as known to the skilled
person.
[0209] In another hybridization method, Northern analysis (see
Current Protocols in Molecular Biology, Ausubel, F. et al., eds.,
John Wiley & Sons, supra) is used to identify the presence of a
polymorphism associated with prostate cancer and/or colorectal
cancer. For Northern analysis, a test sample of RNA is obtained
from the subject by appropriate means. As described herein,
specific hybridization of a nucleic acid probe to RNA from the
subject is indicative of a particular allele complementary to the
probe. For representative examples of use of nucleic acid probes,
see, for example, U.S. Pat. Nos. 5,288,611 and 4,851,330.
[0210] Additionally, or alternatively, a peptide nucleic acid (PNA)
probe can be used in addition to, or instead of, a nucleic acid
probe in the hybridization methods described herein. A PNA is a DNA
mimic having a peptide-like, inorganic backbone, such as
N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or
U) attached to the glycine nitrogen via a methylene carbonyl linker
(see, for example, Nielsen, P., et al., Bioconjug. Chem. 5:3-7
(1994)). The PNA probe can be designed to specifically hybridize to
a molecule in a sample suspected of containing one or more of the
marker alleles or haplotypes that are associated with prostate
cancer and/or colorectal cancer. Hybridization of the PNA probe is
thus diagnostic for prostate cancer and/or colorectal cancer or a
susceptibility to prostate cancer and/or colorectal cancer
[0211] In one embodiment of the invention, a test sample containing
genomic DNA obtained from the subject is collected and the
polymerase chain reaction (PCR) is used to amplify a fragment
comprising one or more markers or haplotypes of the present
invention. As described herein, identification of a particular
marker allele or haplotype associated with prostate cancer and/or
colorectal cancer, can be accomplished using a variety of methods
(e.g., sequence analysis, analysis by restriction digestion,
specific hybridization, single stranded conformation polymorphism
assays (SSCP), electrophoretic analysis, etc.). In another
embodiment, diagnosis is accomplished by expression analysis using
quantitative PCR (kinetic thermal cycling). This technique can, for
example, utilize commercially available technologies, such as
TaqMan.RTM. (Applied Biosystems, Foster City, Calif.). The
technique can assess the presence of an alteration in the
expression or composition of a polypeptide or splicing variant(s)
that is encoded by a nucleic acid associated with prostate cancer
and/or colorectal cancer. Further, the expression of the variant(s)
can be quantified as physically or functionally different.
[0212] In another embodiment of the methods of the invention,
analysis by restriction digestion can be used to detect a
particular allele if the allele results in the creation or
elimination of a restriction site relative to a reference sequence.
Restriction fragment length polymorphism (RFLP) analysis can be
conducted, e.g., as described in Current Protocols in Molecular
Biology, supra. The digestion pattern of the relevant DNA fragment
indicates the presence or absence of the particular allele in the
sample.
[0213] Sequence analysis can also be used to detect specific
alleles or haplotypes associated with prostate cancer and/or
colorectal cancer (e.g. the polymorphic markers of Tables 4 and 5,
and markers in linkage disequilibrium therewith). Therefore, in one
embodiment, determination of the presence or absence of a
particular marker alleles or haplotypes comprises sequence analysis
of a test sample of DNA or RNA obtained from a subject or
individual. PCR or other appropriate methods can be used to amplify
a portion of a nucleic acid associated with prostate cancer and/or
colorectal cancer, and the presence of a specific allele can then
be detected directly by sequencing the polymorphic site (or
multiple polymorphic sites in a haplotype) of the genomic DNA in
the sample.
[0214] Allele-specific oligonucleotides can also be used to detect
the presence of a particular allele in a nucleic acid associated
with prostate cancer and/or colorectal cancer (e.g. the polymorphic
markers of Tables 3 and 4, and markers in linkage disequilibrium
therewith), through the use of dot-blot hybridization of amplified
oligonucleotides with allele-specific oligonucleotide (ASO) probes
(see, for example, Saiki, R. et al., Nature, 324:163-166 (1986)).
An "allele-specific oligonucleotide" (also referred to herein as an
"allele-specific oligonucleotide probe") is an oligonucleotide of
approximately 10-50 base pairs or approximately 15-30 base pairs,
that specifically hybridizes to a nucleic acid associated with
prostate cancer and/or colorectal cancer, and which contains a
specific allele at a polymorphic site (e.g., a marker or haplotype
as described herein). An allele-specific oligonucleotide probe that
is specific for one or more particular a nucleic acid associated
with prostate cancer and/or colorectal cancer can be prepared using
standard methods (see, e.g., Current Protocols in Molecular
Biology, supra). PCR can be used to amplify the desired region. The
DNA containing the amplified region can be dot-blotted using
standard methods (see, e.g., Current Protocols in Molecular
Biology, supra), and the blot can be contacted with the
oligonucleotide probe. The presence of specific hybridization of
the probe to the amplified region can then be detected. Specific
hybridization of an allele-specific oligonucleotide probe to DNA
from the subject is indicative of a specific allele at a
polymorphic site associated with DISEASE (see, e.g., Gibbs, R. et
al., Nucleic Acids Res., 17:2437-2448 (1989) and WO 93/22456).
[0215] In another embodiment, arrays of oligonucleotide probes that
are complementary to target nucleic acid sequence segments from a
subject, can be used to identify particular alleles at polymorphic
sites. For example, an oligonucleotide array can be used.
Oligonucleotide arrays typically comprise a plurality of different
oligonucleotide probes that are coupled to a surface of a substrate
in different known locations. These arrays can generally be
produced using mechanical synthesis methods or light directed
synthesis methods that incorporate a combination of
photolithographic methods and solid phase oligonucleotide synthesis
methods, or by other methods known to the person skilled in the art
(see, e.g., Bier, F. F., et al. Adv Biochem Eng Biotechnol
109:433-53 (2008); Hoheisel, J. D., Nat Rev Genet 7:200-10 (2006);
Fan, J. B., et al. Methods Enzymol 410:57-73 (2006); Raqoussis, J.
& Elvidge, G., Expert Rev Mol Diagn 6:145-52 (2006); Mockler,
T. C., et al Genomics 85:1-15 (2005), and references cited therein,
the entire teachings of each of which are incorporated by reference
herein). Many additional descriptions of the preparation and use of
oligonucleotide arrays for detection of polymorphisms can be found,
for example, in U.S. Pat. No. 6,858,394, U.S. Pat. No. 6,429,027,
U.S. Pat. No. 5,445,934, U.S. Pat. No. 5,700,637, U.S. Pat. No.
5,744,305, U.S. Pat. No. 5,945,334, U.S. Pat. No. 6,054,270, U.S.
Pat. No. 6,300,063, U.S. Pat. No. 6,733,977, U.S. Pat. No.
7,364,858, EP 619 321, and EP 373 203, the entire teachings of
which are incorporated by reference herein.
[0216] Other methods of nucleic acid analysis that are available to
those skilled in the art can be used to detect a particular allele
at a polymorphic site associated with prostate cancer and/or
colorectal cancer (e.g. the polymorphic markers of Tables 3 and 4,
and markers in linkage disequilibrium therewith). Representative
methods include, for example, direct manual sequencing (Church and
Gilbert, Proc. Natl. Acad. Sci. USA, 81: 1991-1995 (1988); Sanger,
F., et al., Proc. Natl. Acad. Sci. USA, 74:5463-5467 (1977);
Beavis, et al., U.S. Pat. No. 5,288,644); automated fluorescent
sequencing; single-stranded conformation polymorphism assays
(SSCP); clamped denaturing gel electrophoresis (CDGE); denaturing
gradient gel electrophoresis (DGGE) (Sheffield, V., et al., Proc.
Natl. Acad. Sci. USA, 86:232-236 (1989)), mobility shift analysis
(Orita, M., et al., Proc. Natl. Acad. Sci. USA, 86:2766-2770
(1989)), restriction enzyme analysis (Flavell, R., et al., Cell,
15:25-41 (1978); Geever, R., et al., Proc. Natl. Acad. Sci. USA,
78:5081-5085 (1981)); heteroduplex analysis; chemical mismatch
cleavage (CMC) (Cotton, R., et al., Proc. Natl. Acad. Sci. USA,
85:4397-4401 (1985)); RNase protection assays (Myers, R., et al.,
Science, 230:1242-1246 (1985); use of polypeptides that recognize
nucleotide mismatches, such as E. coli mutS protein; and
allele-specific PCR.
[0217] In another embodiment of the invention, diagnosis of
prostate cancer and/or colorectal cancer or a susceptibility to
prostate cancer and/or colorectal cancer can be made by examining
expression and/or composition of a polypeptide encoded by a nucleic
acid associated with prostate cancer and/or colorectal cancer in
those instances where the genetic marker(s) or haplotype(s) of the
present invention result in a change in the composition or
expression of the polypeptide. Thus, diagnosis of a susceptibility
to prostate cancer and/or colorectal cancer can be made by
examining expression and/or composition of one of these
polypeptides, or another polypeptide encoded by a nucleic acid
associated with prostate cancer and/or colorectal cancer, in those
instances where the genetic marker or haplotype of the present
invention results in a change in the composition or expression of
the polypeptide. The haplotypes and markers of the present
invention that show association to prostate cancer and/or
colorectal cancer may play a role through their effect on one or
more of these nearby genes. Possible mechanisms affecting these
genes include, e.g., effects on transcription, effects on RNA
splicing, alterations in relative amounts of alternative splice
forms of mRNA, effects on RNA stability, effects on transport from
the nucleus to cytoplasm, and effects on the efficiency and
accuracy of translation.
[0218] Thus, in another embodiment, the variants (markers or
haplotypes) of the invention showing association to prostate cancer
and/or colorectal cancer affect the expression of a nearby gene. It
is well known that regulatory element affecting gene expression may
be located far away, even as far as tenths or hundreds of kilobases
away, from the promoter region of a gene. By assaying for the
presence or absence of at least one allele of at least one
polymorphic marker of the present invention, it is thus possible to
assess the expression level of such nearby genes.
[0219] A variety of methods can be used for detecting protein
expression levels, including enzyme linked immunosorbent assays
(ELISA), Western blots, immunoprecipitations and
immunofluorescence. A test sample from a subject is assessed for
the presence of an alteration in the expression and/or an
alteration in composition of the polypeptide encoded by a nucleic
acid associated with prostate cancer and/or colorectal cancer. An
alteration in expression of a polypeptide encoded by a nucleic acid
associated with prostate cancer and/or colorectal cancer can be,
for example, an alteration in the quantitative polypeptide
expression (i.e., the amount of polypeptide produced). An
alteration in the composition of a polypeptide encoded by a nucleic
acid associated with prostate cancer and/or colorectal cancer is an
alteration in the qualitative polypeptide expression (e.g.,
expression of a mutant polypeptide or of a different splicing
variant). In one embodiment, diagnosis of a susceptibility to
prostate cancer and/or colorectal cancer is made by detecting a
particular splicing variant encoded by a nucleic acid associated
with prostate cancer and/or colorectal cancer, or a particular
pattern of splicing variants.
[0220] Both such alterations (quantitative and qualitative) can
also be present. An "alteration" in the polypeptide expression or
composition, as used herein, refers to an alteration in expression
or composition in a test sample, as compared to the expression or
composition of the polypeptide in a control sample. A control
sample is a sample that corresponds to the test sample (e.g., is
from the same type of cells), and is from a subject who is not
affected by, and/or who does not have a susceptibility to, prostate
cancer and/or colorectal cancer. In one embodiment, the control
sample is from a subject that does not possess a marker allele or
haplotype as described herein. Similarly, the presence of one or
more different splicing variants in the test sample, or the
presence of significantly different amounts of different splicing
variants in the test sample, as compared with the control sample,
can be indicative of a susceptibility to prostate cancer and/or
colorectal cancer. An alteration in the expression or composition
of the polypeptide in the test sample, as compared with the control
sample, can be indicative of a specific allele in the instance
where the allele alters a splice site relative to the reference in
the control sample. Various means of examining expression or
composition of a polypeptide encoded by a nucleic acid are known to
the person skilled in the art and can be used, including
spectroscopy, colorimetry, electrophoresis, isoelectric focusing,
and immunoassays (e.g., David et al., U.S. Pat. No. 4,376,110) such
as immunoblotting (see, e.g., Current Protocols in Molecular
Biology, particularly chapter 10, supra).
[0221] For example, in one embodiment, an antibody (e.g., an
antibody with a detectable label) that is capable of binding to a
polypeptide encoded by a nucleic acid associated with prostate
cancer and/or colorectal cancer can be used. Antibodies can be
polyclonal or monoclonal. An intact antibody, or a fragment thereof
(e.g., Fv, Fab, Fab', F(ab').sub.2) can be used. The term
"labeled", with regard to the probe or antibody, is intended to
encompass direct labeling of the probe or antibody by coupling
(i.e., physically linking) a detectable substance to the probe or
antibody, as well as indirect labeling of the probe or antibody by
reactivity with another reagent that is directly labeled. Examples
of indirect labeling include detection of a primary antibody using
a labeled secondary antibody (e.g., a fluorescently-labeled
secondary antibody) and end-labeling of a DNA probe with biotin
such that it can be detected with fluorescently-labeled
streptavidin.
[0222] In one embodiment of this method, the level or amount of
polypeptide encoded by a nucleic acid associated with prostate
cancer and/or colorectal cancer in a test sample is compared with
the level or amount of the polypeptide in a control sample. A level
or amount of the polypeptide in the test sample that is higher or
lower than the level or amount of the polypeptide in the control
sample, such that the difference is statistically significant, is
indicative of an alteration in the expression of the polypeptide
encoded by the nucleic acid, and is diagnostic for a particular
allele or haplotype responsible for causing the difference in
expression. Alternatively, the composition of the polypeptide in a
test sample is compared with the composition of the polypeptide in
a control sample. In another embodiment, both the level or amount
and the composition of the polypeptide can be assessed in the test
sample and in the control sample.
[0223] In another embodiment, the diagnosis of a susceptibility to
prostate cancer and/or colorectal cancer is made by detecting at
least one marker or haplotypes of the present invention (e.g.,
associated alleles of the markers listed in Tables 1-6, and markers
in linkage disequilibrium therewith), in combination with an
additional protein-based, RNA-based or DNA-based assay. The methods
of the invention can also be used in combination with an analysis
of a subject's family history and risk factors (e.g., environmental
risk factors, lifestyle risk factors).
[0224] Kits
[0225] Kits useful in the methods of the invention comprise
components useful in any of the methods described herein, including
for example, primers for nucleic acid amplification, hybridization
probes, restriction enzymes (e.g., for RFLP analysis),
allele-specific oligonucleotides, antibodies that bind to an
altered polypeptide encoded by a nucleic acid of the invention as
described herein (e.g., a genomic segment comprising at least one
polymorphic marker and/or haplotype of the present invention) or to
a non-altered (native) polypeptide encoded by a nucleic acid of the
invention as described herein, means for amplification of a nucleic
acid associated with prostate cancer and/or colorectal cancer,
means for analyzing the nucleic acid sequence of a nucleic acid
associated with prostate cancer and/or colorectal cancer, means for
analyzing the amino acid sequence of a polypeptide encoded by a
nucleic acid associated with prostate cancer and/or colorectal
cancer (e.g., a prostate cancer and/or colorectal cancer protein
encoded by a prostate cancer and/or colorectal cancer-associated
gene), etc. The kits can for example include necessary buffers,
nucleic acid primers for amplifying nucleic acids of the invention
(e.g., a nucleic acid segment comprising one or more of the
polymorphic markers as described herein), and reagents for
allele-specific detection of the fragments amplified using such
primers and necessary enzymes (e.g., DNA polymerase). Additionally,
kits can provide reagents for assays to be used in combination with
the methods of the present invention, e.g., reagents for use with
other prostate cancer and/or colorectal cancer diagnostic
assays.
[0226] In one embodiment, the invention is a kit for assaying a
sample from a subject to detect the presence of prostate cancer
and/or colorectal cancer, symptoms associated with prostate cancer
and/or colorectal cancer, or a susceptibility to prostate cancer
and/or colorectal cancer in a subject, wherein the kit comprises
reagents necessary for selectively detecting at least one allele of
at least one polymorphism of the present invention in the genome of
the individual. In a particular embodiment, the reagents comprise
at least one contiguous oligonucleotide that hybridizes to a
fragment of the genome of the individual comprising at least one
polymorphism of the present invention. In another embodiment, the
reagents comprise at least one pair of oligonucleotides that
hybridize to opposite strands of a genomic segment obtained from a
subject, wherein each oligonucleotide primer pair is designed to
selectively amplify a fragment of the genome of the individual that
includes at least one polymorphism, wherein the polymorphism is
selected from the group consisting of the polymorphisms as listed
in Tables 1-6, and polymorphic markers in linkage disequilibrium
therewith. In yet another embodiment the fragment is at least 20
base pairs in size. Such oligonucleotides or nucleic acids (e.g.,
oligonucleotide primers) can be designed using portions of the
nucleic acid sequence flanking polymorphisms (e.g., SNPs or
microsatellites) that are indicative of prostate cancer and/or
colorectal cancer. In another embodiment, the kit comprises one or
more labeled nucleic acids capable of allele-specific detection of
one or more specific polymorphic markers or haplotypes associated
with prostate cancer and/or colorectal cancer, and reagents for
detection of the label. Suitable labels include, e.g., a
radioisotope, a fluorescent label, an enzyme label, an enzyme
co-factor label, a magnetic label, a spin label, an epitope
label.
[0227] In particular embodiments, the polymorphic marker or
haplotype to be detected by the reagents of the kit comprises one
or more markers, two or more markers, three or more markers, four
or more markers or five or more markers selected from the group
consisting of the markers set forth in Tables 1-6. In another
embodiment, the marker or haplotype to be detected comprises the
markers set forth in Tables 3 and 4. In another embodiment, the
marker or haplotype to be detected comprises at least one marker
from the group of markers in strong linkage disequilibrium, as
defined by values of r.sup.2 greater than 0.2, to at least one of
the group of markers listed in Tables 3 and 4. In another
embodiment, the marker or haplotype to be detected is selected from
the group consisting of rs10896450, rs7947353, rs11228565 and
rs10943605.
[0228] In one preferred embodiment, the kit for detecting the
markers of the invention comprises a detection oligonucleotide
probe, that hybridizes to a segment of template DNA containing a
SNP polymorphisms to be detected, an enhancer oligonucleotide probe
and an endonuclease. As explained in the above, the detection
oligonucleotide probe comprises a fluorescent moiety or group at
its 3' terminus and a quencher at its 5' terminus, and an enhancer
oligonucleotide, is employed, as described by Kutyavin et al.
(Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be
Gig Harbor Green or Yakima Yellow, or other suitable fluorescent
moieties. The detection probe is designed to hybridize to a short
nucleotide sequence that includes the SNP polymorphism to be
detected. Preferably, the SNP is anywhere from the terminal residue
to -6 residues from the 3' end of the detection probe. The enhancer
is a short oligonucleotide probe which hybridizes to the DNA
template 3' relative to the detection probe. The probes are
designed such that a single nucleotide gap exists between the
detection probe and the enhancer nucleotide probe when both are
bound to the template. The gap creates a synthetic abasic site that
is recognized by an endonuclease, such as Endonuclease IV. The
enzyme cleaves the dye off the fully complementary detection probe,
but cannot cleave a detection probe containing a mismatch. Thus, by
measuring the fluorescence of the released fluorescent moiety,
assessment of the presence of a particular allele defined by
nucleotide sequence of the detection probe can be performed.
[0229] The detection probe can be of any suitable size, although
preferably the probe is relatively short. In one embodiment, the
probe is from 5-100 nucleotides in length. In another embodiment,
the probe is from 10-50 nucleotides in length, and in another
embodiment, the probe is from 12-30 nucleotides in length. Other
lengths of the probe are possible and within scope of the skill of
the average person skilled in the art.
[0230] In a preferred embodiment, the DNA template containing the
SNP polymorphism is amplified by Polymerase Chain Reaction (PCR)
prior to detection, and primers for such amplification are included
in the reagent kit. In such an embodiment, the amplified DNA serves
as the template for the detection probe and the enhancer probe.
[0231] Certain embodiments of the detection probe, the enhancer
probe, and/or the primers used for amplification of the template by
PCR include the use of modified bases, including modified A and
modified G. The use of modified bases can be useful for adjusting
the melting temperature of the nucleotide molecule (probe and/or
primer) to the template DNA, for example for increasing the melting
temperature in regions containing a low percentage of G or C bases,
in which modified A with the capability of forming three hydrogen
bonds to its complementary T can be used, or for decreasing the
melting temperature in regions containing a high percentage of G or
C bases, for example by using modified G bases that form only two
hydrogen bonds to their complementary C base in a double stranded
DNA molecule. In a preferred embodiment, modified bases are used in
the design of the detection nucleotide probe. Any modified base
known to the skilled person can be selected in these methods, and
the selection of suitable bases is well within the scope of the
skilled person based on the teachings herein and known bases
available from commercial sources as known to the skilled
person.
[0232] In one of such embodiments, determination of the presence of
the marker or haplotype is indicative of a susceptibility
(increased susceptibility or decreased susceptibility) to prostate
cancer and/or colorectal cancer. In another embodiment, the
presence of the marker or haplotype is indicative of response to a
therapeutic agent for prostate cancer and/or colorectal cancer. In
another embodiment, the presence of the marker or haplotype is
indicative of prognosis of prostate cancer and/or colorectal
cancer. In yet another embodiment, the presence of the marker or
haplotype is indicative of progress of treatment of prostate cancer
and/or colorectal cancer. Such treatment may include intervention
by surgery, medication or by other means (e.g., lifestyle
changes).
[0233] In a further aspect of the present invention, a
pharmaceutical pack (kit) is provided, the pack comprising a
therapeutic agent and a set of instructions for administration of
the therapeutic agent to humans diagnostically tested for one or
more variants of the present invention, as disclosed herein. The
therapeutic agent can be a small molecule drug, an antibody, a
peptide, an antisense or RNAi molecule, or other therapeutic
molecules. In one embodiment, an individual identified as a carrier
of at least one variant of the present invention is instructed to
take a prescribed dose of the therapeutic agent. In one such
embodiment, an individual identified as a homozygous carrier of at
least one variant of the present invention is instructed to take a
prescribed dose of the therapeutic agent. In another embodiment, an
individual identified as a non-carrier of at least one variant of
the present invention is instructed to take a prescribed dose of
the therapeutic agent.
[0234] In certain embodiments, the kit further comprises a set of
instructions for using the reagents comprising the kit. In certain
embodiments, the kit further comprises a collection of data
comprising correlation data between the polymorphic markers
assessed by the kit and susceptibility to prostate cancer and/or
colorectal cancer.
[0235] Therapeutic Agents
[0236] Variants of the present invention (e.g., the markers of the
invention, e.g., the markers listed in Tables 1-6, e.g., the
markers set forth in Tables 3 and 4, and markers in linkage
disequilibrium therewith, e.g., rs10896450, rs7947353, rs11228565
and rs10943605) can be used to identify novel therapeutic targets
for prostate cancer and/or colorectal cancer. For example, genes
containing, or in linkage disequilibrium with, variants (markers
and/or haplotypes) associated with prostate cancer and/or
colorectal cancer, or their products, as well as genes or their
products that are directly or indirectly regulated by or interact
with these variant genes or their products, can be targeted for the
development of therapeutic agents to treat prostate cancer and/or
colorectal cancer, or prevent or delay onset of symptoms associated
with prostate cancer and/or colorectal cancer. Therapeutic agents
may comprise one or more of, for example, small non-protein and
non-nucleic acid molecules, proteins, peptides, protein fragments,
nucleic acids (DNA, RNA), PNA (peptide nucleic acids), or their
derivatives or mimetics which can modulate the function and/or
levels of the target genes or their gene products.
[0237] The nucleic acids and/or variants of the invention, or
nucleic acids comprising their complementary sequence, may be used
as antisense constructs to control gene expression in cells,
tissues or organs. The methodology associated with antisense
techniques is well known to the skilled artisan, and is described
and reviewed in AntisenseDrug Technology: Principles, Strategies,
and Applications, Crooke, ed., Marcel Dekker Inc., New York (2001).
In general, antisense agents (antisense oligonucleotides) are
comprised of single stranded oligonucleotides (RNA or DNA) that are
capable of binding to a complimentary nucleotide segment. By
binding the appropriate target sequence, an RNA-RNA, DNA-DNA or
RNA-DNA duplex is formed. The antisense oligonucleotides are
complementary to the sense or coding strand of a gene. It is also
possible to form a triple helix, where the antisense
oligonucleotide binds to duplex DNA.
[0238] Several classes of antisense oligonucleotide are known to
those skilled in the art, including cleavers and blockers. The
former bind to target RNA sites, activate intracellular nucleases
(e.g., RnaseH or Rnase L), that cleave the target RNA. Blockers
bind to target RNA, inhibit protein translation by steric hindrance
of the ribosomes. Examples of blockers include nucleic acids,
morpholino compounds, locked nucleic acids and methylphosphonates
(Thompson, Drug Discovery Today, 7:912-917 (2002)). Antisense
oligonucleotides are useful directly as therapeutic agents, and are
also useful for determining and validating gene function, for
example by gene knock-out or gene knock-down experiments. Antisense
technology is further described in Layery et al., Curr. Opin. Drug
Discov. Devel. 6:561-569 (2003), Stephens et al., Curr. Opin. Mol.
Ther. 5:118-122 (2003), Kurreck, Eur. J. Biochem. 270:1628-44
(2003), Dias et al., Mol. Cancer Ter. 1:347-55 (2002), Chen,
Methods Mol. Med. 75:621-636 (2003), Wang et al., Curr. Cancer Drug
Targets 1:177-96 (2001), and Bennett, Antisense Nucleic Acid Drug.
Dev. 12:215-24 (2002).
[0239] In certain embodiments, the antisense agent is an
oligonucleotide that is capable of binding to a nucleotide segment
of the LD Block C11 or LD Block C06, as described herein. Antisense
nucleotides can be from 5-500 nucleotides in length, including
5-200 nucleotides, 5-100 nucleotides, 8-50 nucleotides, and 8-30
nucleotides. In certain preferred embodiments, the antisense
nucleotides is from 14-50 nucleotides in length, including 14-40
nucleotides and 14-30 nucleotides. In certain such embodiments, the
antisense nucleotide is capable of binding to a nucleotide segment
of LD Block C11 as set forth in SEQ ID NO:201.
[0240] The variants described herein can be used for the selection
and design of antisense reagents that are specific for particular
variants. Using information about the variants described herein,
antisense oligonucleotides or other antisense molecules that
specifically target mRNA molecules that contain one or more
variants of the invention can be designed. In this manner,
expression of mRNA molecules that contain one or more variant of
the present invention (markers and/or haplotypes) can be inhibited
or blocked. In one embodiment, the antisense molecules are designed
to specifically bind a particular allelic form (i.e., one or
several variants (alleles and/or haplotypes)) of the target nucleic
acid, thereby inhibiting translation of a product originating from
this specific allele or haplotype, but which do not bind other or
alternate variants at the specific polymorphic sites of the target
nucleic acid molecule.
[0241] As antisense molecules can be used to inactivate mRNA so as
to inhibit gene expression, and thus protein expression, the
molecules can be used to treat a disease or disorder, including
prostate cancer and/or colorectal cancer. The methodology can
involve cleavage by means of ribozymes containing nucleotide
sequences complementary to one or more regions in the mRNA that
attenuate the ability of the mRNA to be translated. Such mRNA
regions include, for example, protein-coding regions, in particular
protein-coding regions corresponding to catalytic activity,
substrate and/or ligand binding sites, or other functional domains
of a protein.
[0242] The phenomenon of RNA interference (RNAi) has been actively
studied for the last decade, since its original discovery in C.
elegans (Fire et al., Nature 391:806-11 (1998)), and in recent
years its potential use in treatment of human disease has been
actively pursued (reviewed in Kim & Rossi, Nature Rev. Genet.
8:173-204 (2007)). RNA interference (RNAi), also called gene
silencing, is based on using double-stranded RNA molecules (dsRNA)
to turn off specific genes. In the cell, cytoplasmic
double-stranded RNA molecules (dsRNA) are processed by cellular
complexes into small interfering RNA (siRNA). The siRNA guide the
targeting of a protein-RNA complex to specific sites on a target
mRNA, leading to cleavage of the mRNA (Thompson, Drug Discovery
Today, 7:912-917 (2002)). The siRNA molecules are typically about
20, 21, 22 or 23 nucleotides in length. Thus, one aspect of the
invention relates to isolated nucleic acid molecules, and the use
of those molecules for RNA interference, i.e. as small interfering
RNA molecules (siRNA). In one embodiment, the isolated nucleic acid
molecules are 18-26 nucleotides in length, preferably 19-25
nucleotides in length, more preferably 20-24 nucleotides in length,
and more preferably 21, 22 or 23 nucleotides in length.
[0243] Another pathway for RNAi-mediated gene silencing originates
in endogenously encoded primary microRNA (pri-miRNA) transcripts,
which are processed in the cell to generate precursor miRNA
(pre-miRNA). These miRNA molecules are exported from the nucleus to
the cytoplasm, where they undergo processing to generate mature
miRNA molecules (miRNA), which direct translational inhibition by
recognizing target sites in the 3' untranslated regions of mRNAs,
and subsequent mRNA degradation by processing P-bodies (reviewed in
Kim & Rossi, Nature Rev. Genet. 8:173-204 (2007)).
[0244] Clinical applications of RNAi include the incorporation of
synthetic siRNA duplexes, which preferably are approximately 20-23
nucleotides in size, and preferably have 3' overlaps of 2
nucleotides. Knockdown of gene expression is established by
sequence-specific design for the target mRNA. Several commercial
sites for optimal design and synthesis of such molecules are known
to those skilled in the art.
[0245] Other applications provide longer siRNA molecules (typically
25-30 nucleotides in length, preferably about 27 nucleotides), as
well as small hairpin RNAs (shRNAs; typically about 29 nucleotides
in length). The latter are naturally expressed, as described in
Amarzguioui et al. (FEBS Lett. 579:5974-81 (2005)). Chemically
synthetic siRNAs and shRNAs are substrates for in vivo processing,
and in some cases provide more potent gene-silencing than shorter
designs (Kim et al., Nature Biotechnol. 23:222-226 (2005); Siolas
et al., Nature Biotechnol. 23:227-231 (2005)). In general siRNAs
provide for transient silencing of gene expression, because their
intracellular concentration is diluted by subsequent cell
divisions. By contrast, expressed shRNAs mediate long-term, stable
knockdown of target transcripts, for as long as transcription of
the shRNA takes place (Marques et al., Nature Biotechnol.
23:559-565 (2006); Brummelkamp et al., Science 296: 550-553
(2002)).
[0246] Since RNAi molecules, including siRNA, miRNA and shRNA, act
in a sequence-dependent manner, the variants of the present
invention (e.g., the markers set forth in Tables 1-6, e.g., the
markers set forth in Tables 3 and 4) can be used to design RNAi
reagents that recognize specific nucleic acid molecules comprising
specific alleles and/or haplotypes (e.g., the alleles and/or
haplotypes of the present invention), while not recognizing nucleic
acid molecules comprising other alleles or haplotypes. These RNAi
reagents can thus recognize and destroy the target nucleic acid
molecules. As with antisense reagents, RNAi reagents can be useful
as therapeutic agents (i.e., for turning off disease-associated
genes or disease-associated gene variants), but may also be useful
for characterizing and validating gene function (e.g., by gene
knock-out or gene knock-down experiments).
[0247] Delivery of RNAi may be performed by a range of
methodologies known to those skilled in the art. Methods utilizing
non-viral delivery include cholesterol, stable nucleic acid-lipid
particle (SNALP), heavy-chain antibody fragment (Fab), aptamers and
nanoparticles. Viral delivery methods include use of lentivirus,
adenovirus and adeno-associated virus. The siRNA molecules are in
some embodiments chemically modified to increase their stability.
This can include modifications at the 2' position of the ribose,
including 2'-O-methylpurines and 2'-fluoropyrimidines, which
provide resistance to Rnase activity. Other chemical modifications
are possible and known to those skilled in the art.
[0248] The following references provide a further summary of RNAi,
and possibilities for targeting specific genes using RNAi: Kim
& Rossi, Nat. Rev. Genet. 8:173-184 (2007), Chen &
Rajewsky, Nat. Rev. Genet. 8: 93-103 (2007), Reynolds, et al., Nat.
Biotechnol. 22:326-330 (2004), Chi et al., Proc. Natl. Acad. Sci.
USA 100:6343-6346 (2003), Vickers et al., J. Biol. Chem.
278:7108-7118 (2003), Agami, Curr. Opin. Chem. Biol. 6:829-834
(2002), Layery, et al., Curr. Opin. Drug Discov. Devel. 6:561-569
(2003), Shi, Trends Genet. 19:9-12 (2003), Shuey et al., Drug
Discov. Today 7:1040-46 (2002), McManus et al., Nat. Rev. Genet.
3:737-747 (2002), Xia et al., Nat. Biotechnol. 20:1006-10 (2002),
Plasterk et al., curr. Opin. Genet. Dev. 10:562-7 (2000), Bosher et
al., Nat. Cell Biol. 2:E31-6 (2000), and Hunter, Curr. Biol.
9:R440-442 (1999).
[0249] A genetic defect leading to increased predisposition or risk
for development of a disease, such as prostate cancer and/or
colorectal cancer, or a defect causing the disease, may be
corrected permanently by administering to a subject carrying the
defect a nucleic acid fragment that incorporates a repair sequence
that supplies the normal/wild-type nucleotide(s) at the site of the
genetic defect. Such site-specific repair sequence may concompass
an RNA/DNA oligonucleotide that operates to promote endogenous
repair of a subject's genomic DNA. The administration of the repair
sequence may be performed by an appropriate vehicle, such as a
complex with polyethelenimine, encapsulated in anionic liposomes, a
viral vector such as an adenovirus vector, or other pharmaceutical
compositions suitable for promoting intracellular uptake of the
administered nucleic acid. The genetic defect may then be overcome,
since the chimeric oligonucleotides induce the incorporation of the
normal sequence into the genome of the subject, leading to
expression of the normal/wild-type gene product. The replacement is
propagated, thus rendering a permanent repair and alleviation of
the symptoms associated with the disease or condition.
[0250] The present invention provides methods for identifying
compounds or agents that can be used to treat prostate cancer
and/or colorectal cancer. Thus, the variants of the invention are
useful as targets for the identification and/or development of
therapeutic agents. Such methods may include assaying the ability
of an agent or compound to modulate the activity and/or expression
of a nucleic acid that includes at least one of the variants
(markers and/or haplotypes) of the present invention, or the
encoded product of the nucleic acid. This in turn can be used to
identify agents or compounds that inhibit or alter the undesired
activity or expression of the encoded nucleic acid product. Assays
for performing such experiments can be performed in cell-based
systems or in cell-free systems, as known to the skilled person.
Cell-based systems include cells naturally expressing the nucleic
acid molecules of interest, or recombinant cells that have been
genetically modified so as to express a certain desired nucleic
acid molecule.
[0251] Variant gene expression in a patient can be assessed by
expression of a variant-containing nucleic acid sequence (for
example, a gene containing at least one variant of the present
invention, which can be transcribed into RNA containing the at
least one variant, and in turn translated into protein), or by
altered expression of a normal/wild-type nucleic acid sequence due
to variants affecting the level or pattern of expression of the
normal transcripts, for example variants in the regulatory or
control region of the gene. Assays for gene expression include
direct nucleic acid assays (mRNA), assays for expressed protein
levels, or assays of collateral compounds involved in a pathway,
for example a signal pathway. Furthermore, the expression of genes
that are up- or down-regulated in response to the signal pathway
can also be assayed. One embodiment includes operably linking a
reporter gene, such as luciferase, to the regulatory region of the
gene(s) of interest.
[0252] Modulators of gene expression can in one embodiment be
identified when a cell is contacted with a candidate compound or
agent, and the expression of mRNA is determined. The expression
level of mRNA in the presence of the candidate compound or agent is
compared to the expression level in the absence of the compound or
agent. Based on this comparison, candidate compounds or agents for
treating prostate cancer and/or colorectal cancer can be identified
as those modulating the gene expression of the variant gene. When
expression of mRNA or the encoded protein is statistically
significantly greater in the presence of the candidate compound or
agent than in its absence, then the candidate compound or agent is
identified as a stimulator or up-regulator of expression of the
nucleic acid. When nucleic acid expression or protein level is
statistically significantly less in the presence of the candidate
compound or agent than in its absence, then the candidate compound
is identified as an inhibitor or down-regulator of the nucleic acid
expression.
[0253] The invention further provides methods of treatment using a
compound identified through drug (compound and/or agent) screening
as a gene modulator (i.e. stimulator and/or inhibitor of gene
expression).
[0254] Methods of Assessing Probability of Response to Therapeutic
Agents, Methods of Monitoring Progress of Treatment and Methods of
Treatment
[0255] As is known in the art, individuals can have differential
responses to a particular therapy (e.g., a therapeutic agent or
therapeutic method). Pharmacogenomics addresses the issue of how
genetic variations (e.g., the variants (markers and/or haplotypes)
of the present invention) affect drug response, due to altered drug
disposition and/or abnormal or altered action of the drug. Thus,
the basis of the differential response may be genetically
determined in part. Clinical outcomes due to genetic variations
affecting drug response may result in toxicity of the drug in
certain individuals (e.g., carriers or non-carriers of the genetic
variants of the present invention), or therapeutic failure of the
drug. Therefore, the variants of the present invention may
determine the manner in which a therapeutic agent and/or method
acts on the body, or the way in which the body metabolizes the
therapeutic agent.
[0256] Accordingly, in one embodiment, the presence of a particular
allele at a polymorphic site or haplotype is indicative of a
different, e.g. a different response rate, to a particular
treatment modality for prostate cancer and/or colorectal cancer.
This means that a patient diagnosed with prostate cancer and/or
colorectal cancer, and carrying a certain allele at a polymorphic
or haplotype of the present invention (e.g., the at-risk and
protective alleles and/or haplotypes of the invention) would
respond better to, or worse to, a specific therapeutic, drug
therapy and/or other therapy used to treat the disease. Therefore,
the presence or absence of the marker allele or haplotype could aid
in deciding what treatment should be used for a the patient. For
example, for a newly diagnosed patient, the presence of a marker or
haplotype of the present invention may be assessed (e.g., through
testing DNA derived from a blood sample, as described herein). If
the patient is positive for a marker allele or haplotype at (that
is, at least one specific allele of the marker, or haplotype, is
present), then the physician recommends one particular therapy,
while if the patient is negative for the at least one allele of a
marker, or a haplotype, then a different course of therapy may be
recommended (which may include recommending that no immediate
therapy, other than serial monitoring for progression of the
disease, be performed). Thus, the patient's carrier status could be
used to help determine whether a particular treatment modality
should be administered. The value lies within the possibilities of
being able to diagnose the disease at an early stage, to select the
most appropriate treatment, and provide information to the
clinician about prognosis/aggressiveness of the disease in order to
be able to apply the most appropriate treatment.
[0257] The present invention also relates to methods of monitoring
progress or effectiveness of a treatment for a prostate cancer
and/or colorectal cancer. This can be done based on the genotype
and/or haplotype status of the markers and haplotypes of the
present invention, i.e., by assessing the absence or presence of at
least one allele of at least one polymorphic marker as disclosed
herein, or by monitoring expression of genes that are associated
with the variants (markers and haplotypes) of the present
invention. The risk gene mRNA or the encoded polypeptide can be
measured in a tissue sample (e.g., a peripheral blood sample, or a
biopsy sample). Expression levels and/or mRNA levels can thus be
determined before and during treatment to monitor its
effectiveness. Alternatively, or concomitantly, the genotype and/or
haplotype status of at least one risk variant for prostate cancer
and/or colorectal cancer as presented herein is determined before
and during treatment to monitor its effectiveness.
[0258] Alternatively, biological networks or metabolic pathways
related to the markers and haplotypes of the present invention can
be monitored by determining mRNA and/or polypeptide levels. This
can be done for example, by monitoring expression levels or
polypeptides for several genes belonging to the network and/or
pathway, in samples taken before and during treatment.
Alternatively, metabolites belonging to the biological network or
metabolic pathway can be determined before and during treatment.
Effectiveness of the treatment is determined by comparing observed
changes in expression levels/metabolite levels during treatment to
corresponding data from healthy subjects.
[0259] In a further aspect, the markers of the present invention
can be used to increase power and effectiveness of clinical trials.
Thus, individuals who are carriers of at least one at-risk variant
of the present invention, i.e. individuals who are carriers of at
least one allele of at least one polymorphic marker conferring
increased risk of developing prostate cancer and/or colorectal
cancer may be more likely to respond to a particular treatment
modality. In one embodiment, individuals who carry at-risk variants
for gene(s) in a pathway and/or metabolic network for which a
particular treatment (e.g., small molecule drug) is targeting, are
more likely to be responders to the treatment. In another
embodiment, individuals who carry at-risk variants for a gene,
which expression and/or function is altered by the at-risk variant,
are more likely to be responders to a treatment modality targeting
that gene, its expression or its gene product. This application can
improve the safety of clinical trials, but can also enhance the
chance that a clinical trial will demonstrate statistically
significant efficacy, which may be limited to a certain sub-group
of the population. Thus, one possible outcome of such a trial is
that carriers of certain genetic variants, e.g., the markers and
haplotypes of the present invention, are statistically
significantly likely to show positive response to the therapeutic
agent, i.e. experience alleviation of symptoms associated with
prostate cancer and/or colorectal cancer when taking the
therapeutic agent or drug as prescribed.
[0260] In a further aspect, the markers and haplotypes of the
present invention can be used for targeting the selection of
pharmaceutical agents for specific individuals. Personalized
selection of treatment modalities, lifestyle changes or combination
of lifestyle changes and administration of particular treatment,
can be realized by the utilization of the at-risk variants of the
present invention. Thus, the knowledge of an individual's status
for particular markers of the present invention, can be useful for
selection of treatment options that target genes or gene products
affected by the at-risk variants of the invention. Certain
combinations of variants may be suitable for one selection of
treatment options, while other gene variant combinations may target
other treatment options. Such combination of variant may include
one variant, two variants, three variants, or four or more
variants, as needed to determine with clinically reliable accuracy
the selection of treatment module.
[0261] Computer-Implemented Aspects
[0262] As understood by those of ordinary skill in the art, the
methods and information described herein may be implemented, in all
or in part, as computer executable instructions on known computer
readable media. For example, the methods described herein may be
implemented in hardware. Alternatively, the method may be
implemented in software stored in, for example, one or more
memories or other computer readable medium and implemented on one
or more processors. As is known, the processors may be associated
with one or more controllers, calculation units and/or other units
of a computer system, or implanted in firmware as desired. If
implemented in software, the routines may be stored in any computer
readable memory such as in RAM, ROM, flash memory, a magnetic disk,
a laser disk, or other storage medium, as is also known. Likewise,
this software may be delivered to a computing device via any known
delivery method including, for example, over a communication
channel such as a telephone line, the Internet, a wireless
connection, etc., or via a transportable medium, such as a computer
readable disk, flash drive, etc.
[0263] More generally, and as understood by those of ordinary skill
in the art, the various steps described above may be implemented as
various blocks, operations, tools, modules and techniques which, in
turn, may be implemented in hardware, firmware, software, or any
combination of hardware, firmware, and/or software. When
implemented in hardware, some or all of the blocks, operations,
techniques, etc. may be implemented in, for example, a custom
integrated circuit (IC), an application specific integrated circuit
(ASIC), a field programmable logic array (FPGA), a programmable
logic array (PLA), etc.
[0264] When implemented in software, the software may be stored in
any known computer readable medium such as on a magnetic disk, an
optical disk, or other storage medium, in a RAM or ROM or flash
memory of a computer, processor, hard disk drive, optical disk
drive, tape drive, etc. Likewise, the software may be delivered to
a user or a computing system via any known delivery method
including, for example, on a computer readable disk or other
transportable computer storage mechanism.
[0265] The FIGURE illustrates an example of a suitable computing
system environment 100 on which a system for the steps of the
claimed method and apparatus may be implemented. The computing
system environment 100 is only one example of a suitable computing
environment and is not intended to suggest any limitation as to the
scope of use or functionality of the method or apparatus of the
claims. Neither should the computing environment 100 be interpreted
as having any dependency or requirement relating to any one or
combination of components illustrated in the exemplary operating
environment 100.
[0266] The steps of the claimed method and system are operational
with numerous other general purpose or special purpose computing
system environments or configurations. Examples of well known
computing systems, environments, and/or configurations that may be
suitable for use with the methods or system of the claims include,
but are not limited to, personal computers, server computers,
hand-held or laptop devices, multiprocessor systems,
microprocessor-based systems, set top boxes, programmable consumer
electronics, network PCs, minicomputers, mainframe computers,
distributed computing environments that include any of the above
systems or devices; and the like.
[0267] The steps of the claimed method and system may be described
in the general context of computer-executable instructions, such as
program modules, being executed by a computer. Generally, program
modules include routines, programs, objects, components, data
structures, etc. that perform particular tasks or implement
particular abstract data types. The methods and apparatus may also
be practiced in distributed computing environments where tasks are
performed by remote processing devices that are linked through a
communications network. In both integrated and distributed
computing environments, program modules may be located in both
local and remote computer storage media including memory storage
devices.
[0268] With reference to the FIGURE, an exemplary system for
implementing the steps of the claimed method and system includes a
general purpose computing device in the form of a computer 110.
Components of computer 110 may include, but are not limited to, a
processing unit 120, a system memory 130, and a system bus 121 that
couples various system components including the system memory to
the processing unit 120. The system bus 121 may be any of several
types of bus structures including a memory bus or memory
controller, a peripheral bus, and a local bus using any of a
variety of bus architectures. By way of example, and not
limitation, such architectures include Industry Standard
Architecture (USA) bus, Micro Channel Architecture (MCA) bus,
Enhanced ISA (EISA) bus, Video Electronics Standards Association
(VESA) local bus, and Peripheral Component Interconnect (PCI) bus
also known as Mezzanine bus.
[0269] Computer 110 typically includes a variety of computer
readable media. Computer readable media can be any available media
that can be accessed by computer 110 and includes both volatile and
nonvolatile media, removable and non-removable media. By way of
example, and not limitation, computer readable media may comprise
computer storage media and communication media. Computer storage
media includes both volatile and nonvolatile, removable and
non-removable media implemented in any method or technology for
storage of information such as computer readable instructions, data
structures, program modules or other data. Computer storage media
includes, but is not limited to, RAM, ROM, EEPROM, flash memory or
other memory technology, CD-ROM, digital versatile disks (DVD) or
other optical disk storage, magnetic cassettes, magnetic tape,
magnetic disk storage or other magnetic storage devices, or any
other medium which can be used to store the desired information and
which can accessed by computer 110. Communication media typically
embodies computer readable instructions, data structures, program
modules or other data in a modulated data signal such as a carrier
wave or other transport mechanism and includes any information
delivery media. The term "modulated data signal" means a signal
that has one or more of its characteristics set or changed in such
a manner as to encode information in the signal. By way of example,
and not limitation, communication media includes wired media such
as a wired network or direct-wired connection, and wireless media
such as acoustic, RF, infrared and other wireless media.
Combinations of the any of the above should also be included within
the scope of computer readable media.
[0270] The system memory 130 includes computer storage media in the
form of volatile and/or nonvolatile memory such as read only memory
(ROM) 131 and random access memory (RAM) 132. A basic input/output
system 133 (BIOS), containing the basic routines that help to
transfer information between elements within computer 110, such as
during start-up, is typically stored in ROM 131. RAM 132 typically
contains data and/or program modules that are immediately
accessible to and/or presently being operated on by processing unit
120. By way of example, and not limitation, the FIGURE illustrates
operating system 134, application programs 135, other program
modules 136, and program data 137.
[0271] The computer 110 may also include other
removable/non-removable, volatile/nonvolatile computer storage
media. By way of example only, the FIGURE illustrates a hard disk
drive 140 that reads from or writes to non-removable, nonvolatile
magnetic media, a magnetic disk drive 151 that reads from or writes
to a removable, nonvolatile magnetic disk 152, and an optical disk
drive 155 that reads from or writes to a removable, nonvolatile
optical disk 156 such as a CD ROM or other optical media. Other
removable/non-removable, volatile/nonvolatile computer storage
media that can be used in the exemplary operating environment
include, but are not limited to, magnetic tape cassettes, flash
memory cards, digital versatile disks, digital video tape, solid
state RAM, solid state ROM, and the like. The hard disk drive 141
is typically connected to the system bus 121 through a
non-removable memory interface such as interface 140, and magnetic
disk drive 151 and optical disk drive 155 are typically connected
to the system bus 121 by a removable memory interface, such as
interface 150.
[0272] The drives and their associated computer storage media
discussed above and illustrated in the FIGURE, provide storage of
computer readable instructions, data structures, program modules
and other data for the computer 110. In the FIGURE, for example,
hard disk drive 141 is illustrated as storing operating system 144,
application programs 145, other program modules 146, and program
data 147. Note that these components can either be the same as or
different from operating system 134, application programs 135,
other program modules 136, and program data 137. Operating system
144, application programs 145, other program modules 146, and
program data 147 are given different numbers here to illustrate
that, at a minimum, they are different copies. A user may enter
commands and information into the computer 20 through input devices
such as a keyboard 162 and pointing device 161, commonly referred
to as a mouse, trackball or touch pad. Other input devices (not
shown) may include a microphone, joystick, game pad, satellite
dish, scanner, or the like. These and other input devices are often
connected to the processing unit 120 through a user input interface
160 that is coupled to the system bus, but may be connected by
other interface and bus structures, such as a parallel port, game
port or a universal serial bus (USB). A monitor 191 or other type
of display device is also connected to the system bus 121 via an
interface, such as a video interface 190. In addition to the
monitor, computers may also include other peripheral output devices
such as speakers 197 and printer 196, which may be connected
through an output peripheral interface 190.
[0273] The computer 110 may operate in a networked environment
using logical connections to one or more remote computers, such as
a remote computer 180. The remote computer 180 may be a personal
computer, a server, a router, a network PC, a peer device or other
common network node, and typically includes many or all of the
elements described above relative to the computer 110, although
only a memory storage device 181 has been illustrated in the
FIGURE. The logical connections depicted in FIGURE include a local
area network (LAN) 171 and a wide area network (WAN) 173, but may
also include other networks. Such networking environments are
commonplace in offices, enterprise-wide computer networks,
intranets and the Internet.
[0274] When used in a LAN networking environment, the computer 110
is connected to the LAN 171 through a network interface or adapter
170. When used in a WAN networking environment, the computer 110
typically includes a modem 172 or other means for establishing
communications over the WAN 173, such as the Internet. The modem
172, which may be internal or external, may be connected to the
system bus 121 via the user input interface 160, or other
appropriate mechanism. In a networked environment, program modules
depicted relative to the computer 110, or portions thereof, may be
stored in the remote memory storage device. By way of example, and
not limitation, the FIGURE illustrates remote application programs
185 as residing on memory device 181. It will be appreciated that
the network connections shown are exemplary and other means of
establishing a communications link between the computers may be
used.
[0275] Although the forgoing text sets forth a detailed description
of numerous different embodiments of the invention, it should be
understood that the scope of the invention is defined by the words
of the claims set forth at the end of this patent. The detailed
description is to be construed as exemplary only and does not
describe every possibly embodiment of the invention because
describing every possible embodiment would be impractical, if not
impossible. Numerous alternative embodiments could be implemented,
using either current technology or technology developed after the
filing date of this patent, which would still fall within the scope
of the claims defining the invention.
[0276] While the risk evaluation system and method, and other
elements, have been described as preferably being implemented in
software, they may be implemented in hardware, firmware, etc., and
may be implemented by any other processor. Thus, the elements
described herein may be implemented in a standard multi-purpose CPU
or on specifically designed hardware or firmware such as an
application-specific integrated circuit (ASIC) or other hard-wired
device as desired, including, but not limited to, the computer 110
of the FIGURE. When implemented in software, the software routine
may be stored in any computer readable memory such as on a magnetic
disk, a laser disk, or other storage medium, in a RAM or ROM of a
computer or processor, in any database, etc. Likewise, this
software may be delivered to a user or a diagnostic system via any
known or desired delivery method including, for example, on a
computer readable disk or other transportable computer storage
mechanism or over a communication channel such as a telephone line,
the interne, wireless communication, etc. (which are viewed as
being the same as or interchangeable with providing such software
via a transportable storage medium).
[0277] Thus, many modifications and variations may be made in the
techniques and structures described and illustrated herein without
departing from the spirit and scope of the present invention. Thus,
it should be understood that the methods and apparatus described
herein are illustrative only and are not limiting upon the scope of
the invention.
[0278] Accordingly, the invention relates to computer-implemented
applications using the polymorphic markers and haplotypes described
herein, and genotype and/or disease-association data derived
therefrom. Such applications can be useful for storing,
manipulating or otherwise analyzing genotype data that is useful in
the methods of the invention. One example pertains to storing
genotype information derived from an individual on readable media,
so as to be able to provide the genotype information to a third
party (e.g., the individual, a guardian of the individual, a health
care provider or genetic analysis service provider), or for
deriving information from the genotype data, e.g., by comparing the
genotype data to information about genetic risk factors
contributing to increased susceptibility to prostate and/or
colorectal cancer, and reporting results based on such
comparison.
[0279] In general terms, computer-readable media has capabilities
of storing (i) identifier information for at least one polymorphic
marker or a haplotype, as described herein; (ii) an indicator of
the frequency of at least one allele of said at least one marker,
or the frequency of a haplotype, in individuals with prostate
cancer and/or colorectal cancer; and an indicator of the frequency
of at least one allele of said at least one marker, or the
frequency of a haplotype, in a reference population. The reference
population can be a disease-free population of individuals.
Alternatively, the reference population is a random sample from the
general population, and is thus representative of the population at
large. The frequency indicator may be a calculated frequency, a
count of alleles and/or haplotype copies, or normalized or
otherwise manipulated values of the actual frequencies that are
suitable for the particular medium.
[0280] The markers and haplotypes described herein to be associated
with increased susceptibility (e.g., increased risk) of prostate
and colorectal cancer, are in certain embodiments useful for
interpretation and/or analysis of genotype data. Thus in certain
embodiments, an identification of an at-risk allele for prostate
cancer and/or colorectal cancer, as shown herein, or an allele at a
polymorphic marker in LD with any one of the markers shown herein
to be associated with these cancers, is indicative of the
individual from whom the genotype data originates is at increased
risk of prostate cancer and/or colorectal cancer. In one such
embodiment, genotype data is generated for at least one such
polymorphic marker, or a marker in linkage disequilibrium
therewith. The genotype data is subsequently made available to a
third party, such as the individual from whom the data originates,
his/her guardian or representative, a physician or health care
worker, genetic counselor, or insurance agent, for example via a
user interface accessible over the internet, together with an
interpretation of the genotype data, e.g., in the form of a risk
measure (such as an absolute risk (AR), risk ratio (RR) or odds
ratio (OR)) for the disease. In another embodiment, at-risk markers
identified in a genotype dataset derived from an individual are
assessed and results from the assessment of the risk conferred by
the presence of such at-risk variants in the dataset are made
available to the third party, for example via a secure web
interface, or by other communication means. The results of such
risk assessment can be reported in numeric form (e.g., by risk
values, such as absolute risk, relative risk, and/or an odds ratio,
or by a percentage increase in risk compared with a reference), by
graphical means, or by other means suitable to illustrate the risk
to the individual from whom the genotype data is derived.
[0281] Nucleic Acids and Polypeptides
[0282] The nucleic acids and polypeptides described herein can be
used in methods an kits of the present invention, as described in
the above.
[0283] An "isolated" nucleic acid molecule, as used herein, is one
that is separated from nucleic acids that normally flank the gene
or nucleotide sequence (as in genomic sequences) and/or has been
completely or partially purified from other transcribed sequences
(e.g., as in an RNA library). For example, an isolated nucleic acid
of the invention can be substantially isolated with respect to the
complex cellular milieu in which it naturally occurs, or culture
medium when produced by recombinant techniques, or chemical
precursors or other chemicals when chemically synthesized. In some
instances, the isolated material will form part of a composition
(for example, a crude extract containing other substances), buffer
system or reagent mix. In other circumstances, the material can be
purified to essential homogeneity, for example as determined by
polyacrylamide gel electrophoresis (PAGE) or column chromatography
(e.g., HPLC). An isolated nucleic acid molecule of the invention
can comprise at least about 50%, at least about 80% or at least
about 90% (on a molar basis) of all macromolecular species present.
With regard to genomic DNA, the term "isolated" also can refer to
nucleic acid molecules that are separated from the chromosome with
which the genomic DNA is naturally associated. For example, the
isolated nucleic acid molecule can contain less than about 250 kb,
200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3
kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the
nucleic acid molecule in the genomic DNA of the cell from which the
nucleic acid molecule is derived.
[0284] The nucleic acid molecule can be fused to other coding or
regulatory sequences and still be considered isolated. Thus,
recombinant DNA contained in a vector is included in the definition
of "isolated" as used herein. Also, isolated nucleic acid molecules
include recombinant DNA molecules in heterologous host cells or
heterologous organisms, as well as partially or substantially
purified DNA molecules in solution. "Isolated" nucleic acid
molecules also encompass in vivo and in vitro RNA transcripts of
the DNA molecules of the present invention. An isolated nucleic
acid molecule or nucleotide sequence can include a nucleic acid
molecule or nucleotide sequence that is synthesized chemically or
by recombinant means. Such isolated nucleotide sequences are
useful, for example, in the manufacture of the encoded polypeptide,
as probes for isolating homologous sequences (e.g., from other
mammalian species), for gene mapping (e.g., by in situ
hybridization with chromosomes), or for detecting expression of the
gene in tissue (e.g., human tissue), such as by Northern blot
analysis or other hybridization techniques.
[0285] The invention also pertains to nucleic acid molecules that
hybridize under high stringency hybridization conditions, such as
for selective hybridization, to a nucleotide sequence described
herein (e.g., nucleic acid molecules that specifically hybridize to
a nucleotide sequence containing a polymorphic site associated with
a marker or haplotype described herein). Such nucleic acid
molecules can be detected and/or isolated by allele- or
sequence-specific hybridization (e.g., under high stringency
conditions). Stringency conditions and methods for nucleic acid
hybridizations are well known to the skilled person (see, e.g.,
Current Protocols in Molecular Biology, Ausubel, F. et al, John
Wiley & Sons, (1998), and Kraus, M. and Aaronson, S., Methods
Enzymol., 200:546-556 (1991), the entire teachings of which are
incorporated by reference herein.
[0286] The percent identity of two nucleotide or amino acid
sequences can be determined by aligning the sequences for optimal
comparison purposes (e.g., gaps can be introduced in the sequence
of a first sequence). The nucleotides or amino acids at
corresponding positions are then compared, and 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.times.100). In certain embodiments,
the length of a sequence aligned for comparison purposes is at
least 30%, at least 40%, at least 50%, at least 60%, at least 70%,
at least 80%, at least 90%, or at least 95%, of the length of the
reference sequence. The actual comparison of the two sequences can
be accomplished by well-known methods, for example, using a
mathematical algorithm. A non-limiting example of such a
mathematical algorithm is described in Karlin, S, and Altschul, S.,
Proc. Natl. Acad. Sci. USA, 90:5873-5877 (1993). Such an algorithm
is incorporated into the NBLAST and XBLAST programs (version 2.0),
as described in Altschul, S. et al., Nucleic Acids Res.,
25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST
programs, the default parameters of the respective programs (e.g.,
NBLAST) can be used. See the website on the world wide web at
ncbi.nlm.nih.gov. In one embodiment, parameters for sequence
comparison can be set at score=100, wordlength=12, or can be varied
(e.g., W=5 or W=20).
[0287] Other examples include the algorithm of Myers and Miller,
CABIOS (1989), ADVANCE and ADAM as described in Torellis, A. and
Robotti, C., Comput. Appl. Biosci. 10:3-5 (1994); and FASTA
described in Pearson, W. and Lipman, D., Proc. Natl. Acad. Sci.
USA, 85:2444-48 (1988). In another embodiment, the percent identity
between two amino acid sequences can be accomplished using the GAP
program in the GCG software package (Accelrys, Cambridge, UK).
[0288] The present invention also provides isolated nucleic acid
molecules that contain a fragment or portion that hybridizes under
highly stringent conditions to a nucleic acid that comprises, or
consists of, the nucleotide sequence of LD Block C06 and/or LD
Block C11, as defined herein, or a nucleotide sequence comprising,
or consisting of, the complement of the nucleotide sequence of LD
Block C06 and/or LD Block C11, wherein the nucleotide sequence
comprises at least one polymorphic allele contained in the markers
and haplotypes described herein. The nucleic acid fragments of the
invention are at least about 15, at least about 18, 20, 23 or 25
nucleotides, and can be 30, 40, 50, 100, 200, 500, 1000, 10,000 or
more nucleotides in length.
[0289] The nucleic acid fragments of the invention are used as
probes or primers in assays such as those described herein.
"Probes" or "primers" are oligonucleotides that hybridize in a
base-specific manner to a complementary strand of a nucleic acid
molecule. In addition to DNA and RNA, such probes and primers
include polypeptide nucleic acids (PNA), as described in Nielsen,
P. et al., Science 254:1497-1500 (1991). A probe or primer
comprises a region of nucleotide sequence that hybridizes to at
least about 15, typically about 20-25, and in certain embodiments
about 40, 50 or 75, consecutive nucleotides of a nucleic acid
molecule. In one embodiment, the probe or primer comprises at least
one allele of at least one polymorphic marker or at least one
haplotype described herein, or the complement thereof. In
particular embodiments, a probe or primer can comprise 100 or fewer
nucleotides; for example, in certain embodiments from 6 to 50
nucleotides, or, for example, from 12 to 30 nucleotides. In other
embodiments, the probe or primer is at least 70% identical, at
least 80% identical, at least 85% identical, at least 90%
identical, or at least 95% identical, to the contiguous nucleotide
sequence or to the complement of the contiguous nucleotide
sequence. In another embodiment, the probe or primer is capable of
selectively hybridizing to the contiguous nucleotide sequence or to
the complement of the contiguous nucleotide sequence. Often, the
probe or primer further comprises a label, e.g., a radioisotope, a
fluorescent label, an enzyme label, an enzyme co-factor label, a
magnetic label, a spin label, an epitope label.
[0290] The nucleic acid molecules of the invention, such as those
described above, can be identified and isolated using standard
molecular biology techniques well known to the skilled person. The
amplified DNA can be labeled (e.g., radiolabeled) and used as a
probe for screening a cDNA library derived from human cells. The
cDNA can be derived from mRNA and contained in a suitable vector.
Corresponding clones can be isolated, DNA can obtained following in
vivo excision, and the cloned insert can be sequenced in either or
both orientations by art-recognized methods to identify the correct
reading frame encoding a polypeptide of the appropriate molecular
weight. Using these or similar methods, the polypeptide and the DNA
encoding the polypeptide can be isolated, sequenced and further
characterized.
[0291] Antibodies
[0292] The invention also provides antibodies which bind to an
epitope comprising either a variant amino acid sequence (e.g.,
comprising an amino acid substitution) encoded by a variant allele
or the reference amino acid sequence encoded by the corresponding
non-variant or wild-type allele. The term "antibody" as used herein
refers to immunoglobulin molecules and immunologically active
portions of immunoglobulin molecules, i.e., molecules that contain
antigen-binding sites that specifically bind an antigen. A molecule
that specifically binds to a polypeptide of the invention is a
molecule that binds to that polypeptide or a fragment thereof, but
does not substantially bind other molecules in a sample, e.g., a
biological sample, which naturally contains the polypeptide.
Examples of immunologically active portions of immunoglobulin
molecules include F(ab) and F(ab').sub.2 fragments which can be
generated by treating the antibody with an enzyme such as pepsin.
The invention provides polyclonal and monoclonal antibodies that
bind to a polypeptide of the invention. 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 of a polypeptide of the invention. A monoclonal
antibody composition thus typically displays a single binding
affinity for a particular polypeptide of the invention with which
it immunoreacts.
[0293] Polyclonal antibodies can be prepared as described above by
immunizing a suitable subject with a desired immunogen, e.g.,
polypeptide of the invention or a fragment thereof. The antibody
titer in the immunized subject can be monitored over time by
standard techniques, such as with an enzyme linked immunosorbent
assay (ELISA) using immobilized polypeptide. If desired, the
antibody molecules directed against the polypeptide can be isolated
from the mammal (e.g., from the blood) and further purified by
well-known techniques, such as protein A chromatography to obtain
the IgG fraction. At an appropriate time after immunization, e.g.,
when the antibody titers are highest, antibody-producing cells can
be obtained from the subject and used to prepare monoclonal
antibodies by standard techniques, such as the hybridoma technique
originally described by Kohler and Milstein, Nature 256:495-497
(1975), the human B cell hybridoma technique (Kozbor et al.,
Immunol. Today 4: 72 (1983)), the EBV-hybridoma technique (Cole et
al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 1985,
Inc., pp. 77-96) or trioma techniques. The technology for producing
hybridomas is well known (see generally Current Protocols in
Immunology (1994) Coligan et al., (eds.) John Wiley & Sons,
Inc., New York, N.Y.). Briefly, an immortal cell line (typically a
myeloma) is fused to lymphocytes (typically splenocytes) from a
mammal immunized with an immunogen as described above, and the
culture supernatants of the resulting hybridoma cells are screened
to identify a hybridoma producing a monoclonal antibody that binds
a polypeptide of the invention.
[0294] Any of the many well known protocols used for fusing
lymphocytes and immortalized cell lines can be applied for the
purpose of generating a monoclonal antibody to a polypeptide of the
invention (see, e.g., Current Protocols in Immunology, supra;
Galfre et al., Nature 266:55052 (1977); R. H. Kenneth, in
Monoclonal Antibodies: A New Dimension In Biological Analyses,
Plenum Publishing Corp., New York, N.Y. (1980); and Lerner, Yale J.
Biol. Med. 54:387-402 (1981)). Moreover, the ordinarily skilled
worker will appreciate that there are many variations of such
methods that also would be useful.
[0295] Alternative to preparing monoclonal antibody-secreting
hybridomas, a monoclonal antibody to a polypeptide of the invention
can be identified and isolated by screening a recombinant
combinatorial immunoglobulin library (e.g., an antibody phage
display library) with the polypeptide to thereby isolate
immunoglobulin library members that bind the polypeptide. Kits for
generating and screening phage display libraries are commercially
available (e.g., the Pharmacia Recombinant Phage Antibody System,
Catalog No. 27-9400-01; and the Stratagene SurfZAP.TM. Phage
Display Kit, Catalog No. 240612). Additionally, examples of methods
and reagents particularly amenable for use in generating and
screening antibody display library can be found in, for example,
U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT
Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT
Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT
Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT
Publication No. WO 90/02809; Fuchs et al., Bio/Technology 9:
1370-1372 (1991); Hay et al., Hum. Antibod. Hybridomas 3:81-85
(1992); Huse et al., Science 246: 1275-1281 (1989); and Griffiths
et al., EMBO J. 12:725-734 (1993).
[0296] Additionally, recombinant antibodies, such as chimeric and
humanized monoclonal antibodies, comprising both human and
non-human portions, which can be made using standard recombinant
DNA techniques, are within the scope of the invention. Such
chimeric and humanized monoclonal antibodies can be produced by
recombinant DNA techniques known in the art.
[0297] In general, antibodies of the invention (e.g., a monoclonal
antibody) can be used to isolate a polypeptide of the invention by
standard techniques, such as affinity chromatography or
immunoprecipitation. A polypeptide-specific antibody can facilitate
the purification of natural polypeptide from cells and of
recombinantly produced polypeptide expressed in host cells.
Moreover, an antibody specific for a polypeptide of the invention
can be used to detect the polypeptide (e.g., in a cellular lysate,
cell supernatant, or tissue sample) in order to evaluate the
abundance and pattern of expression of the polypeptide. Antibodies
can be used diagnostically to monitor protein levels in tissue as
part of a clinical testing procedure, e.g., to, for example,
determine the efficacy of a given treatment regimen. The antibody
can be coupled to a detectable substance to facilitate its
detection. Examples of detectable substances include various
enzymes, prosthetic groups, fluorescent materials, luminescent
materials, bioluminescent materials, and radioactive materials.
Examples of suitable enzymes include horseradish peroxidase,
alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;
examples of suitable prosthetic group complexes include
streptavidin/biotin and avidin/biotin; examples of suitable
fluorescent materials include umbelliferone, fluorescein,
fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine
fluorescein, dansyl chloride or phycoerythrin; an example of a
luminescent material includes luminol; examples of bioluminescent
materials include luciferase, luciferin, and aequorin, and examples
of suitable radioactive material include .sup.125I, .sup.131I,
.sup.35S or .sup.3H.
[0298] Antibodies may also be useful in pharmacogenomic analysis.
In such embodiments, antibodies against variant proteins encoded by
nucleic acids according to the invention, such as variant proteins
that are encoded by nucleic acids that contain at least one
polymorphic marker of the invention, can be used to identify
individuals that require modified treatment modalities.
[0299] Antibodies can furthermore be useful for assessing
expression of variant proteins in disease states, such as in active
stages of a cancer, such as prostate cancer and/or colorectal
cancer, or in an individual with a predisposition to a cancer
related to the function of the protein, in particular prostate
cancer and colorectal cancer. Antibodies specific for a variant
protein of the present invention that is encoded by a nucleic acid
that comprises at least one polymorphic marker or haplotype as
described herein can be used to screen for the presence of the
variant protein, for example to screen for a predisposition to
prostate cancer and/or colorectal cancer, as indicated by the
presence of the variant protein.
[0300] Antibodies can be used in other methods. Thus, antibodies
are useful as diagnostic tools for evaluating proteins, such as
variant proteins of the invention, in conjunction with analysis by
electrophoretic mobility, isoelectric point, tryptic or other
protease digest, or for use in other physical assays known to those
skilled in the art. Antibodies may also be used in tissue typing.
In one such embodiment, a specific variant protein has been
correlated with expression in a specific tissue type, and
antibodies specific for the variant protein can then be used to
identify the specific tissue type.
[0301] Subcellular localization of proteins, including variant
proteins, can also be determined using antibodies, and can be
applied to assess aberrant subcellular localization of the protein
in cells in various tissues. Such use can be applied in genetic
testing, but also in monitoring a particular treatment modality. In
the case where treatment is aimed at correcting the expression
level or presence of the variant protein or aberrant tissue
distribution or developmental expression of the variant protein,
antibodies specific for the variant protein or fragments thereof
can be used to monitor therapeutic efficacy.
[0302] Antibodies are further useful for inhibiting variant protein
function, for example by blocking the binding of a variant protein
to a binding molecule or partner. Such uses can also be applied in
a therapeutic context in which treatment involves inhibiting a
variant protein's function. An antibody can be for example be used
to block or competitively inhibit binding, thereby modulating
(i.e., agonizing or antagonizing) the activity of the protein.
Antibodies can be prepared against specific protein fragments
containing sites required for specific function or against an
intact protein that is associated with a cell or cell membrane. For
administration in vivo, an antibody may be linked with an
additional therapeutic payload, such as radionuclide, an enzyme, an
immunogenic epitope, or a cytotoxic agent, including bacterial
toxins (diphtheria or plant toxins, such as ricin). The in vivo
half-life of an antibody or a fragment thereof may be increased by
pegylation through conjugation to polyethylene glycol.
[0303] The present invention further relates to kits for using
antibodies in the methods described herein. This includes, but is
not limited to, kits for detecting the presence of a variant
protein in a test sample. One preferred embodiment comprises
antibodies such as a labelled or labelable antibody and a compound
or agent for detecting variant proteins in a biological sample,
means for determining the amount or the presence and/or absence of
variant protein in the sample, and means for comparing the amount
of variant protein in the sample with a standard, as well as
instructions for use of the kit.
[0304] The present invention will now be exemplified by the
following non-limiting example.
EXEMPLIFICATION
Example 1
Identification of Markers and LD Block Regions Associated with
Prostate Cancer
[0305] Patients Involved in the Genetics Study
[0306] A population based list of all prostate and colorectal
cancer patients that were diagnosed in Iceland from 1955 to 2005
form the basis for this study. Patients have been invited to join
the study since 2001 on an ongoing basis. As of June 2007, blood
samples from 1,850 prostate cancer and 1,169 colorectal cancer
patients have been recruited. Genomic DNA from those samples, as
well as samples from over 27,000 control individuals was extracted
and genotyped.
[0307] Genotyping
[0308] A genome-wide scan of 1,645 Icelandic individuals diagnosed
with Prostate Cancer, 1,010 colorectal cancer patients and 27,049
population controls was performed using Infinium HumanHap300 SNP
chips from Illumina for assaying approximately 317,000 single
nucleotide polymorphisms (SNPs) on a single chip (Illumina, San
Diego, Calif., USA). SNP genotyping for replication in other
case-control cohorts was carried using the Centaurus platform
(Nanogen).
[0309] Statistical Methods for Association and Haplotype
Analysis
[0310] For single marker association to the disease, Fisher exact
test was used to calculate a two-sided P-value for each individual
allele. When presenting the results, we used allelic frequencies
rather than carrier frequencies for SNPs and haplotypes. The
program NEMO (NEsted Models; Gretarsdottir, et al., Nat Genet. 2003
October; 35(2):131-8) was used both to study marker-marker
association and to calculate linkage disequilibrium (LD) between
markers. With NEMO, haplotype frequencies are estimated by maximum
likelihood and the differences between patients and controls are
tested using a generalized likelihood ratio test. The maximum
likelihood estimates, likelihood ratios and P-values are computed
with the aid of the EM-algorithm directly for the observed data,
and hence the loss of information due to the uncertainty with phase
and missing genotypes is automatically captured by the likelihood
ratios, and under most situations, large sample theory can be used
to reliably determine statistical significance. The relative risk
(RR) of an allele or a haplotype, i.e., the risk of an allele
compared to all other alleles of the same marker, is calculated
assuming the multiplicative model (Terwilliger, J. D. & Ott, J.
A haplotype-based `haplotype relative risk` approach to detecting
allelic associations. Hum. Hered. 42, 337-46 (1992) and Falk, C. T.
& Rubinstein, P. Haplotype relative risks: an easy reliable way
to construct a proper control sample for risk calculations. Ann.
Hum. Genet. 51 (Pt 3), 227-33 (1987)), together with the population
attributable risk (PAR). When controls are considered unaffected
(i.e., disease-free), the relative risk is replaced by an estimate
for the odds ratio (OR) of the particular marker allele or
haplotype.
[0311] As a measure of LD, we use two standard definitions of LD,
D' and R.sup.2 (Lewontin, R., Genetics, 49:49-67 (1964) and Hill,
W. G. and A. Robertson, Theor. Appl. Genet., 22:226-231 (1968)) as
they provide complementary information on the amount of LD. For the
purpose of estimating D' and R.sup.2, the frequencies of all
two-marker allele combinations are estimated using maximum
likelihood methods and the deviation from linkage disequilibrium is
evaluated using a likelihood ratio test. The standard definitions
of D' and R.sup.2 are extended to include microsatellites by
averaging over the values for all possible allele combinations of
the two markers weighted by the marginal allele probabilities.
[0312] Results
[0313] Through analysis of over 300,000 markers across the genome,
we identified two regions that are associated with prostate and
colorectal cancer. In Table 1, we show results of association of
markers rs10896450 and rs7947353 on Chr 11q13.3 to prostate cancer.
The two markers are fully correlated (D'=1 and r.sup.2=1; see
footnote of Table 1) and do therefore essentially represent the
same association signal The G allele of SNP marker rs10896450
confers increased risk of prostate cancer, with an odds ratio (OR)
of 1.17 in the Icelandic samples (P=6.6.times.10.sup.-5).
[0314] To validate the initial discovery, we attempted to genotype
the rs10896450 SNP marker in prostate cancer cohorts from the
Netherlands, Spain and US (Chicago, Ill.). However, the design of
the Centaurus assay failed for this marker and we therefore
selected a fully correlated SNP rs7947353 (D'=1 and r.sup.2=1; see
footnote of Table 1) for further genotyping and analysis in the
replication samples. The results for allele A of SNP marker
rs7947353 from the replication cohorts are shown in Table 1, and
are comparable to the results for the Icelandic discovery cohort.
The observed risk in the Spanish cohort is somewhat lower than in
Iceland, while the US cohort has a higher risk. Overall, the
association is significant with a p-value of
1.43.times.10.sup.6.
[0315] A second association signal was detected on Chromosome 6 for
prostate cancer (Table 2a). The signal was replicated in Dutch and
Spanish cohort, both which gave increased risk conferred by the G
allele of the rs10943605 SNP marker, although only the replication
in the Dutch cohort is statistically significant. The G allele of
the rs10943605 SNP marker was also found to be associated with
increased risk of developing colorectal cancer, with an OR of 1.14
in the Icelandic colorectal cancer samples (P=4.8.times.10.sup.-3)
(Table 2b).
TABLE-US-00002 TABLE 1 Association results for 11q13.3 and prostate
cancer in Iceland discovery cohort, and replication cohorts from
The Netherlands, Spain, and the US Study population (N cases/N
controls) Frequency Variant (allele) Cases Controls OR P value
Iceland(1,645/21,474) rs10896450 (G).sup.a 0.505 0.466 1.17 6.6
.times. 10.sup.-5 rs7947353 (A).sup.a 0.505 0.466 1.17 6.6 .times.
10.sup.-5 The Netherlands (998/2,014) rs7947353 (A) 0.528 0.500
1.12 0.042 Spain (455/1,066) rs7947353 (A) 0.579 0.564 1.06 0.450
Chicago, Illinois (661/292) rs7947353 (A) 0.545 0.493 1.23 0.035
All above combined (3,759/24,846) rs7947353 (A) -- 0.506 1.15 1.43
.times. 10.sup.-6 .sup.aCorrelation between the two markers see
below (results are based on analysis of 2,340 Icelanders: M1 M2 D'
r.sup.2 rs10896450 rs7947353 1 1
TABLE-US-00003 TABLE 2a Association results for 6q14.1 and prostate
cancer in Icelandic discovery cohorts, and replication cohorts from
The Netherlands and Spain. Study population (N cases/N controls)
Frequency Variant (allele) Cases Controls OR P value Iceland PrCa
(1,645/21,472) rs10943605 (G) 0.597 0.557 1.18 2.72 .times.
10.sup.-5 The Netherlands PrCa (910/2,006) rs10943605 (G) 0.530
0.490 1.17 6.04 .times. 10.sup.-3 Spain PrCa (436/1,417) rs10943605
(G) 0.567 0.553 1.06 0.480 All above combined (2,991/24,895)
rs10943605 (G) -- 0.533 1.16 9.35 .times. 10.sup.-7
TABLE-US-00004 TABLE 2b Association results for 6q14.1 and
colorectal cancer in Iceland Study population (N cases/N controls)
Frequency Variant (allele) Cases Controls OR P value Iceland ColCa
(1,010/27,033) rs10943605 (G) 0.591 0.558 1.14 4.8 .times.
10.sup.-3
TABLE-US-00005 TABLE 3 SNP markers that are in linkage
disequilibrium with marker rs10943605 on Chromosome 6. Marker 1
Marker 1 Marker 2 D' r.sup.2 p-value location Seq ID No: rs611737
rs10943605 0.631963 0.293866 3.91E-09 79300773 1 rs666982
rs10943605 0.605842 0.284949 6.11E-09 79316431 2 rs685245
rs10943605 0.606322 0.29663 1.77E-08 79327502 3 rs547472 rs10943605
0.608391 0.291941 4.51E-09 79341083 4 rs654628 rs10943605 0.603324
0.288712 6.47E-09 79343805 5 rs605697 rs10943605 0.622444 0.296062
6.91E-09 79345910 6 rs605264 rs10943605 0.605842 0.284949 6.11E-09
79346003 7 rs603964 rs10943605 0.609097 0.293439 6.80E-09 79346271
8 rs612489 rs10943605 0.604036 0.290201 9.72E-09 79346309 9
rs484582 rs10943605 0.610497 0.30416 4.78E-09 79346824 10 rs597283
rs10943605 0.572594 0.27296 3.74E-08 79347449 11 rs596810
rs10943605 0.590052 0.272681 2.36E-08 79347562 12 rs596337
rs10943605 0.600542 0.282979 1.11E-08 79347676 13 rs655566
rs10943605 0.597614 0.277093 1.90E-08 79348564 14 rs689389
rs10943605 0.608391 0.291941 4.51E-09 79348661 15 rs846452
rs10943605 0.60564 0.286192 7.77E-09 79348887 16 rs674105
rs10943605 0.605842 0.284949 6.11E-09 79349688 17 rs236867
rs10943605 0.605842 0.284949 6.11E-09 79355383 18 rs236872
rs10943605 0.593491 0.304327 7.89E-09 79358008 19 rs236873
rs10943605 0.592785 0.282009 1.33E-08 79358580 20 rs236877
rs10943605 0.608391 0.291941 4.51E-09 79362203 21 rs70478
rs10943605 0.564166 0.209862 3.01E-06 79364899 22 rs70480
rs10943605 0.568404 0.216181 1.39E-06 79365324 23 rs236882
rs10943605 0.695923 0.256498 5.08E-08 79372832 24 rs236884
rs10943605 0.700831 0.26597 3.12E-08 79376244 25 rs236888
rs10943605 0.741063 0.286153 1.20E-08 79378960 26 rs236861
rs10943605 0.689267 0.264436 2.73E-07 79390866 27 rs236862
rs10943605 0.65937 0.248439 1.40E-07 79391691 28 rs236855
rs10943605 0.74615 0.29984 5.25E-09 79398610. 29 rs12210702
rs10943605 0.886957 0.355449 2.28E-11 79426052 30 rs9359338
rs10943605 0.897621 0.450682 1.86E-13 79453470 31 rs9352611
rs10943605 0.89472 0.436416 7.36E-13 79453687 32 rs10943567
rs10943605 0.901397 0.4471 6.06E-14 79459170 33 rs10943568
rs10943605 0.898063 0.444367 5.16E-13 79460926 34 rs9343786
rs10943605 0.901397 0.4471 6.06E-14 79471447 35 rs4706718
rs10943605 0.901397 0.4471 6.06E-14 79473602 36 rs9341739
rs10943605 0.899434 0.433323 2.58E-13 79475795 37 rs9352613
rs10943605 0.901397 0.4471 6.06E-14 79481152 38 rs13198615
rs10943605 0.620748 0.264225 2.31E-08 79487271 39 rs1180823
rs10943605 0.786316 0.274692 3.17E-09 79489645 40 rs1180828
rs10943605 0.620748 0.264225 2.31E-08 79492141 41 rs9343798
rs10943605 0.620748 0.264225 2.31E-08 79512001 42 rs7382016
rs10943605 0.620748 0.264225 2.31E-08 79512500 43 rs7759829
rs10943605 1 0.257426 5.01E-10 79513725 44 rs7759687 rs10943605
0.910286 0.229805 3.16E-07 79513734 45 rs9361426 rs10943605
0.620748 0.264225 2.31E-08 79514269 46 rs1158575 rs10943605
0.620748 0.264225 2.31E-08 79515925 47 rs9359344 rs10943605
0.620748 0.264225 2.31E-08 79517752 48 rs4141594 rs10943605
0.502039 0.207557 9.50E-07 79517914 49 rs9343820 rs10943605 1
0.87395 2.70E-31 79537177 50 rs1876389 rs10943605 0.824869 0.421093
3.32E-13 79538651 51 rs1021987 rs10943605 1 0.21875 2.66E-09
79539884 52 rs1507152 rs10943605 0.83431 0.329234 2.01E-10 79540193
53 rs1507153 rs10943605 1 0.509466 2.18E-18 79541105 54 rs9343824
rs10943605 1 0.537205 1.54E-18 79554288 55 rs1507149 rs10943605
0.960507 0.683059 4.95E-22 79556805 56 rs9343827 rs10943605 1
0.967033 1.10E-35 79557755 57 rs6926463 rs10943605 0.942137
0.382849 1.82E-12 79559890 58 rs9361448 rs10943605 1 0.300546
1.55E-11 79579645 59 rs12195716 rs10943605 1 0.967033 1.10E-35
79592131 60 rs6902294 rs10943605 1 0.21875 2.66E-09 79593001 61
rs1567168 rs10943605 1 0.967033 1.10E-35 79593174 62 rs2135767
rs10943605 0.943831 0.389733 6.65E-13 79593386 63 rs9352662
rs10943605 0.939889 0.390142 2.32E-11 79598210 64 rs1027813
rs10943605 1 1 1.22E-37 79608837 65 rs1567167 rs10943605 1 1
1.14E-36 79610546 66 rs12196485 rs10943605 1 0.550265 1.01E-19
79613590 67 rs9352663 rs10943605 1 0.550265 1.01E-19 79614883 68
rs971994 rs10943605 1 1 9.93E-37 79616321 69 rs4421161 rs10943605 1
1 6.05E-38 79620938 70 rs12176511 rs10943605 1 0.715909 1.15E-25
79622440 71 rs9352664 rs10943605 1 1 6.05E-38 79622881 72 rs9352666
rs10943605 1 1 2.00E-36 79628903 73 rs9352667 rs10943605 1 1
6.05E-38 79629015 74 rs9352668 rs10943605 1 0.715909 2.11E-25
79629397 75 rs9448584 rs10943605 1 1 6.05E-38 79629518 76 rs9361459
rs10943605 1 0.715909 7.04E-25 79629641 77 rs9341753 rs10943605 1
0.361702 6.05E-14 79634515 78 rs9352669 rs10943605 1 1 2.00E-36
79640860 79 rs9341754 rs10943605 1 0.966443 8.10E-35 79641692 80
rs9343844 rs10943605 1 1 1.30E-37 79643182 81 rs9350792 rs10943605
1 0.550265 1.01E-19 79643892 82 rs9361460 rs10943605 1 1 6.05E-38
79646186 83 rs9359354 rs10943605 1 1 8.67E-36 79647104 84 rs2174743
rs10943605 1 1 1.30E-37 79648524 85 rs6908105 rs10943605 1 0.516024
7.87E-19 79651816 86 rs12192086 rs10943605 1 0.360294 5.04E-14
79657229 87 rs2174742 rs10943605 1 1 1.22E-37 79666820 88 rs9352675
rs10943605 1 1 2.30E-37 79669519 89 rs1354832 rs10943605 1 0.966849
1.92E-35 79670482 90 rs4706079 rs10943605 1 1 2.00E-36 79671927 91
rs7756858 rs10943605 1 1 2.45E-37 79676687 92 rs9448594 rs10943605
1 0.355054 2.69E-12 79679933 93 rs12196457 rs10943605 1 0.550265
1.01E-19 79684462 94 rs9343853 rs10943605 1 0.375 1.67E-14 79699300
95 rs7740307 rs10943605 1 0.525 2.34E-19 79710873 96 rs10943605
rs10943605 1 1 -- 79712196 97 rs2275291 rs10943605 1 0.351955
9.65E-13 79713281 98 rs2275290 rs10943605 1 0.525 3.77E-19 79713289
99 rs1984195 rs10943605 1 1 1.30E-37 79714110 100 rs2174739
rs10943605 1 1 1.14E-37 79715889 101 rs9448600 rs10943605 1 0.525
2.34E-19 79719788 102 rs3805746 rs10943605 1 0.525 3.77E-19
79729157 103 rs3805747 rs10943605 1 1 1.22E-37 79729241 104
rs10943608 rs10943605 1 0.565217 6.62E-20 79731648 105 rs9350797
rs10943605 1 0.360294 5.04E-14 79732420 106 rs11964204 rs10943605 1
0.525 2.34E-19 79732781 107 rs9343856 rs10943605 1 1 1.30E-37
79734930 108 rs1538235 rs10943605 1 1 7.59E-37 79746169 109
rs1572584 rs10943605 1 1 6.05E-38 79747009 110 rs1572585 rs10943605
1 1 3.77E-36 79747295 111 rs1890229 rs10943605 1 1 6.05E-38
79751748 112 rs3818839 rs10943605 1 0.380941 1.44E-14 79757044 113
rs9359360 rs10943605 1 0.575195 7.14E-19 79759515 114 rs9359361
rs10943605 1 0.367498 1.07E-13 79762302 115 rs9361477 rs10943605 1
0.558824 9.59E-20 79767525 116 rs9448607 rs10943605 1 0.757211
5.03E-26 79772339 117 rs9352683 rs10943605 1 1 4.94E-36 79775514
118 rs9443638 rs10943605 1 1 2.00E-36 79777586 119 rs4706747
rs10943605 1 1 1.30E-37 79779358 120 rs9361480 rs10943605 1 1
2.89E-34 79781148 121 rs1338023 rs10943605 1 0.365871 4.42E-14
79785047 122 rs2050660 rs10943605 1 1 6.05E-38 79791445 123
rs9448610 rs10943605 1 0.733202 5.86E-26 79796341 124 rs1538233
rs10943605 1 1 6.05E-38 79800454 125 rs9343861 rs10943605 1
0.509466 2.18E-18 79801587 126 rs10943613 rs10943605 1 0.740385
5.66E-26 79801826 127 rs11758432 rs10943605 1 0.375 1.67E-14
79806313 128 rs9361482 rs10943605 1 0.733202 2.00E-25 79807104 129
rs9343863 rs10943605 1 1 6.05E-38 79809511 130 rs2050663 rs10943605
1 1 2.30E-37 79810113 131 rs9448616 rs10943605 1 0.360294 5.04E-14
79813653 132 rs9352686 rs10943605 1 1 2.45E-37 79814942 133
rs2152951 rs10943605 1 1 6.05E-38 79818891 134 rs9343865 rs10943605
1 0.368421 4.53E-14 79821914 135 rs9343867 rs10943605 1 0.364105
5.50E-14 79829072 136 rs1547731 rs10943605 1 1 1.14E-37 79832823
137 rs9352688 rs10943605 1 0.360294 5.04E-14 79832882 138
rs10455120 rs10943605 1 0.444999 1.18E-15 79836486 139 rs9343869
rs10943605 1 0.360294 7.16E-14 79841140 140 rs9352691 rs10943605 1
0.550265 1.01E-19 79842326 141 rs7753531 rs10943605 1 0.709974
7.37E-25 79846715 142 rs7776138 rs10943605 1 0.375 1.67E-14
79851212 143 rs9359364 rs10943605 0.947194 0.482034 1.37E-13
79852711 144 rs9352693 rs10943605 1 0.352274 3.20E-13 79854791 145
rs7767100 rs10943605 0.964821 0.930648 1.26E-29 79867252 146
rs9443644 rs10943605 0.937107 0.333308 3.02E-11 79867363 147
rs12197385 rs10943605 1 0.266602 4.88E-10 79872695 148 rs9361489
rs10943605 0.965965 0.933016 1.07E-31 79873504 149 rs949846
rs10943605 0.950814 0.497465 6.74E-16 79874315 150 rs6916081
rs10943605 0.941241 0.345568 4.80E-12 79874571 151 rs1415310
rs10943605 0.856953 0.419639 3.80E-13 79879033 152 rs9443645
rs10943605 0.931848 0.839777 1.03E-27 79879643 153 rs10943616
rs10943605 0.853077 0.40045 1.48E-12 79880260 154 rs6940949
rs10943605 0.876626 0.288616 1.29E-09 79880754 155 rs7768535
rs10943605 0.930436 0.292034 1.28E-09 79892231 156 rs3920791
rs10943605 0.869223 0.261765 6.14E-09 79893453 157 rs1361043
rs10943605 0.873498 0.269641 3.81E-09 79893786 158 rs9343876
rs10943605 0.806769 0.225158 1.01E-07 79901219 159 rs9352701
rs10943605 0.876903 0.28836 1.27E-09 79916596 160 rs9361497
rs10943605 0.876903 0.28836 1.27E-09 79916649 161 rs9294130
rs10943605 0.746969 0.282652 8.22E-09 79917888 162 Linkage
disequilibrium was calculated based on HapMap CEU population data
(http://www.hapmap.org). Location of correlated markers is given
with respect to NCBI Build 36 of the Human genome assembly.
TABLE-US-00006 TABLE 4 SNP markers that are in linkage
disequilibrium with marker rs10896450 on Chromosome 11. Linkage
disequilibrium was calculated based on HapMap CEU population data
(http://www.hapmap.org). Location of correlated markers is given
with respect to NCBI Build 36 of the Human genome assembly. Marker
1 Seq ID Pos in Seq Marker 1 Marker 2 D' r.sup.2 p-value location
No: ID: 201 rs7128814 rs10896450 0.754033 0.328273 7.44E-09
68709630 163 300 rs10896444 rs10896450 0.950801 0.522291 5.93E-15
68723823 164 14493 rs10896445 rs10896450 0.951635 0.522873 3.85E-15
68724217 165 14887 rs4255548 rs10896450 1 0.620339 2.97E-22
68730546 166 21216 rs7117034 rs10896450 1 0.257642 2.43E-10
68731718 167 22388 rs4495900 rs10896450 1 0.606213 5.17E-21
68732695 168 23365 rs11228563 rs10896450 1 0.373812 1.43E-13
68733572 169 24242 rs12281017 rs10896450 1 0.295093 8.65E-11
68734077 170 24747 rs11228565 rs10896450 1 0.249586 7.96E-10
68735156 171 25826 rs4620729 rs10896450 1 1 4.70E-38 68736911 172
27581 rs11821008 rs10896450 1 0.329609 1.51E-12 68737211 173 27881
rs11825796 rs10896450 1 0.311982 7.96E-12 68737364 174 28034
rs4451736 rs10896450 1 0.964531 2.83E-34 68739279 175 29949
rs12278923 rs10896450 1 0.959809 3.04E-31 68740137 176 30807
rs7929962 rs10896450 1 1 4.70E-38 68742159 177 32829 rs7109672
rs10896450 1 0.967195 8.12E-36 68747686 178 38356 rs10896448
rs10896450 1 1 4.70E-38 68748325 179 38995 rs12795301 rs10896450 1
0.241803 5.99E-10 68748861 180 39531 rs7122190 rs10896450 1
0.967195 8.12E-36 68750364 181 41034 rs6591374 rs10896450 1 1
1.90E-37 68750408 182 41078 rs7931342 rs10896450 1 0.967195
1.58E-35 68751073 183 41743 rs10896449 rs10896450 1 1 4.70E-38
68751243 184 41913 rs7130881 rs10896450 1 0.241803 5.99E-10
68752534 185 43204 rs12362678 rs10896450 1 0.967195 8.12E-36
68752746 186 43416 rs9787877 rs10896450 1 1 4.70E-38 68753085 187
43755 rs11603288 rs10896450 1 0.242151 1.13E-09 68753358 188 44028
rs4644650 rs10896450 1 0.967195 8.12E-36 68754694 189 45364
rs7950547 rs10896450 0.953052 0.582711 4.00E-15 68755364 190 46034
rs11228580 rs10896450 1 0.229339 1.58E-09 68758918 191 49588
rs7939250 rs10896450 1 1 1.87E-37 68759526 192 50196 rs7106762
rs10896450 1 1 4.70E-38 68760282 193 50952 rs12417087 rs10896450 1
0.221577 3.17E-09 68760555 194 51225 rs11228581 rs10896450 1
0.337143 7.39E-13 68760586 195 51256 rs7947353 rs10896450 1 1
1.19E-35 68761559 196 52229 rs10896450 rs10896450 1 1 -- 68764690
197 55360 rs11228583 rs10896450 1 0.965547 6.06E-35 68765690 198
56360 rs12799883 rs10896450 1 1 1.90E-37 68767227 199 57897
rs3884627 rs10896450 1 0.425723 6.96E-16 68782375 200 73045
TABLE-US-00007 TABLE 5 Polymorphic markers within the C11 region,
between position 68,709,630 and 68,782,375 in NCBI Build 36. Shown
is marker ID (rs-names), position in Build 36, strand and
polymorphism type, where (--/N), N being any one nucleotide, or a
plurality of nucleotides, corresponding to an insertion/ deletion
polymorphism (i.e. either the nucleotide(s) is present or not).
Position Marker ID Build 36 Strand Polymorphism rs7128814 68709630
+ A/G rs34033330 68709734 + --/T rs4993568 68709920 + G/T rs4993567
68709926 + C/G rs11228548 68710333 + C/T rs11228549 68710384 + C/T
rs10896441 68710484 + A/G rs10792027 68710514 + C/G rs10792028
68710515 + C/T rs11228550 68710833 + C/T rs12294054 68711092 + A/G
rs11228551 68711570 + A/T rs11228552 68711592 + C/T rs10219207
68713596 + A/G rs12809032 68713686 + C/T rs11606280 68713966 + A/G
rs35691765 68715000 + --/G rs4495899 68715236 + G/T rs12800787
68715895 + C/T rs4930664 68715976 + A/G rs4930665 68715984 + A/T
rs4072598 68716265 - G/T rs11228553 68716760 + G/T rs10896442
68716789 + A/G rs12223972 68716967 + A/G rs12796709 68719501 + A/C
rs34461339 68719872 + --/G rs12803641 68720487 + C/T rs12808650
68720536 + C/G rs12808185 68720581 + A/C rs12808690 68720599 + C/G
rs12808846 68720638 + C/G rs12808599 68720804 + A/T rs12808603
68720810 + A/T rs12785256 68720824 + A/G rs11228554 68720854 + C/T
rs11602052 68721150 + C/G rs11433399 68721158 + --/G rs10896443
68722211 + G/T rs11228555 68722341 + C/T rs10792029 68723458 + A/G
rs4930666 68723812 + C/T rs10896444 68723823 + A/C rs34531633
68724028 + G/T rs11228556 68724029 + G/T rs10896445 68724217 + C/T
rs11228557 68724542 + A/G rs10792030 68725391 + A/G rs12417971
68726384 + C/T rs11383798 68726876 + --/G rs7126286 68726993 + C/T
rs34210900 68727006 + --/G rs3934653 68727096 - A/C rs12049842
68727624 + G/T rs9783326 68727749 + C/T rs7927331 68729100 + A/G
rs7930375 68729233 + C/G rs7945442 68729323 + C/T rs9783278
68729551 + A/C rs9783279 68729568 + A/C rs9783280 68729612 + A/G
rs11824548 68729893 + A/G rs7934295 68730254 + C/T rs4255548
68730546 + A/G rs7483742 68730628 + G/T rs7949811 68730632 + G/T
rs12792553 68730645 + A/C rs12792562 68730662 + A/C rs12793009
68730931 + C/T rs12793759 68731131 + A/G rs9943593 68731168 + A/G
rs11228558 68731439 + C/T rs10896446 68731695 + C/T rs7117034
68731718 + C/T rs11228559 68731861 + C/T rs11228560 68731965 + C/T
rs7926098 68732100 + C/T rs12287117 68732101 + C/G rs7942465
68732362 + C/T rs11228561 68732444 + C/G rs7929389 68732558 + A/T
rs4495900 68732695 + C/T rs11228562 68732747 + G/T rs11228563
68733572 + A/G rs10792031 68733592 + A/G rs12418968 68733711 + C/T
rs12281017 68734077 + A/G rs4930667 68734625 + C/T rs12422130
68734751 + A/G rs11228564 68735154 + C/T rs11228565 68735156 + A/G
rs4357697 68735224 + G/T rs7926037 68735253 + C/G rs11228566
68735849 + C/T rs11228567 68736126 + A/G rs7937094 68736282 + C/T
rs11228568 68736438 + G/T rs11228569 68736819 + C/T rs4620729
68736911 + A/C rs11821008 68737211 + A/G rs11825791 68737337 + C/G
rs11825796 68737364 + A/G rs4930668 68737404 + G/T rs10896447
68737451 + A/C rs4265599 68737642 + A/T rs12275055 68737935 + A/G
rs4268514 68738060 + C/G rs28613836 68738536 + C/T rs9665814
68738604 + C/T rs4930669 68738956 + C/T rs4451736 68739279 + A/G
rs5792471 68739686 + --/C rs4988608 68739767 + A/G rs4988607
68739830 + G/T rs12278923 68740137 + A/C rs7939803 68740276 + C/T
rs10792032 68741178 + A/G rs12294067 68741228 + A/G rs11421935
68741320 + --/G rs11228570 68741410 + C/T rs11228571 68741445 + C/T
rs11351679 68742057 + --/T rs7929962 68742159 + C/T rs12282709
68742244 + A/C rs28686842 68742981 + C/G rs12790802 68743071 + A/C
rs11824985 68743246 + A/G rs12785252 68743916 + A/C rs12785424
68743958 + A/C rs7941085 68744228 + G/T rs11228572 68744280 + A/G
rs7119440 68744363 + A/G rs35024453 68744479 + --/T rs7119681
68744563 + A/G rs7945227 68745639 + A/G rs10792033 68745774 + A/G
rs28706904 68746828 + C/T rs35911114 68746864 + --/A rs7121816
68746871 + G/T rs34326593 68746958 + --/C rs7109672 68747686 + A/G
rs12270972 68748240 + A/G rs10896448 68748325 + C/G rs34655741
68748385 + --/T rs35960410 68748742 + --/A rs12795301 68748861 +
A/C rs11228573 68749659 + G/T rs11228574 68750098 + A/T rs35007842
68750196 + --/G rs7122190 68750364 + C/T rs6591374 68750408 + A/G
rs28367011 68750751 + C/T rs36082692 68751072 + --/G rs7931342
68751073 + G/T rs10896449 68751243 + A/G rs10750845 68751541 + A/G
rs35730578 68751818 + --/TG rs11228575 68751854 + A/G rs12365199
68751856 + A/G rs11228576 68752122 + A/G rs7130881 68752534 + A/G
rs12362678 68752746 + C/G rs11603219 68753019 + A/G rs9787877
68753085 + C/T rs11603288 68753358 + A/G rs11228577 68753390 + C/T
rs4644650 68754694 + C/T rs5792472 68754765 + --/G rs4569015
68754981 + C/T rs7950547 68755364 + C/T rs7935842 68755540 + G/T
rs4576823 68755685 + A/G rs35572423 68755750 + --/A rs7931312
68757543 + A/G rs34699416 68757796 + --/C rs4930670 68757828 + C/T
rs11605287 68758302 + G/T rs11228579 68758793 + G/T rs11228580
68758918 + C/T rs7925434 68759208 + A/T rs7939151 68759472 + A/G
rs7939250 68759526 + A/G rs7118074 68759999 + G/T rs12788188
68760157 + A/T rs7106762 68760282 + C/T rs34000592 68760510 + --/T
rs12417087 68760555 + A/T rs11228581 68760586 + C/T rs9667638
68760915 + A/T rs28852414 68761492 + A/G rs28876082 68761493 + G/T
rs7947353 68761559 + A/G rs7947298 68761677 + A/C rs11826508
68762658 + A/G rs34384086 68763007 + --/C rs36091743 68763507 +
--/T rs11228582 68763813 + A/T rs7104671 68763950 + C/G rs12802068
68764310 + A/G rs12802553 68764311 + A/G rs36101702 68764356 +
--/TT rs10896450 68764690 + A/G rs12808564 68765268 + A/G
rs11228583 68765690 + G/T rs11228584 68766043 + A/G rs10560769
68766333 + --/TT rs12293259 68766814 + G/T rs12799883 68767227 +
G/T rs4451737 68767444 + C/T rs3925012 68767493 + C/T rs4131929
68768714 - C/T rs12270641 68768820 + A/T rs35310215 68769540 + --/G
rs35836017 68769588 + --/C rs34255287 68769711 + A/G rs7127508
68770593 + C/T rs7111780 68770972 + A/G rs7111993 68771116 + A/G
rs7112311 68771118 + A/G rs11603876 68771837 + A/T rs12282656
68772304 + A/G rs7119988 68772447 + A/G rs36031129 68772686 + --/CC
rs11404080 68773007 + --/T rs35921293 68773009 + --/T rs10896451
68773469 + A/C rs34887827 68774015 + C/T rs12420858 68774110 + C/G
rs11228585 68774254 + C/T rs10530250 68774509 + (LARGE DELETION)/--
rs11228586 68774667 + C/T rs11228587 68774847 + A/G rs4930671
68774950 + A/G rs10896452 68775074 + C/T rs11606813 68775164 + C/T
rs12225965 68775407 + A/G rs34717487 68775561 + G/T
rs4930672 68775807 + A/G rs12293276 68775830 + A/G rs7118966
68775848 + C/T rs7102758 68775981 + A/G rs12421619 68775992 + C/T
rs35400111 68776233 + --/G rs11228588 68776545 + A/G rs34223044
68776551 + --/C rs11828682 68776692 + A/G rs7118204 68777260 + A/G
rs12806580 68777418 + C/T rs35349840 68777566 + --/G rs10896453
68777614 + A/G rs10792034 68777793 + C/T rs4531476 68778231 + C/G
rs11228589 68778253 + A/G rs11228590 68778283 + C/T rs11228591
68779388 + A/C rs35087861 68779558 + --/G rs11228593 68779604 + A/G
rs11228594 68779663 + A/G rs11228595 68779946 + C/T rs7127913
68780032 + C/G rs10736673 68780073 + C/T rs11228596 68780341 + A/G
rs11228597 68780850 + A/G rs36061232 68781372 + --/A rs11602505
68781617 + C/G rs7928306 68781639 + C/T rs11228598 68781757 + A/G
rs7121952 68781886 + C/T rs12792211 68782129 + A/G rs7122303
68782158 + C/T rs3884627 68782375 - A/C
TABLE-US-00008 TABLE 6 Polymorphic markers within the C06 region,
between position 79,300,773 and 79,917,888 in NCBI Build 36. Shown
is marker ID (rs-names), position in Build 36, strand and
polymorphism type, where (--/N), N being any nucleotide or a
plurality of nucleotides, corresponding to an insertion/deletion
polymorphism (i.e. either the nucleotide(s) is present or not, as
indicated). Position Marker ID Build 36 Strand Polymorphism
rs611737 79300773 + A/T rs626819 79301359 + A/G rs6910813 79302376
+ C/T rs12214422 79302660 + A/G rs644560 79303061 + C/T rs9352604
79303344 + A/G rs9448457 79303808 + C/T rs686492 79305307 + C/T
rs9448458 79305343 + A/G rs6929235 79305516 + C/T rs34452249
79305637 + --/A rs7749430 79305957 + A/G rs817878 79306182 + C/T
rs9443588 79306226 + A/G rs9448459 79306228 + A/G rs7749697
79306342 + C/T rs768590 79306749 + C/T rs9448460 79306888 + A/G
rs35921129 79307666 + --/G rs586228 79308383 + C/T rs34460368
79308541 + --/C rs680095 79309251 + G/T rs36120289 79309395 + --/T
rs681322 79309441 + A/G rs681802 79309548 + A/C rs36181646 79310146
+ --/T rs7742933 79310346 + C/G rs7742862 79310526 + A/T rs34040490
79311019 + --/A rs9359329 79311380 + C/T rs9294118 79311509 + A/T
rs9341737 79311928 + G/T rs9443589 79312030 + C/G rs1506767
79312288 + A/C rs9448462 79312500 + A/G rs9359330 79312505 + C/T
rs817881 79312760 + A/T rs9448463 79312774 + A/G rs817882 79312776
+ A/G rs4321794 79312812 + A/G rs817883 79313522 + C/G rs9448464
79313952 + A/C rs590624 79314042 - A/C rs9448465 79314256 + A/C
rs34720156 79314273 + --/C/T rs9443590 79314631 + A/G rs587503
79314716 - C/G rs9448466 79315160 + A/G rs682852 79315205 + A/T
rs9443591 79315537 + C/T rs12183583 79315477 + C/T rs12202264
79315943 + A/G rs9443592 79316009 + A/G rs35257893 79316335 + --/C
rs666982 79316431 + C/T rs9443593 79316432 + C/T rs34323328
79316810 + --/T rs654652 79316879 + G/T rs12528215 79316955 + A/C
rs34348581 79317371 + --/A rs652356 79317426 + A/T rs651900
79317529 - G/T rs651894 79317535 - G/T rs10565029 79317635 + --/AAA
rs10590702 79317656 + --/AAA rs17823349 79318539 + C/T rs35611717
79319004 + --/TTT rs2024994 79319262 + C/T rs34242911 79319291 +
--/A rs6932288 79319758 + G/T rs16890129 79319993 + C/T rs600913
79320040 + C/T rs1625514 79320259 + C/T rs10611862 79320291 + --/AC
rs10695566 79320376 + --/C/T/TA rs28652972 79320377 + C/T
rs34108696 79320377 + --/TA rs13214614 79320385 + C/G rs13214617
79320392 + A/G rs817886 79320395 + --/A/G/GT rs28736801 79320394 +
A/G rs13214437 79320413 + C/T rs13214632 79320425 + C/G rs12200116
79320434 + A/G rs12213654 79320441 + C/T rs13200111 79320447 + C/T
rs9341738 79320646 + G/T rs1616969 79320658 - A/C rs12215356
79320880 + A/G rs3063781 79321086 + --/GATA rs616011 79321162 + C/T
rs685093 79321296 + C/T rs1321599 79321507 + C/T rs12195790
79321512 + A/T rs12215690 79321527 + A/G rs9448467 79321532 + A/G
rs10214428 79321604 + A/G rs5877614 79321661 + --/ATGT rs35273466
79321666 + --/TGTA rs10214574 79321924 + C/T rs12203729 79321949 +
A/G rs653092 79322088 - A/G rs34332845 79322089 + CA/TG rs653091
79322089 - C/T rs12190592 79322474 + C/T rs669241 79322487 - C/T
rs13328234 79322502 + C/T rs11963866 79322524 + A/T rs668305
79322704 - A/G rs9448468 79322719 + C/T rs656825 79322983 - A/T
rs656806 79322991 - C/T rs656767 79323027 - C/T rs636717 79323460 -
C/T rs623155 79324200 - A/G rs1588045 79324435 - A/G rs1588044
79324438 - A/G rs12154026 79324811 + C/T rs36029617 79324861 + A/C
rs627261 79324993 - A/T rs9448469 79325158 + A/T rs12196214
79325431 + C/T rs625065 79325534 + C/T rs625051 79325550 + G/T
rs623658 79325869 - A/G rs611493 79326235 + A/G rs34644016 79326358
+ --/C rs7762380 79326371 + C/T rs2063044 79327042 - A/G rs2057299
79327290 + C/T rs685245 79327502 + G/T rs9443594 79327549 + A/G
rs594889 79327616 + --/A/T rs2321446 79328223 + C/G rs2321447
79328224 + C/T rs9294119 79328300 + A/G rs12200457 79328690 + G/T
rs675860 79328980 - C/T rs1395451 79329158 - A/C rs5877615 79329487
+ --/AG rs33932619 79329488 + --/AG rs2307940 79329492 - --/TC
rs9448471 79329660 + C/T rs627504 79329799 - C/T rs817874 79329815
- A/T rs34927882 79330116 + --/C rs4532413 79330118 + A/G rs7755570
79330301 + A/G rs624930 79330391 - A/G rs7755650 79330536 + A/C
rs11321290 79330606 + --/A rs4055943 79330613 + --/AA rs5877616
79330615 + --/A/AA rs623900 79330662 + A/C rs35720273 79331059 +
A/T rs9448472 79331128 + C/T rs1354783 79331316 - A/G rs9448473
79332278 + A/C rs9448474 79332375 + A/G rs9448475 79332618 + C/T
rs10485132 79333000 - A/G rs9448476 79333023 + G/T rs9361409
79333075 + C/T rs6936674 79333218 + A/C rs599356 79333269 + C/G
rs9448477 79333362 + C/G rs35610189 79333362 + --/C rs9350762
79333552 + C/T rs35356866 79333742 + --/A rs9443595 79333782 + C/T
rs817873 79333940 + A/C rs34056090 79334129 + --/G rs35568407
79334141 + --/C rs35329543 79334333 + --/G rs1180729 79334524 + A/T
rs12203331 79334532 + C/T rs11966608 79335281 + C/T rs12527974
79335652 + C/T rs2321448 79335824 + A/C rs4357091 79335896 + A/T
rs35401847 79336555 + --/A rs34962042 79336668 + --/G rs34243415
79336793 + --/C rs660115 79336811 - A/G rs665915 79336879 + C/T
rs2321449 79337577 + A/C rs10214706 79337707 + A/G rs645217
79337828 - C/T rs9448478 79338056 + A/T rs1180712 79339059 + G/T
rs34586728 79339119 + A/C rs34371761 79339519 + --/A rs5877617
79339832 + --/C rs12202205 79340216 + C/T rs2022199 79340391 - C/T
rs5877618 79340404 + --/A rs34256059 79340405 + --/A rs5877619
79340411 + --/A rs35771902 79340412 + --/A rs2022198 79340494 - C/T
rs615980 79340588 + C/T rs35269485 79340618 + --/A rs2022197
79340630 - C/T rs616526 79340734 + A/G rs547472 79341083 + C/T
rs4706714 79341084 + A/C rs9448479 79341414 + C/T rs671940 79342180
- C/T rs2321450 79342370 + C/G rs662430 79342674 + C/T rs12214043
79342882 + A/T rs34757416 79342885 + --/CA rs1853111 79342888 + C/T
rs34922104 79342890 + --/TT rs12207739 79342893 + A/T rs28643317
79342897 + A/T rs28498695 79342903 + A/T rs28394665 79342909 + A/T
rs10455117 79342926 + A/T rs474764 79342934 + G/T rs28436215
79342992 + A/C rs10455118 79343162 + A/C rs28662236 79343365 + A/G
rs34757274 79343581 + --/C rs654628 79343805 - C/T rs11755496
79343990 + C/G rs528850 79344165 + C/G rs16890160 79344345 + C/T
rs1033691 79344906 + C/T rs1964131 79345300 + --/A/G rs1964132
79345301 + A/G rs627292 79345308 - A/G rs627289 79345314 - C/G
rs7767332 79345618 + A/T rs9448480 79345810 + C/T rs605822 79345825
+ A/G rs605697 79345910 + A/G rs605264 79346003 + C/T
rs603964 79346271 - A/G rs612489 79346309 - G/T rs484582 79346824 +
G/T rs35610422 79346949 + --/G rs35763342 79347019 + --/T rs9448481
79347164 + C/G rs9448482 79347421 + C/T rs597283 79347449 - C/G
rs596810 79347562 - C/T rs596337 79347676 - C/T rs34739094 79347711
+ --/G rs9448484 79347965 + C/T rs655566 79348564 - A/G rs581416
79348610 - C/G rs689389 79348661 - A/G rs846453 79348794 - C/G
rs846452 79348887 - A/G rs11755342 79349385 + C/T rs34223893
79349579 + --/G rs674105 79349688 - A/G rs9448485 79350112 + A/G
rs9443596 79350335 + A/G rs12181074 79350315 + A/G rs17225876
79350594 + C/T rs11751885 79350686 + A/G rs7746355 79351241 + A/C
rs7746614 79351279 + C/T rs34541692 79351399 + --/A rs699174
79351582 - A/G rs9448486 79351645 + A/C rs699175 79351931 - C/T
rs699176 79352012 - A/G rs236863 79352234 - A/G rs12207987 79352301
+ G/T rs13201882 79352366 + A/G rs9448487 79352398 + G/T rs9443597
79352413 + C/T rs9448488 79352736 + C/T rs9443598 79352745 + C/T
rs9448489 79352746 + A/G rs3967379 79353019 + C/T rs236864 79353190
+ C/G rs12209919 79353401 + A/G rs12209974 79353466 + C/G rs236865
79353475 + C/G rs9443599 79354012 + A/G rs236866 79354277 - A/G
rs1137258 79354328 + A/G rs9448490 79354814 + A/C rs17332393
79355181 + C/T rs11759337 79355380 + A/G rs236867 79355383 + C/T
rs9448491 79355466 + A/G rs236868 79355488 + G/T rs236869 79355706
+ C/T rs9443600 79356397 + G/T rs236870 79356774 + C/T rs236871
79356925 + C/T rs16890184 79357098 + C/T rs9443601 79357369 + A/G
rs9448492 79357532 + C/T rs236872 79358008 - C/T rs9448493 79358214
+ C/T rs7776020 79358245 + C/T rs236873 79358580 - A/G rs11753657
79358850 + A/C rs34736990 79359228 + --/T rs11461852 79359513 +
--/T rs9448495 79359564 + C/T rs9448496 79359649 + A/G rs9448497
79360057 + C/T rs236874 79360347 + A/G rs9443602 79360653 + C/T
rs192101 79360986 + A/G rs35198424 79361056 + --/A rs236875
79361403 + A/C rs11366261 79361558 + --/A rs236876 79362007 + C/G
rs12203300 79362176 + A/T rs236877 79362203 + A/G rs9448498
79362482 + A/G rs11756326 79362950 + A/G rs9448499 79363791 + A/C
rs9448500 79363928 + A/T rs10485131 79364083 - C/T rs7770444
79364354 + C/T rs11757555 79364553 + A/C rs236878 79364707 - G/T
rs910955 79364822 + A/G rs70478 79364899 + C/T rs70480 79365324 +
A/G rs5877620 79365398 + --/T rs731449 79365401 - A/G/T rs35967646
79365405 + --/A rs9294120 79365528 + C/T rs35822945 79365869 + --/T
rs9343779 79365908 + A/G rs699178 79366002 + C/T rs2750022 79366008
+ A/C rs699179 79366252 + A/G rs699180 79366351 + C/T rs9448502
79366447 + A/C rs35286686 79366524 + --/T rs9448503 79366694 + C/G
rs35383112 79367223 + --/A rs699181 79367333 + C/T rs7356833
79367828 + A/G rs7356834 79367837 + A/G rs34785800 79367950 + --/T
rs7356836 79367968 + A/G rs5877621 79368047 + --/C rs7356840
79368100 + A/G rs7356843 79368150 + G/T rs9294121 79368152 + G/T
rs7356844 79368157 + A/G rs236879 79368578 - A/C rs34335044
79368627 + --/C rs9448504 79369400 + C/G rs9448505 79369555 + C/T
rs9448506 79369591 + A/T rs9359332 79369685 + G/T rs236880 79369811
- A/T rs9448507 79370086 + A/G rs9448508 79370320 + A/G rs9443603
79370631 + A/C rs236881 79370661 - C/G rs9448509 79371433 + A/G
rs11964133 79371604 + C/T rs35268570 79371715 + --/G rs498037
79371989 - A/G rs1570075 79372076 + A/C rs1567097 79372765 - A/T
rs1567096 79372799 - A/G rs236882 79372832 + A/G rs12200556
79372896 + C/T rs10806133 79372949 + C/T rs35217057 79373409 +
--/TGGA rs717364 79374159 + A/G rs11757996 79374370 + C/T rs1995650
79375007 - C/T rs500391 79375065 + A/G rs596057 79375070 - A/C
rs34948829 79375296 + G/T rs2021855 79375397 - A/T rs17226851
79375471 + A/G rs984157 79375681 - C/T rs1395447 79376010 - C/T
rs9361411 79376022 + A/G rs236883 79376130 - A/C rs236884 79376244
+ C/G rs9448510 79376314 + C/T rs12197910 79376609 + C/T rs2307943
79376998 + --/AA rs10539915 79376999 + --/AA rs4551135 79377021 +
G/T rs10943547 79378077 + A/G rs236885 79378204 + A/G rs236886
79378253 + A/C rs10943548 79378357 + C/T rs35488554 79378364 + A/C
rs236887 79378393 - A/T rs16890218 79378495 + G/T rs236888 79378960
+ C/T rs236889 79379130 - A/G rs16890224 79379278 + A/T rs1407102
79379719 + C/T rs17825291 79379916 + C/T rs34286917 79380641 + --/A
rs1012026 79381031 + A/G rs236890 79381351 + A/C rs236891 79381414
+ C/T rs1012027 79381592 + C/T rs34331673 79382209 + --/G rs9448511
79382811 + C/T rs17227220 79382837 + A/G rs16890230 79382886 + A/T
rs236892 79382966 - C/T rs12189761 79382972 + A/T rs12209692
79383101 + A/G rs1395446 79383114 - A/C rs34707756 79383315 + --/A
rs16890234 79383336 + A/G rs2021251 79383492 - C/G rs10943549
79383908 + C/T rs699182 79384047 + G/T rs3035341 79384211 +
--/AAAAA rs34681522 79384257 + --/T rs1186428 79384269 - A/G
rs2022521 79384282 - G/T rs817889 79384562 - A/G rs6931841 79384660
+ C/T rs6932494 79384868 + A/G rs9359333 79384897 + C/T rs12213548
79385071 + G/T rs12525083 79385670 + G/T rs11970272 79385707 + C/T
rs10455349 79387663 + C/G rs2063045 79388058 - A/G rs11757737
79388316 + A/C rs12197137 79388567 + A/G rs9448512 79389055 + A/T
rs35065237 79389616 + --/T rs10630134 79389747 + --/TA rs34896371
79389748 + --/TA rs34598417 79389756 + --/AT rs236859 79389835 -
C/T rs6454064 79389958 + G/T rs6454065 79390047 + G/T rs41501448
79390057 + C/T rs10640580 79390177 + --/CACA rs34677786 79390178 +
--/CACA rs10565820 79390187 + --/CA rs10542873 79390189 + --/CA
rs10536481 79390190 + --/AC rs6454066 79390202 + C/T rs6454067
79390311 + C/T rs1567095 79390707 - C/T rs1570001 79390750 + C/T
rs236860 79390814 - C/T rs236861 79390866 + C/T rs12530012 79390899
+ C/T rs9443604 79391001 + C/G rs12530067 79391157 + C/T rs12530068
79391178 + C/T rs12530072 79391243 + C/T rs4286729 79391508 + C/T
rs236862 79391691 - A/G rs35710435 79391916 + --/G rs5877622
79391938 + --/G rs12190115 79392540 + A/G rs699183 79392730 + A/G
rs34692849 79392774 + --/T rs10943550 79392824 + G/T rs10943551
79393059 + G/T rs11413951 79393172 + --/A rs35198419 79393180 +
--/A rs35839290 79393308 + C/T rs11752300 79393726 + C/T rs12200526
79393754 + C/T rs12193597 79393898 + A/G rs12524686 79394235 + C/G
rs35481326 79394369 + --/C rs659108 79395159 - G/T rs7775572
79395255 + C/T rs7755578 79395265 + A/G rs12195709 79395315 + A/G
rs7775782 79395445 + C/T rs7755682 79395539 + C/T rs12210711
79396008 + A/G rs236853 79396185 - A/G rs34570358 79396388 +
--/T
rs35919105 79396567 + C/T rs12530353 79396617 + A/G rs6940529
79396666 + A/C rs12530368 79396668 + A/G rs6940555 79396714 + A/C
rs6941006 79396789 + A/G rs6920658 79396993 + C/T rs11755479
79397125 + A/T rs12665819 79397185 + A/G rs9448513 79397377 + A/G
rs12191138 79397842 + C/G rs10615883 79397992 + --/TC rs10563095
79397998 + --/TC rs236854 79398400 + G/T rs236855 79398610 - A/G
rs9443605 79398716 + C/T rs497885 79398799 + G/T rs2321764 79399237
+ C/G rs5018093 79399607 + C/T rs12201840 79399748 + C/T rs9448514
79399769 + A/C rs34938165 79400028 + --/GA rs35821097 79400053 +
--/C rs7774339 79400463 + C/T rs236856 79400485 + A/G rs236857
79401130 + C/T rs9448515 79401281 + A/G rs236858 79401284 + C/T
rs699184 79401788 - A/C rs512778 79401865 + A/G rs9361413 79401968
+ A/G rs3220157 79402127 + (CA)24/25/ 26/28/29/30/ 31/33 rs36212818
79402095 + --/ CACACA CACA rs5877623 79402087 + --/ CACACA CACA
rs33979908 79402121 + --/ CACACA CACACA rs9361414 79402167 + G/T
rs5877624 79402681 + --/G rs541337 79402708 + A/G rs2321765
79402846 + C/G rs699185 79403177 + A/G rs236848 79403803 + A/G
rs11965655 79403862 + A/G rs236849 79403916 - A/G rs10701196
79403945 + --/AA rs35128239 79404539 + --/C rs236850 79405375 + A/C
rs6904390 79405458 + A/T rs6909051 79405613 + C/T rs12206138
79405708 + C/T rs34566789 79405761 + --/C rs6909339 79405768 + C/G
rs6909644 79405797 + A/G rs6909663 79405829 + G/T rs6910018
79405963 + A/G rs171050 79406031 + A/G rs236851 79406471 + A/G
rs236852 79406611 + A/C rs35683036 79406788 + --/C rs7763429
79407488 + A/G rs28797508 79407906 + A/T rs34457432 79407905 + --/A
rs28845244 79407909 + A/T rs11967330 79408002 + G/T rs9766611
79408248 + C/G rs9767153 79408285 + C/T rs11967401 79408313 + G/T
rs34710160 79408331 + --/T rs9767594 79408340 + A/G rs9767160
79408362 + C/T rs9766716 79408582 + C/T rs9766717 79408597 + C/T
rs9767724 79408721 + A/G rs9767248 79408857 + C/T rs11755206
79408909 + C/T rs11755256 79408948 + G/T rs663954 79408987 + C/G
rs35768463 79409014 + C/G rs2202590 79409231 - A/C rs34750624
79409440 + --/AACA rs12527236 79409757 + C/G rs7740665 79410184 +
C/T rs4547970 79410315 + A/G rs34273395 79410347 + --/T rs10455350
79410646 + A/G rs583747 79411314 - A/T rs10455351 79411324 + G/T
rs34113682 79411805 + --/C rs6936649 79411878 + A/T rs6913931
79412046 + C/T rs9343780 79412054 + C/T rs1172263 79412098 - A/T
rs7751786 79412433 + A/T rs1069028 79412764 - A/C rs4706716
79412775 + G/T rs7738229 79412794 + A/T rs7756398 79412809 + A/C
rs7756411 79412884 + A/C rs7756809 79412901 + A/G rs7756442
79412946 + A/G rs34345701 79412986 + G/T rs9448517 79413089 + G/T
rs11753268 79413379 + A/G rs2202589 79413464 - A/G rs2202588
79413475 - C/T rs11758439 79413558 + C/T rs7761199 79413617 + A/G
rs11753781 79413684 + A/C rs10455119 79413685 + A/G rs34530796
79414858 + --/T rs9448518 79414973 + A/G rs9443606 79415015 + C/G
rs9443607 79415153 + C/T rs13213955 79415197 + A/T rs9350767
79415702 + A/C rs7772851 79416038 + C/T rs6454070 79416268 + A/C
rs7773660 79416279 + A/G rs7773550 79416449 + A/G rs9448519
79416456 + C/G rs7773732 79416491 + A/C rs9448520 79416508 + A/G
rs9361418 79416542 + C/T rs7774017 79416543 + A/G rs34978259
79416789 + --/C rs13199250 79416845 + A/C rs12528155 79417363 + A/G
rs12528140 79417430 + A/C rs12524711 79417477 + A/G rs12528168
79417483 + A/G rs12529963 79417494 + A/T rs12525058 79417555 + A/T
rs12528513 79417619 + C/G rs35973698 79417626 + --/A rs9448521
79418135 + C/T rs13204264 79418289 + A/C rs13204489 79418306 + G/T
rs13220434 79418337 + C/T rs13204504 79418338 + A/G rs13204411
79418403 + A/C rs10943555 79418521 + A/G rs12182690 79418612 + C/T
rs11758282 79418731 + A/G rs10943556 79418749 + A/C rs11758301
79418757 + G/T rs12182714 79418795 + A/C rs10943557 79418878 + C/T
rs10943558 79418957 + A/G rs10943559 79418973 + A/C rs12529060
79419023 + G/T rs12529083 79419172 + A/G rs12529066 79419210 + C/T
rs13208861 79419298 + C/G rs35723058 79419309 + --/T rs12524083
79419353 + C/T rs4481395 79420009 + A/G rs9359334 79420248 + C/G
rs12662183 79420296 + A/G rs13202661 79421089 + G/T rs2321767
79421453 + C/T rs6921541 79421621 + C/T rs11750986 79422024 + C/T
rs11755647 79422090 + A/C rs35959932 79422201 + --/C rs34291901
79422318 + A/T rs9343782 79422366 + G/T rs34044761 79424096 + --/G
rs11399404 79424247 + --/A rs17234476 79425078 + G/T rs5877625
79425313 + --/T rs35681689 79425314 + --/T rs34020492 79425316 +
--/T rs13220214 79425378 + G/T rs12210702 79426052 + A/G rs12525652
79426301 + A/C rs1938554 79426313 + C/G rs12525655 79426333 + C/T
rs35676724 79426360 + --/T rs12525674 79426408 + C/T rs12527490
79426534 + A/T rs36020193 79426610 + --/T rs12530352 79426691 + A/G
rs12526918 79426820 + A/G rs12215953 79426831 + C/T rs2154396
79426988 + C/T rs10943560 79427137 + C/T rs35902159 79427208 +
--/AAT rs6941828 79427531 + C/G rs17234622 79427610 + A/G
rs10485130 79427659 - A/G rs10485129 79427902 - C/T rs17826325
79427930 + C/T rs10485128 79428165 - A/C rs9361420 79428649 + A/G
rs17826379 79428843 + A/C rs9443608 79429038 + A/T rs7768733
79429515 + C/T rs12194701 79429556 + A/G rs12528303 79429558 + A/C
rs7752431 79429626 + C/T rs12524924 79429653 + C/T rs12524949
79429719 + A/G rs1938555 79430010 + A/G rs1938556 79430133 + A/G
rs11962962 79430380 + C/G rs35016983 79430502 + --/T rs12661567
79430711 + C/T rs9448524 79430774 + C/G rs12196899 79431241 + A/G
rs7453195 79431988 + G/T rs35095504 79432065 + C/T rs11756592
79432239 + C/T rs12198749 79432255 + C/T rs11754162 79432324 + A/G
rs11964250 79432345 + C/T rs11756635 79432372 + C/T rs12198976
79432495 + C/G rs11758823 79432516 + A/G rs12526451 79432811 + A/G
rs35824053 79432979 + --/GT rs9361422 79434457 + C/G rs12527341
79434703 + C/T rs34470324 79434880 + --/T rs16890254 79435141 + G/T
rs11751443 79435191 + A/G rs10943561 79435271 + A/G rs34358078
79435272 + AT/GC rs10943562 79435272 + C/T rs11758593 79435318 +
G/T rs11759124 79435551 + A/T rs17234902 79435793 + A/G rs1954659
79436179 - G/T rs9443609 79436197 + A/C rs1954658 79436315 - G/T
rs11756825 79436318 + A/G rs1954657 79436419 - A/G rs34627531
79436474 + A/G rs17826615 79436664 + C/T rs17235062 79436828 + C/G
rs9359335 79436942 + C/T rs16890261 79437480 + A/G rs34327517
79437516 + --/C rs17235125 79437555 + A/G rs17235167 79437614 +
C/G
rs17235209 79437636 + C/T rs34645505 79437645 + --/C rs17826801
79437741 + A/G rs16890263 79438616 + C/T rs2321768 79438791 + A/T
rs12201253 79439572 + G/T rs34671943 79439692 + --/C rs6914850
79439950 + C/G rs12194506 79440009 + A/G rs1938553 79440281 - A/C
rs1938552 79442027 - C/G rs1938551 79442188 - A/G rs1938550
79442759 - G/T rs1938549 79442785 - C/G rs4371819 79443838 + A/G
rs3207577 79443876 + G/T rs2226283 79444234 - C/T rs34263174
79444643 + --/C rs9443610 79444913 + C/T rs6901727 79444923 + A/G
rs9359337 79446035 + C/T rs9352610 79446117 + A/G rs4590226
79446611 + C/G rs4568410 79448079 + A/G rs4358581 79448365 + A/G
rs36159891 79448536 + --/G rs12214797 79448885 + A/G rs12203087
79449566 + C/T rs1938548 79450052 + A/G rs237114 79450160 + C/G
rs237113 79450255 + C/T rs9448526 79450659 + A/G rs9294124 79450941
+ C/T rs237112 79451719 + A/G rs9443611 79451898 + C/T rs28510272
79452108 + G/T rs5877626 79452148 + --/T rs28715651 79452155 + C/T
rs36084918 79452165 + --/T rs237111 79452657 + A/C rs9359338
79453470 + C/T rs9352611 79453687 + C/T rs9448528 79453785 + C/T
rs190210 79455101 - A/G rs633117 79456053 + C/T rs36071262 79456190
+ --/T rs578709 79456303 + C/T rs9448529 79456446 + A/G rs631308
79456494 + C/T rs580694 79456568 + C/G rs496269 79457094 - A/G
rs10678940 79457699 + --/AATG rs35912544 79457700 + --/AATG
rs35640072 79457977 + --/C rs639370 79458132 + C/T rs2307947
79458723 + --/AAG rs1180811 79458783 + A/G rs10943567 79459170 +
C/T rs500306 79459437 + C/T rs621121 79459440 - A/G rs524008
79459763 + A/C rs605868 79460512 + A/C rs553313 79460609 + A/G
rs605016 79460685 - C/G rs553545 79460686 + A/C rs10943568 79460926
+ G/T rs557062 79461079 + C/T rs9359339 79461851 + A/G rs1099816
79461906 + A/G rs1099817 79462027 + A/C rs11760142 79462156 + A/G
rs36155678 79462155 + --/A rs237117 79462475 - C/T rs34503722
79462774 + --/T rs36003173 79463000 + CAT/TGG rs9352612 79463306 +
C/T rs35073587 79463953 + --/T rs237116 79465318 - A/G rs13219002
79465340 + G/T rs36187425 79465396 + --/T rs4116296 79465874 + A/C
rs9688758 79465988 + C/T rs36167084 79466143 + --/A rs11759842
79466549 + G/T rs237115 79467111 + A/G rs11751263 79467773 + C/T
rs10591157 79468622 + --/AGG rs1180810 79468743 + C/G rs12192387
79468754 + C/T rs9361423 79468991 + G/T rs13197296 79469397 + A/C
rs13197299 79469399 + A/C rs13197312 79469415 + A/T rs13197402
79469451 + A/C rs13197429 79469504 + A/C rs13197432 79469507 + A/C
rs237110 79469629 - C/G rs35083334 79470193 + --/T rs34384472
79470458 + --/C rs35723904 79470956 + --/T rs237109 79471413 - A/T
rs9343786 79471447 + A/C rs34396685 79471699 + --/G rs237108
79471734 + C/T rs28526821 79472111 + A/G rs9343787 79472325 + A/C
rs9343788 79472577 + A/G rs237107 79472599 + A/G rs11337252
79472738 + --/A rs11322370 79472755 + --/A rs9448533 79473558 + A/G
rs4706718 79473602 + A/G rs7773448 79474075 + C/T rs12662772
79474252 + C/G rs34988548 79474267 + --/T rs34521774 79474321 +
--/A rs16890280 79474935 + C/T rs1180809 79474961 + A/G rs35874347
79475533 + --/C rs9341739 79475795 + C/G rs10485127 79476149 - C/T
rs1782783 79476375 - A/G rs34305826 79476572 + --/C rs11758421
79477277 + A/G rs1180829 79477495 - A/G rs17642139 79477518 + C/T
rs11380286 79477603 + --/G rs7748153 79477872 + C/T rs9341740
79479508 + G/T rs34794581 79480689 + --/G rs10613222 79480812 + --/
ATATAT ATAT rs10613221 79480824 + --/AT rs35653902 79480973 + --/G
rs9352613 79481152 + A/G rs11363389 79481250 + --/A rs10589550
79481315 + --/ ATATAT AT rs34184424 79481323 + --/ATAT rs1180812
79481799 + G/T rs1180813 79482210 + C/T rs1180814 79482234 + A/G
rs10455352 79482310 + A/G rs1180815 79482567 + C/T rs1185719
79483043 + A/G rs1180816 79483108 + A/C rs9343789 79483300 + A/G
rs9341741 79483557 + A/G rs35281441 79483695 + A/C rs1180817
79483705 + A/G rs6923778 79483808 + A/G rs1180818 79483938 + C/G
rs35304238 79484265 + --/A rs28702778 79484289 + A/C rs28667093
79484464 + A/G rs12197635 79484466 + A/G rs11403769 79484690 + --/A
rs33917829 79484698 + --/A rs35564110 79484699 + --/A rs1180819
79484743 + A/G rs1180820 79485455 + A/G rs1543481 79485804 + C/G
rs1543482 79485857 + A/G rs1543483 79485890 + A/T rs1180821
79486391 + A/G rs9448534 79486474 + C/T rs28831831 79486721 + C/T
rs2224461 79487062 + A/G rs2208518 79487184 + G/T rs13198615
79487271 + A/G rs3920564 79487560 + G/T rs6915548 79487586 + A/G
rs1180822 79487770 + A/G rs35129774 79488647 + --/G rs1180823
79489645 + A/G rs13210865 79489811 + A/G rs7746175 79489924 + A/T
rs11370388 79489978 + --/A rs35746612 79489979 + --/A rs35105486
79489988 + --/A rs1180824 79490242 + A/G rs1180825 79490569 + G/T
rs1180826 79491321 + C/G rs1180827 79491347 + C/G rs28634504
79491970 + A/G rs1180828 79492141 + C/G rs3035346 79492475 +
--/G/GTG rs35410463 79492476 + --/GTG rs34535315 79492501 + --/G
rs35742744 79492502 + --/T rs1184721 79492711 + C/T rs1185343
79492909 + C/G rs34508299 79492924 + --/T rs2224462 79493658 + C/G
rs12192834 79493674 + C/T rs7767460 79493730 + G/T rs6454073
79494060 + A/G rs7768079 79494100 + G/T rs7747874 79494113 + C/T
rs7747911 79494214 + A/T rs35940523 79494339 + --/A rs9448536
79494391 + C/G rs9448537 79494467 + A/G rs10943570 79494466 + A/G
rs5877627 79494624 + --/CT rs35909564 79494627 + --/CT rs3035349
79494638 + --/CT/T rs1570177 79494647 + C/T rs2321769 79494679 +
G/T rs34358401 79494750 + A/G rs7752898 79494868 + C/T rs9448538
79495167 + G/T rs2145685 79495471 + A/G rs9341742 79496948 + C/T
rs9343792 79497004 + C/T rs9343793 79497122 + C/T rs12202166
79497374 + A/G rs6901911 79497718 + A/G rs35458046 79497892 + --/C
rs7740607 79498009 + C/T rs9352615 79498212 + C/G rs9352616
79498222 + C/T rs9352617 79498373 + A/C rs9448540 79498394 + G/T
rs7746203 79498898 + A/G rs9352618 79499147 + C/T rs9352619
79499433 + A/G rs11752556 79499668 + C/T rs7751066 79499807 + A/C
rs9352620 79500266 + G/T rs11380936 79500730 + --/A rs6900332
79501060 + C/T rs9448542 79501084 + A/C rs35258079 79501132 + --/C
rs9448543 79501153 + A/T rs12661502 79501197 + C/T rs9350769
79501280 + A/G rs9448544 79501600 + C/T rs9343794 79501644 + A/G
rs7450313 79501839 + C/T rs4470810 79502002 + G/T rs1080857
79502085 + C/T rs4470811 79502097 + C/T rs2321770 79502127 + C/T
rs7767636 79502775 + A/G rs7768125 79503108 + A/G rs9343796
79503266 + C/T rs9443612 79503406 + C/T rs12215204 79503784 +
A/G
rs9448545 79504354 + C/T rs9352621 79504806 + A/C rs9341743
79504981 + A/G rs9352622 79505238 + A/T rs9352623 79505367 + A/C
rs7745733 79506026 + C/T rs9359341 79506207 + C/T rs7746057
79506232 + A/C rs4706063 79506593 + A/G rs4706721 79506594 + A/G
rs4706064 79506627 + C/T rs4312941 79506920 + A/G rs7382759
79507470 + A/C rs6454075 79507724 + A/G rs4498306 79507894 + C/T
rs36170402 79507898 + --/G rs4299783 79508072 + C/T rs7766318
79508234 + A/C rs12213140 79508449 + A/G rs4501390 79508621 + G/T
rs4543321 79508705 + C/T rs4604236 79508754 + A/C rs36170201
79508906 + --/C rs9448546 79509562 + C/T rs6900430 79510134 + A/G
rs9448548 79510151 + A/G rs35040883 79510284 + --/C rs6905141
79510644 + A/G rs7743640 79510794 + A/G rs7744731 79511190 + C/G
rs9361425 79511397 + C/T rs9352625 79511473 + A/G rs10428859
79511532 + C/T rs2180910 79511716 + G/T rs13199483 79511789 + G/T
rs9352626 79511810 + C/T rs9343798 79512001 + A/G rs9352627
79512305 + C/T rs12528134 79512322 + A/G rs7382016 79512500 + A/T
rs7382311 79512662 + A/G rs7383685 79512701 + C/T rs35420186
79512878 + --/CAA rs9448549 79512991 + A/G rs9350771 79513107 + C/T
rs9350772 79513288 + A/C rs9350773 79513424 + A/C rs9359343
79513450 + A/G rs2145686 79513681 + A/C rs7759829 79513725 + C/G
rs7759687 79513734 + A/G rs7760429 79513941 + A/G rs7760193
79514040 + A/C rs9352628 79514166 + G/T rs9361426 79514269 + A/C
rs9448551 79514294 + C/T rs1998252 79514720 + C/T rs10943576
79514771 + G/T rs34981854 79514975 + --/G rs34769649 79515326 +
--/T rs7766517 79515467 + C/T rs7766791 79515472 + A/G rs10559249
79515694 + --/GTGT rs5877628 79515693 + --/TG rs3035376 79515718 +
--/GT rs1319575 79515770 + C/T rs3918524 79515816 + A/G rs1158575
79515925 + C/T rs4706066 79516496 + C/T rs2145687 79516920 + C/T
rs2145688 79516936 + C/T rs34523548 79517003 + --/T rs35884007
79517112 + --/G rs35363076 79517166 + --/G rs961680 79517338 + A/T
rs9359344 79517752 + A/G rs4141594 79517914 + A/C rs9443614
79517919 + A/G rs9350774 79518322 + A/G rs9294125 79518365 + A/T
rs35542025 79518386 + --/A rs12528472 79518434 + C/G rs1475046
79518520 + A/G rs9294126 79518524 + A/C rs9352629 79518599 + A/T
rs10943577 79518602 + C/G rs9343800 79518691 + A/G rs9352630
79518911 + C/T rs9352631 79518916 + A/G rs9352632 79518945 + C/G
rs9343801 79518994 + A/G rs12196839 79519152 + A/G rs9352633
79519342 + C/G rs9352634 79519344 + A/G rs4706722 79519416 + C/T
rs4706723 79519455 + C/G rs35622574 79519529 + --/C rs4706724
79519540 + A/G rs9448553 79520364 + G/T rs9350775 79520504 + A/G
rs9350776 79520564 + A/G rs4590227 79520629 + A/G rs7451373
79520890 + C/T rs9350777 79520900 + A/C rs9361427 79521580 + A/T
rs2321771 79522159 + C/T rs6454077 79522624 + A/G rs4706725
79523110 + A/G rs4706726 79523256 + C/G rs4706727 79523430 + C/T
rs4706728 79523530 + G/T rs4706729 79524311 + G/T rs4706730
79524622 + A/G rs35493328 79524755 + --/A rs9343804 79524771 + A/G
rs9343805 79524845 + G/T rs4706731 79525017 + C/T rs6916201
79525202 + C/T rs4706732 79525233 + A/C rs4706733 79525331 + C/T
rs4706734 79525369 + C/T rs4706067 79525544 + A/G rs4706735
79525556 + C/T rs4706068 79525824 + C/T rs7758474 79525893 + C/G
rs7758382 79526025 + C/T rs7758411 79526113 + A/G rs7758668
79526149 + C/G rs7758709 79526220 + A/C rs9343809 79526430 + A/G
rs9352638 79526528 + A/G rs9352639 79526557 + A/G rs9352640
79526632 + C/T rs9359345 79526635 + A/C rs9361430 79526795 + C/T
rs9361431 79526796 + A/G rs12215488 79526895 + A/G rs4277969
79527116 + C/T rs9343810 79527190 + C/G rs9343811 79527285 + C/T
rs36159791 79527300 + --/G rs6939408 79527324 + A/G rs9361432
79527332 + A/G rs9352641 79527639 + A/G rs9361433 79527970 + A/G
rs9352642 79528071 + A/C rs4706069 79528287 + C/T rs11751339
79528440 + A/C rs4706070 79528478 + A/G rs36193003 79528479 + AA/GG
rs4706071 79528479 + A/G rs9359346 79528869 + A/G rs7746103
79529063 + C/T rs9352645 79529280 + C/G rs7746449 79529347 + A/C
rs9352646 79529377 + A/G rs4419638 79529395 + C/G rs36146147
79529439 + --/G rs9341748 79529663 + A/G rs9343814 79529792 + C/G
rs9448558 79529987 + C/G rs10943581 79530174 + C/T rs28716526
79530437 + A/G rs11752708 79530459 + G/T rs11752686 79530498 + C/T
rs6899455 79530697 + C/T rs34374962 79530898 + A/C rs9448559
79531201 + A/G rs6920807 79531450 + A/T rs2135769 79532044 + A/G
rs4706736 79532195 + A/T rs4706072 79532210 + A/G rs1588086
79532606 + C/T rs1588087 79532636 + A/T rs2321772 79532909 + G/T
rs9443616 79532925 + A/G rs2321773 79532962 + A/G rs2321774
79533169 + C/T rs9443617 79533254 + A/G rs34749198 79533559 + --/T
rs1073211 79533575 - C/T rs28845538 79533674 + C/T rs2135770
79533747 + A/C rs9341750 79534203 + C/T rs6938951 79534339 + A/C
rs6939263 79534367 + C/T rs9359348 79534401 + A/T rs6900794
79534563 + C/T rs34763883 79534693 + --/A rs6901015 79534742 + C/T
rs6924048 79534918 + C/T rs36084053 79535093 + --/C rs10943583
79535183 + C/G rs35165607 79535238 + --/C rs34534036 79535250 +
--/C rs11755934 79535340 + C/T rs2321775 79535509 + C/T rs9359350
79535870 + C/G rs9361437 79536054 + C/T rs9361438 79536280 + C/T
rs9352648 79536460 + A/G rs9341751 79536555 + C/T rs9448560
79536601 + A/G rs9448561 79536715 + A/G rs9343820 79537177 + A/T
rs11965322 79537414 + A/T rs36082173 79537823 + --/T rs6923812
79538338 + C/T rs9350781 79538534 + A/T rs1876389 79538651 + A/T
rs35000167 79538888 + --/T rs11961822 79539174 + A/G rs35722542
79539754 + --/A rs12663824 79539849 + A/C rs1021987 79539884 + C/G
rs1507151 79539965 + C/T rs1507152 79540193 + C/T rs1567169
79540652 + C/T rs1507153 79541105 + A/C rs35498910 79541112 + --/T
rs9448562 79541799 + G/T rs1876390 79542282 + C/T rs9448563
79543216 + A/G rs9448564 79543231 + C/T rs9448565 79543237 + C/T
rs16890304 79543377 + A/G rs1876391 79543470 + C/T rs6454082
79544001 + C/T rs4555886 79544101 + A/T rs34032635 79544308 + --/T
rs34806029 79544385 + --/G rs11758151 79544940 + C/T rs11758164
79544958 + G/T rs6928279 79545677 + C/T rs9361440 79546395 + A/C
rs9352649 79546502 + G/T rs34850892 79547499 + --/C rs9361441
79547685 + A/G rs35665788 79547866 + --/T rs35275890 79549004 +
--/A rs35562053 79549016 + A/T rs6935486 79549211 + A/G rs9359351
79549252 + A/G rs11755568 79550337 + C/T rs34268443 79550347 + --/C
rs6942344 79550522 + C/T rs2321893 79550527 + C/T rs9352650
79550613 + A/G rs11751437 79550636 + A/G rs9361442 79550764 + A/G
rs6904016 79550772 + C/T
rs4055608 79550977 + C/T rs9350782 79551187 + A/G rs9352652
79551451 + A/G rs10806148 79551623 + A/G rs34335705 79552378 + C/T
rs12181706 79552458 + C/G rs9361443 79552769 + A/C rs2874642
79552903 + A/G rs12176501 79553029 + C/T rs9343822 79553040 + A/T
rs7773850 79553042 + A/T rs7773851 79553044 + A/T rs11757519
79553160 + C/T rs35940795 79553244 + --/C rs35004706 79553408 +
--/C rs9352653 79553582 + A/G rs9343823 79553825 + A/C rs9343824
79554288 + A/G rs35245361 79554378 + --/A/T rs1507155 79554584 +
A/G rs2021541 79554588 + A/G rs13210672 79554590 + A/G rs9343826
79554632 + A/G rs1507156 79554776 + A/G rs34136836 79555385 + --/G
rs34958301 79556015 + --/G rs9361444 79556792 + C/T rs1507149
79556805 - C/G rs9352654 79557000 + A/G rs9343827 79557755 + A/G
rs9359352 79558729 + C/T rs7757382 79558996 + C/G rs10943585
79559128 + C/G rs9361445 79559275 + C/T rs5877629 79559295 + --/T
rs1827992 79559524 - A/G rs7762022 79559578 + A/C rs6926463
79559890 + A/G rs6454083 79560137 + C/T rs9352655 79560142 + A/T
rs1507154 79560419 + C/T rs1476304 79560439 + C/T rs1476305
79560605 + G/T rs4628052 79560919 + A/G rs13200035 79561004 + C/T
rs13214259 79561046 + A/C rs13200136 79561064 + C/T rs13214670
79561072 + A/G rs13214372 79561084 + A/G rs13200153 79561107 + C/T
rs13214383 79561121 + A/G rs28781665 79561419 + A/G rs1848194
79562087 + C/T rs35374025 79562246 + --/T rs1911513 79562355 + A/G
rs9448568 79562434 + A/G rs7774691 79562517 + C/G rs9352657
79562804 + C/G rs7741245 79563215 + A/G rs7741407 79563307 + A/G
rs7761613 79563435 + C/T rs35613790 79563516 + --/A rs6454084
79563604 + A/G rs4446522 79564225 + A/T rs6931419 79564240 + A/T
rs4334937 79564258 + C/T rs12527806 79564386 + A/T rs3967330
79564533 + A/C rs9448572 79565438 + G/T rs10943587 79565451 + C/T
rs9443619 79565631 + C/T rs7756996 79566086 + A/C rs11753266
79566107 + C/T rs1857957 79566184 - C/G rs28759673 79566270 + G/T
rs2321896 79566463 + C/G rs41503746 79566463 - C/G rs35414898
79566540 + --/A rs34037147 79566911 + --/C rs10943588 79567713 +
A/C rs11751036 79567797 + C/T rs2202662 79568057 - G/T rs2202661
79568299 - A/G rs2202660 79568463 - G/T rs9448573 79569097 + C/T
rs6913028 79570309 + C/T rs6454085 79570611 + C/G rs4706737
79570764 + A/G rs35196425 79570832 + --/T rs4706075 79570837 + C/G
rs4706076 79570871 + C/CA/T/TG rs4706738 79570872 + A/G rs2202659
79571328 - A/G rs12662944 79571375 + A/T rs9350784 79572125 + C/T
rs9350785 79572304 + C/T rs9448574 79573020 + A/C rs9448575
79573525 + G/T rs1814219 79573704 - G/T rs13216900 79573706 + A/G
rs34791687 79573717 + --/G rs9350786 79574025 + G/T rs35713298
79574030 + --/GGG rs13217367 79574256 + A/T rs9343834 79574390 +
A/G rs12203336 79575034 + G/T rs35790661 79575375 + --/CA rs2202658
79576388 - C/T rs906320 79576561 - A/G rs41269335 79576661 + G/T
rs34943334 79576824 + A/G rs906319 79577408 - C/T rs41269337
79577988 + A/G rs6454086 79578882 + C/T rs9361448 79579645 + G/T
rs9352659 79580583 + A/G rs9448576 79580987 + C/G rs2202663
79581585 + C/T rs1395655 79581612 + C/T rs7773491 79582941 + C/T
rs4640849 79583469 + A/G rs35044999 79584659 + --/C rs12524858
79586232 + G/T rs2202664 79586366 + C/G rs9448577 79586917 + C/G
rs28814638 79587149 + A/G rs34428579 79587468 + --/A rs12209635
79588934 + C/T rs955765 79589329 - A/G rs5877630 79589377 + --/G
rs9448578 79589928 + G/T rs4706739 79590001 + C/T rs12213359
79590746 + A/C rs10556588 79592115 + --/AGAA rs12195716 79592131 +
C/T rs6902294 79593001 + G/T rs1567168 79593174 + A/C rs2174740
79593284 + A/G rs2135767 79593386 + C/T rs6454088 79594398 + C/T
rs12194457 79595224 + A/G rs35356883 79595302 + --/G rs12194642
79595510 + A/G rs9343838 79595869 + A/G rs10639111 79596351 +
--/GAGA rs34962848 79596352 + --/GAGA rs34665735 79596358 + --/AGAG
rs35366557 79596414 + --/G rs16890324 79596828 + A/G rs13217987
79597357 + A/G rs1963638 79597835 + G/T rs2013420 79597934 + A/G
rs16890325 79597947 + C/T rs9352662 79598210 + A/G rs28626679
79598705 + C/G rs35393092 79598862 + --/T rs16890326 79599251 + C/T
rs34305313 79600125 + --/A rs33920803 79600126 + --/A rs12110531
79600198 + C/G rs6912683 79600211 + A/C rs16890328 79600713 + A/C
rs7754715 79600777 + A/G rs34253750 79601120 + --/G rs13208855
79602240 + G/T rs16890330 79602923 + A/C rs1021986 79603853 + C/G
rs35242601 79604056 + --/T rs13220688 79604565 + C/T rs16890331
79605080 + C/T rs1507150 79605316 + A/T rs4706077 79605564 + A/G
rs10806150 79605891 + A/G rs12664947 79606191 + A/T rs1542977
79607026 + G/T rs35949145 79607341 + --/A rs2174741 79607599 + A/C
rs34567509 79608189 + --/C rs9448579 79608431 + C/T rs9448580
79608531 + C/G rs1027813 79608837 - A/C rs35909912 79609084 + C/T
rs34385822 79609087 + C/T rs35544399 79609089 + C/T rs34033174
79609112 + C/T rs5877631 79609384 + --/T rs35937908 79609385 + --/T
rs34696113 79609390 + --/T rs33954612 79609391 + --/T rs12664403
79610047 + G/T rs2135766 79610075 - A/G rs9448581 79610097 + A/G
rs35179848 79610136 + A/C rs11332279 79610357 + --/A rs1567167
79610546 - A/G rs4415132 79610826 + C/T rs6926537 79610912 + A/T
rs17741785 79610991 + A/G rs1507148 79611110 - C/T rs4409146
79611326 + C/T rs34490997 79611333 + --/G rs9361451 79611774 + C/T
rs16890334 79612885 + C/T rs12196485 79613590 + A/G rs4147183
79613765 + C/G rs36024489 79614221 + G/T rs9352663 79614883 + C/T
rs35934464 79615331 + --/C rs971994 79616321 - C/G rs7454053
79616439 + A/G rs10223389 79616629 + A/G rs12214796 79617787 + C/T
rs17798356 79618153 + A/G rs12190108 79619374 + C/T rs4421161
79620938 + A/G rs12213652 79621099 + A/G rs2321894 79621148 + A/G
rs9448583 79621405 + A/G rs9361454 79621963 + --/G/T rs12176511
79622440 + A/G rs34132605 79622874 + --/G rs9352664 79622881 + G/T
rs10455354 79622949 + A/G rs2874643 79623036 + A/G rs1960542
79623362 + C/T rs9352665 79624438 + C/G rs9361455 79624601 + A/G
rs34916187 79624764 + --/G rs12661039 79625256 + C/T rs4682456
79625580 - C/T rs7449459 79625728 + C/T rs6936109 79626595 + A/G
rs12201183 79626839 + A/G rs6937465 79627064 + G/T rs9361458
79627515 + C/T rs11381253 79627547 + --/A rs34502239 79627557 +
--/A rs9765849 79627608 + A/G rs9352666 79628903 + C/G rs9352667
79629015 + C/T rs9352668 79629397 + A/G rs9448584 79629518 + G/T
rs9448585 79629560 + A/G rs9361459 79629641 + A/G rs9343841
79630723 + C/G rs6923327 79631594 + A/G rs10943595 79632010 + C/G
rs34199187 79632011 + CC/GT rs10943596 79632011 + C/T rs34658311
79632386 + A/T rs11444087 79632386 + --/T
rs7760883 79632388 + --/A/T rs35635397 79632389 + --/A rs16890347
79632927 + C/T rs9443621 79633218 + A/G rs41269339 79634131 + C/G
rs9350789 79634363 + A/C rs9341753 79634515 + C/T rs12153837
79635921 + A/C rs12527589 79636178 + C/T rs10455355 79636221 + C/T
rs34431699 79637008 + --/C rs6941317 79637771 + A/C rs7738062
79638242 + C/G rs4706740 79639381 + A/C rs34204884 79639456 + C/T
rs9443622 79639509 + C/T rs4706078 79639525 + C/T rs35373380
79639573 + C/T rs12193104 79639633 + A/G rs12660767 79639652 + C/T
rs35962544 79639717 + --/AA rs12193319 79640156 + A/C rs6454089
79640821 + C/T rs9352669 79640860 + G/T rs9352670 79641152 + A/G
rs9341754 79641692 + A/C rs34538995 79641946 + --/GAAA rs9448586
79642219 + A/G rs34409101 79642323 + --/T rs9343843 79642344 + C/T
rs35304712 79643086 + C/T rs9343844 79643182 + A/T rs9350792
79643892 + A/G rs35439908 79645611 + --/G rs9448587 79645751 + A/G
rs9341755 79645767 + C/G rs9361460 79646186 + C/G rs9448588
79646780 + G/T rs9359354 79647104 + A/G rs35560175 79647373 + --/A
rs34453824 79647874 + --/C rs2174743 79648524 - C/T rs2135772
79648767 - A/C rs1021988 79649380 - A/G rs35897423 79650428 + --/C
rs9352671 79651798 + A/C rs6908105 79651816 + A/G rs4055605
79651890 + --/TCTTA rs35817888 79651891 + --/TCTTA rs35754813
79652867 + --/A rs2321895 79654080 + C/T rs35355117 79654223 + --/C
rs9352672 79654253 + C/T rs34228023 79654468 + --/A rs35503114
79654971 + --/T rs34717008 79655526 + C/T rs36108843 79655546 +
--/C rs34900932 79655547 + --/T rs34933654 79655550 + C/T
rs34963207 79656023 + --/A rs9361462 79656183 + A/G rs35606311
79656863 + --/A rs12192086 79657229 + A/G rs9448589 79657767 + G/T
rs9352673 79659462 + G/T rs9359355 79659533 + A/G rs9343845
79659752 + A/G rs36114710 79659754 + A/G rs9352674 79660060 + G/T
rs35774009 79662784 + --/A rs36087293 79663083 + --/G rs9448590
79663148 + C/G rs9448591 79663209 + C/T rs36004777 79663275 + --/A
rs4327648 79663334 + C/T rs10525714 79664847 + --/ ATATAT ATATATA
TATATAT AT rs35395481 79664848 + --/ ATATAT ATATATA TATATAT AT
rs34482864 79664856 + --/AT rs10700674 79664871 + --/AT rs7776322
79666464 + A/T rs2174742 79666820 + G/T rs2135771 79667075 + C/T
rs6941107 79667642 + A/G rs10943600 79668224 + A/G rs9343846
79668848 + A/T rs35533616 79669465 + --/A rs9352675 79669519 + A/G
rs1354831 79670295 + C/T rs1354832 79670482 + C/T rs35112046
79671111 + --/C rs9443623 79671372 + C/T rs4706079 79671927 + A/G
rs4706742 79672269 + C/T rs4706743 79672512 + G/T rs2174744
79673008 + A/T rs9448592 79673037 + C/G rs35935416 79673657 + --/T
rs6915030 79674241 + C/T rs9361466 79675071 + C/T rs10806151
79676098 + C/T rs11402304 79676284 + --/T rs7756858 79676687 + A/G
rs9443624 79676995 + A/G rs6921318 79677095 + A/G rs7758407
79677426 + C/G rs34373655 79677787 + --/T rs9361467 79677817 + A/G
rs9343848 79677820 + C/T rs9361468 79677933 + A/G rs9448594
79679933 + A/T rs9448595 79680349 + A/G rs1963080 79681257 + A/G
rs5877633 79681440 + --/G rs35590303 79682202 + --/C rs2063124
79683041 + C/T rs7756648 79683805 + A/T rs35313944 79684092 + --/A
rs9343849 79684179 + A/G rs12196457 79684462 + A/T rs7767182
79685667 + A/C rs35777909 79685724 + --/G rs36012949 79685747 +
--/C rs9448596 79686148 + C/T rs9443626 79686283 + C/G rs9352676
79686718 + A/G rs7750836 79688302 + C/G rs9350794 79688561 + C/T
rs7755754 79689008 + A/G rs36181347 79689691 + --/A rs7760866
79689848 + C/G rs9361472 79690160 + G/T rs36132801 79690225 + --/G
rs9448597 79690306 + C/T rs9689724 79690631 + A/G rs9343851
79690827 + C/G rs34433262 79690888 + --/C rs9688928 79691098 + A/C
rs28826982 79691188 + A/G rs34236947 79691189 + AC/GG rs28811946
79691189 + C/G rs9359358 79692407 + C/T rs2089416 79692807 + G/T
rs34521933 79693343 + --/C rs2135768 79693482 + C/T rs7744604
79694234 + A/C rs10755377 79694644 + C/T rs5877634 79696377 + --/T
rs11430514 79697407 + --/T rs35387172 79697408 + --/T rs9350795
79697410 + A/T rs12665761 79697747 + C/T rs13205569 79697785 + G/T
rs2321897 79698887 + C/T rs1911512 79699043 + C/T rs9343853
79699300 + C/T rs12660760 79699828 + C/T rs12660770 79699923 + C/T
rs35416532 79700122 + --/TTT rs9343854 79700770 + A/C rs1044313
79702339 - A/T rs35580162 79703022 + --/C rs35881759 79703274 +
--/C rs35125759 79703290 + --/C rs1044309 79703294 - C/T rs34261531
79703338 + --/C rs5877635 79704127 + --/T rs35000895 79704129 +
--/T rs4464748 79704697 + C/G rs10654924 79706512 + --/AA
rs34701016 79706513 + --/AA rs13191571 79706985 + G/T rs36155238
79706984 + --/T rs36160851 79706985 + --/T rs36170973 79706986 +
--/T rs36132527 79707051 + --/G rs11547229 79707066 + A/G rs6900790
79707081 + C/T rs34609668 79707212 + G/T rs2485701 79707264 + A/G
rs1876387 79707310 + A/G rs1876388 79707370 + G/T rs34463462
79707429 + G/T rs10574664 79707958 + --/AC rs28606484 79709319 +
C/T rs9350796 79710116 + C/T rs6454090 79710425 + --/ A/AA/AA
A/T/TT rs6454091 79710426 + A/T rs35306286 79710425 + --/AAA
rs11370303 79710434 + --/A rs11432700 79710436 + --/A rs11447037
79710449 + --/A rs9443629 79710479 + A/C rs34717491 79710843 + --/C
rs7740307 79710873 + A/T rs9688399 79711374 + A/G rs5877636
79711409 + --/A rs33977407 79711410 + --/A rs10943605 79712196 +
A/G rs1135076 79712453 - A/G rs1056960 79712497 - C/T rs34050775
79713035 + --/A rs36048894 79713183 - A/C rs1056959 79713195 - A/G
rs1056958 79713223 - C/T rs2275291 79713281 - A/T rs2275290
79713289 - C/T rs9361473 79713761 + C/T rs1984195 79714110 - C/T
rs11370597 79714395 + --/C rs1283320 79714834 + C/G rs35766012
79714947 + --/T rs35205946 79715066 + --/G rs4706745 79715247 + C/T
rs2063123 79715254 + C/T rs12529691 79715751 + A/G rs2174739
79715889 + A/G rs9343855 79716132 + G/T rs34526870 79716648 + --/C
rs35018864 79717062 + --/C rs2050661 79717844 - A/G rs28623652
79718361 + C/T rs9443630 79718517 + G/T rs10943606 79718496 + G/T
rs9448600 79719788 + A/C rs9443631 79720837 + C/T rs9443632
79721159 + C/T rs10455356 79721467 + C/T rs7753358 79721929 + A/T
rs11316583 79723594 + --/T rs5877637 79724015 + --/A rs35159735
79724505 + --/C rs34936739 79725919 + --/C rs35865427 79726072 +
--/C rs12665739 79727563 + C/T rs6940635 79727692 + C/T rs946022
79728852 + G/T rs3805746 79729157 + C/T rs3805747 79729241 + A/G
rs34841569 79729665 - A/C rs4706746 79730895 + A/G rs13202531
79730981 + C/T
rs35504170 79731083 + --/C rs10943608 79731648 + C/T rs3834844
79731991 + --/CTT rs3763160 79731994 + A/G rs9350797 79732420 + A/G
rs11964204 79732781 + A/G rs10943609 79733047 + A/T rs1572586
79733060 + C/T rs1538234 79733298 + C/T rs3834845 79733766 + --/C
rs34920411 79734822 + --/C rs9343856 79734930 + A/G rs10531246
79735174 + --/TAAT rs34584316 79736188 + --/T rs12663267 79736218 +
C/G rs7742746 79736246 + G/T rs7742874 79736287 + A/G rs7742431
79736296 + A/G rs34480532 79736437 + --/A rs7768255 79736633 + A/G
rs7768001 79736672 + A/C rs7768414 79736727 + C/G rs9443633
79736782 + C/T rs9448601 79738088 + C/T rs9448602 79738107 + A/G
rs4406190 79738370 + A/G rs10806154 79739086 + C/T rs12190940
79739190 + A/G rs7741943 79739286 + A/G rs9448603 79739333 + A/G
rs36146106 79739418 + --/A rs9352679 79739848 + A/G rs9341756
79739909 + C/T rs9350798 79739980 + A/C rs9341757 79739993 + G/T
rs7766920 79740022 + C/T rs7746653 79740031 + C/G rs7751287
79740610 + A/G rs36166556 79740631 + --/T rs36128361 79741059 + C/G
rs10943610 79741136 + A/G rs9352681 79741292 + A/G rs9343857
79741450 + C/G rs9343858 79741488 + C/T rs12182951 79742891 + A/G
rs12182952 79742924 + A/C rs9448604 79743377 + A/G rs9448605
79743416 + G/T rs36149780 79743416 + G/T rs4594915 79743583 + A/C
rs11282710 79744026 + --/ TTCAAG CACC rs36124591 79744030 + --/
AAGCAC CTTC rs34344828 79744037 + --/ TTCAAG CAC rs7750810 79744283
+ A/T rs12209235 79745085 + C/T rs34362578 79745461 + --/G
rs4624830 79745780 + A/T rs1538235 79746169 + C/T rs1572584
79747009 + A/G rs34246619 79747058 + --/A rs1572585 79747295 + C/T
rs10943611 79747894 + A/G rs9343859 79749118 + A/C rs11547228
79749470 - C/T rs10642979 79750856 + --/GT rs35922935 79750857 +
--/GT rs35769552 79751527 + --/G rs1890229 79751748 + C/T rs1890230
79752043 + A/G rs9352682 79752074 + C/T rs35730468 79753387 +
--/AAT rs4623209 79753656 + G/T rs35399714 79753801 + --/T
rs12529043 79754574 + A/G rs10943612 79755099 + C/T rs35529955
79755508 + --/T rs4144107 79755536 + --/A/C rs34495466 79755537 +
--/A rs3902856 79756556 + C/T rs1415862 79756757 + A/G rs1415863
79756878 + A/G rs3818839 79757044 + C/G rs34665480 79757153 + A/C
rs35828088 79757480 + --/A rs9359359 79757699 + C/T rs3841156
79757786 - --/AGA rs3841155 79757996 - --/TCT rs7749615 79758494 +
G/T rs6454092 79758691 + A/G rs12208915 79759454 + A/G rs9359360
79759515 + C/T rs9359361 79762302 + C/G rs35279139 79762390 + --/T
rs6940637 79762564 + C/T rs6904138 79763733 + A/G rs35057263
79763873 - C/T rs41269341 79764094 + C/T rs11752126 79764642 + C/T
rs7747479 79764719 + A/C rs36000864 79767181 + A/G rs9443636
79767375 + C/T rs9361477 79767525 + C/T rs13218407 79767680 + A/C
rs13218727 79767681 + A/G rs9361478 79768691 + A/G rs34042644
79769661 + G/T rs2065986 79769884 + C/T rs9443637 79771427 + C/T
rs13191068 79771586 + C/T rs11965967 79771803 + C/T rs9448607
79772339 + A/G rs6907674 79773483 + A/T rs35415106 79774112 +
--/TTT rs9352683 79775514 + G/T rs34509958 79776185 + --/G
rs9443638 79777586 + A/T rs9448608 79777881 + C/T rs1933238
79778128 + A/C rs11754374 79778672 + G/T rs7766491 79778959 + C/T
rs4706747 79779358 + A/G rs4706748 79779391 + A/G rs4637600
79780227 + A/T rs9350799 79780370 + A/C rs9361479 79780474 + A/T
rs35887627 79780475 + AC/TT rs9359362 79780475 + C/T rs9361480
79781148 + A/G rs34015061 79781739 + --/T rs9361481 79783469 + A/T
rs36092348 79784000 - A/G rs1338023 79785047 + G/T rs9350800
79786208 + A/C rs11754419 79786367 + A/G rs9718121 79786606 + A/T
rs35727754 79786754 + --/A rs1832396 79787561 - C/G rs34244224
79787746 + A/C rs34815601 79788716 + --/A rs11315927 79789321 +
--/T rs9352685 79790968 + C/T rs2050659 79791088 + A/C rs2050660
79791445 + C/T rs35999901 79791481 + --/G rs28449859 79791564 + C/T
rs34111968 79791750 + --/A rs9443639 79791873 + C/T rs7775074
79792805 + C/G rs34655287 79792904 + --/A rs11326550 79792916 +
--/A rs7742034 79793825 + A/G rs28532298 79795101 + C/T rs35744497
79795678 + C/T rs9448609 79795708 + A/G rs3929865 79795727 + C/T
rs9343860 79795729 + A/G rs3929866 79795824 + A/G rs13218541
79795927 + C/T rs3929867 79796069 + A/G rs9448610 79796341 + A/G
rs6918296 79797639 + C/T rs4565265 79798677 + A/G rs2095724
79798820 + C/T rs7741282 79799097 + A/G rs35793703 79799130 + --/G
rs2105143 79799666 + A/G rs1538233 79800454 + G/T rs7751422
79800799 + C/T rs35760468 79800851 + --/G rs9343861 79801587 + A/C
rs10943613 79801826 + C/T rs11963444 79802291 + C/G rs34875528
79803382 + --/A rs9359363 79803610 + C/T rs9448612 79803872 + A/G
rs12180022 79803813 + A/G rs9448613 79803942 + A/G rs9448614
79804316 + C/T rs4706749 79804772 + C/T rs1415861 79805047 + C/T
rs5877639 79805108 + --/TTT rs4055439 79805107 - --/AAA rs35633350
79805108 + --/TTT rs34124549 79805944 + --/A rs11758432 79806313 +
C/T rs6454094 79806528 + C/T rs9361482 79807104 + C/T rs35197393
79807335 + --/T rs34887019 79807963 + --/T rs9343862 79808197 + C/G
rs35686657 79809315 - C/T rs9343863 79809511 + C/T rs2050662
79809792 + C/G rs9361483 79810005 + C/T rs2050663 79810113 + C/T
rs7739298 79811079 + A/G rs35594811 79811779 + A/C rs9448616
79813653 + A/G rs34896515 79814085 + --/C rs13204088 79814157 + A/C
rs34581263 79814707 + --/G rs34999680 79814872 + --/C rs9361484
79814937 + A/C rs9352686 79814942 + G/T rs34193659 79815383 + --/C
rs28404148 79815386 + A/C rs34818907 79815757 + --/C rs9361485
79816451 + C/T rs35355402 79817319 + --/C rs4706080 79817716 + C/T
rs9361486 79818479 + C/T rs2152951 79818891 + A/G rs35469490
79819211 + --/C rs9448617 79819766 + A/G rs12182597 79819707 + A/G
rs11968462 79819711 + C/T rs9350801 79819985 + C/G rs9448618
79820526 + G/T rs6928507 79820970 + A/C rs6928518 79820984 + A/G
rs6929315 79821334 + C/T rs9343865 79821914 + A/T rs11760038
79822663 + A/G rs34192988 79822723 + --/G rs9969106 79822922 + G/T
rs6454095 79823093 + C/T rs12110918 79823270 + A/G rs9443640
79823496 + C/T rs28393972 79823721 + C/G rs28587408 79823722 + G/T
rs11292616 79823758 + --/A rs6915558 79825775 + A/T rs10528595
79826027 + --/ TATATA TATATAT ATATATA rs10631256 79826038 + --/ATAT
rs34479070 79826039 + --/ATAT rs10668885 79826050 + --/ ATATAT AT
rs10668886 79826051 + --/ ATATAT AT/TATA TATATA
rs35594282 79826052 + --/ TATATA TATA rs34850134 79826053 + --/
ATATAT ATATAT rs10943614 79826062 + A/T rs7753638 79826260 + C/T
rs6917206 79826433 + C/G rs11295038 79826554 + --/A rs7454519
79827581 + C/G rs9343867 79829072 + G/T rs6925447 79829270 + C/T
rs9448620 79829965 + C/G rs10688271 79832242 + --/CA rs1547731
79832823 + A/G rs9352688 79832882 + A/G rs28562383 79833897 + A/T
rs9448623 79834479 + C/T rs9968921 79835098 + A/G rs34949474
79835636 + A/C rs10455120 79836486 + G/T rs12529731 79837484 + A/G
rs9352689 79839533 + C/T rs9361488 79839593 + C/T rs7744876
79839756 + A/G rs9352690 79840271 + A/C rs3857447 79840542 + C/T
rs28361939 79840905 + G/T rs13216433 79841107 + G/T rs9343869
79841140 + C/G rs34915363 79841523 + --/T rs9448624 79841582 + G/T
rs35664126 79841883 + --/A rs9443641 79842023 + A/C rs9352691
79842326 + C/T rs34821012 79843195 + --/A rs3812161 79843364 - G/T
rs12526671 79844774 + C/G rs1413967 79845731 - A/C rs9343870
79846192 + G/T rs7753531 79846715 + A/C rs1413969 79847701 - C/T
rs1413968 79847761 - C/T rs4055438 79848331 + --/CACA rs1415860
79848500 - C/T rs13212056 79849331 + A/C rs7776432 79851211 + G/T
rs36017295 79851212 + GC/TT rs7776138 79851212 + C/T rs1415859
79851577 - C/T rs35716913 79851705 + --/T rs12154147 79852063 + C/T
rs12212124 79852485 + C/T rs9359364 79852711 + A/G rs9443642
79853322 + G/T rs9448625 79853356 + C/T rs9352693 79854791 + A/T
rs9443643 79855557 + A/G rs12664690 79856551 + C/T rs9352694
79857537 + A/G rs13206256 79860401 + A/G rs11963526 79860546 + A/G
rs4706750 79862281 + A/G rs7773757 79862756 + A/G rs5877640
79865118 + --/T rs35313660 79865119 + --/T rs12193154 79866583 +
C/T rs7767100 79867252 + A/C rs9443644 79867363 + A/G rs7767711
79867419 + A/G rs12214911 79867844 + C/T rs4507549 79868299 + C/T
rs9448627 79868502 + A/G rs6899909 79868551 + A/C rs12660124
79868563 + A/G rs28379467 79868586 + A/C rs9689135 79868589 + A/C
rs9689136 79868593 + A/C rs6906253 79869724 + A/C rs34349727
79870222 + --/T rs1538232 79870555 + C/T rs7749916 79870911 + A/G
rs12195753 79872084 + C/T rs34664515 79872349 + --/C rs12197385
79872695 + A/C rs11968729 79872968 + A/T rs9361489 79873504 + C/T
rs4144106 79873950 + A/C rs5877641 79874047 + --/TTT rs35186945
79874048 + --/TTT rs5877642 79874056 + --/TTT rs34582407 79874057 +
--/TT rs4055440 79874065 + --/T/TT/TTT rs34285696 79874066 + --/TT
rs5877644 79874142 + --/A rs5877645 79874154 + --/A rs949846
79874315 - A/G rs35175594 79874354 + --/T rs6916081 79874571 + C/T
rs9341758 79876533 + C/T rs9343871 79876838 + C/T rs11967829
79876870 + A/T rs4460185 79877129 + A/G rs12203969 79877616 + G/T
rs35921542 79878727 + --/T rs1415310 79879033 + C/T rs34887350
79879491 + --/CA rs9443645 79879643 + C/T rs35532958 79879775 +
--/G rs12208017 79880090 + G/T rs10943616 79880260 + A/G rs6940949
79880754 + A/G rs6904124 79881799 + C/G rs34131532 79882366 + --/GA
rs34222053 79882584 + --/G rs9361491 79882867 + C/T rs9352696
79882949 + A/T rs34096134 79883539 + --/A rs13437410 79883867 + C/G
rs1337128 79884042 + A/G rs1415311 79884599 + A/C rs9352697
79885302 + G/T rs6902186 79886779 + A/T rs6902217 79886841 + A/G
rs35067617 79886856 + --/A rs34297827 79887590 + --/A rs7747226
79888212 + A/G rs7747540 79888379 + G/T rs1577793 79888739 + A/G
rs34004133 79889589 + --/G rs9448636 79890158 + C/T rs9448637
79890797 + C/G rs6454096 79891729 + A/G rs7768264 79891856 + C/G
rs7768535 79892231 + C/T rs11285425 79892473 + --/T rs9688601
79892482 + C/T rs11361003 79892488 + --/T rs11362933 79892493 +
--/T rs12055857 79892585 + A/G rs12055858 79892634 + A/G rs9294129
79892802 + A/C rs9443647 79892908 + C/G rs34216559 79893168 + --/A
rs3920791 79893453 - G/T rs1361043 79893786 - A/G rs5877646
79893802 + --/A rs1577794 79894899 - A/G rs7771746 79895912 + C/T
rs7751626 79895992 + A/C rs7751628 79895996 + A/C rs7751918
79896046 + A/G rs11757274 79896170 + A/G rs1832281 79896696 - G/T
rs34002011 79897278 + --/C rs9448638 79897415 + A/G rs9448639
79897548 + C/T rs36080847 79897705 + --/C rs35178487 79897768 +
--/C rs9448640 79898041 + A/G rs6938269 79898250 + A/G rs34749590
79898414 + --/C rs6900032 79898558 + C/G rs6899945 79898698 + C/T
rs1856089 79898889 - G/T rs1856090 79899041 - A/G rs28793115
79899460 + A/G rs6906655 79900092 + A/G rs6929531 79900136 + C/T
rs2210948 79900755 - C/T rs9359366 79900866 + A/G rs9343875
79901113 + C/T rs9343876 79901219 + A/G rs9448642 79901713 + C/T
rs9341760 79901973 + A/G rs9361493 79903957 + C/T rs34851468
79903998 + --/C rs2321960 79904819 + C/T rs4547969 79905337 + C/G
rs2321961 79905575 + C/T rs9361496 79905887 + A/G rs6922885
79906095 + C/T rs6900076 79906130 + A/T rs34635585 79906257 + --/AA
rs12527205 79906518 + C/T rs6916942 79907146 + A/G rs13192783
79907675 + G/T rs35970033 79907754 + --/GTGT rs13207216 79907776 +
C/G rs9448644 79909382 + A/C rs956550 79909459 - A/G/T rs11450125
79909773 + --/A rs35277763 79909871 + --/C rs9443648 79910324 + A/G
rs17785485 79910945 + C/T rs17723508 79911083 + A/G rs9448645
79911477 + A/G rs6904674 79912150 + A/C rs28369551 79912158 + A/T
rs6933121 79912963 + C/T rs7768622 79913223 + G/T rs10484946
79913349 - A/G rs12196543 79914619 + A/G rs9448647 79915916 + A/T
rs9352701 79916596 + A/G rs9361497 79916649 + C/T rs9448648
79916948 + A/G rs9294130 79917888 + A/G
Example 2
[0316] Further analysis of marker rs11228565, which is located
within LD Block C11 and in LD with rs10896450 (D'=1, r.sup.2=0.25),
was performed, with results as shown in Table 7.
[0317] Highly significant association of the A allele of rs11228565
to prostate cancer was revealed, with combined P-value for all
cohorts genome-wide significant (P=6.7.times.10.sup.-12). The odds
ratio (OR) for rs11228565 after adjusting for rs10896450 was
determined to be 1.16 (P value=4.9 E-04) when using results for all
populations except Finland (i.e. where we have results for both
markers rs11228565 and rs10896450 in: Iceland, Chicago,
Netherlands, Nashville and Spain cohorts.
TABLE-US-00009 TABLE 7 Association of rs11228565 with prostate
cancer. Study Case Controls Control population Marker Allele P
value OR Cases (n) Freq. (n) Freq. Iceland rs11228565 A 7.72E-03
1.23 1784 0.209 771 0.176 The rs11228565 A 2.15E-02 1.17 992 0.229
1781 0.202 Netherlands Spain rs11228565 A 3.42E-01 1.09 394 0.240
1399 0.224 Finland rs11228565 A 3.22E-06 1.30 2643 0.210 1689 0.169
Chicago, rs11228565 A 8.00E-02 1.16 755 0.235 878 0.210 USA
Nashville, rs11228565 A 8.49E-05 1.43 592 0.291 685 0.223 USA All
rs11228565 A 6.70E-12 1.23 7160 -- 7203 -- combined
Sequence CWU 1
1
2011599DNAHomo sapiens 1ctttctctcc tctagcactt cctgcagttg tttatatttc
cattgttgtt actcagcctc 60atttaaggcc ttctacatta tgttttccac taagatgaat
gaaccacttc aagggggaat 120aaacttgcca tcaatggaca tgattaaaca
taggcaagac catctcttaa gaattctctt 180tcacaaaaca atttactttg
ttataaaaga cagaaggaaa aatctatttt attatcagaa 240ttataccatt
aacacctagc aactattatt tcttcatttg ttccattgtt aacatgagaw
300attaaagtct tttgatgttc tcattttttt ctttgcctca gtttctgaac
tctagtacag 360gtcttgctga cctaagatgt tttgggagat gtgaaaaagg
atgaatgctg agtttgaaat 420gctgctcaat ataaggcaga agttgtccaa
gaagccaaac aggatgtaaa cttccagatt 480gtatagatat taccggataa
ttgcatttgc ctttacctac tataatatgc cttagcttcc 540caaagtgcta
ggattactgg cgtgatgtat ttactgtcga cagaactcca ataaagaac
5992599DNAHomo sapiens 2acatgggtca tatatacatc aatttgttcg atacacatat
atcaggacca ccttcataac 60tattcataac tcatcctata acctgttaaa tatatatgct
tagccaactt gttcaacata 120aaactcctac cccaacttat cttcactcaa
aatgcctact aatggctttg gccagaggca 180tgcttcccag tctgcaagat
agccacctta cagtctataa ccctttacaa aaaaataaag 240tatccttcct
aaatttgtag gtcctgtgat tttttaactt gacacactga gtcctgttty
300tggctggagg tgcacttcct agcctgccag catggccacc tttataagaa
atagtctctt 360cttttcaaat attttttttt gtaagttacc atatcttgtg
atgaggattt ttcacttaaa 420tgtgtaaaat aatatatgga aagtgcttag
catactgcct gatatgtagc aggtacttaa 480aaactagcac ctgtcatatt
attactgata cattcaccta cttcctgttt tcttcaggcc 540tctttcctaa
ggaatgctga ggtgttcacc agttactgaa gaagaggaag tcactaaag
5993599DNAHomo sapiens 3atcttcaata agattatcta agattgtatt agacaaaata
agaaaagctt ttagcatgat 60aacaagtaga tttttgaatg aatgaatccc cagggaagtc
ctacgaaagg tgggtggtat 120agagaagcaa ggaaactgag gctcagagat
gttgagcaag ttataaagaa aataagcagc 180aaagctagga tccaaatcaa
gttcagtatg tttgcaatgt caaggaagtt tctattattt 240ctgcaagaaa
cattagtggc attttccact ccagagtttc tttaaaggac atatgctggk
300gaactccagt tatttgtcaa ctctgtctcc ctagaaatct ctttagatta
gagttatcat 360catcctttgg catttcaaac cctgcacaac atgtttataa
ttggatggtc tgataaatga 420tcctgcataa accagccact aacatctttg
aacttcctct gtcatttcct atgcagaatt 480cctcttaagt gcctcataca
cagtttgatg tgccctcttt taaagtagat atgcactgat 540cctatcagtg
tctaaactac cacctgactg taaagtagcc cttttaaaat ctattcttt
5994599DNAHomo sapiens 4ataattgcat cattttagct attcatgccc tgagatttta
attttcaaaa tattttcatt 60tatacccaat ctttatttct gttaataaga agcatactct
ataaatgatc aatgaataaa 120atccattgat gatataagca acttagttta
gccaccttct cttttactaa gtctcttaac 180acaatctgca aaaagagaaa
actgttagtc tttattacat tttctattaa ccttttaata 240gaattgcagt
aagcatgagc aaaagcaaaa tttgtggtat gaaacaaaat tgttacttay
300acttcactaa acagtgccag catatgttat aatttcagca ttaatttaac
aaggttaaat 360ttataggaca aatgttagaa attctctagg gttttctagg
aaactaacat ttcatgatga 420gaaggcttgt ttaagttatt ttattttttt
gtttaagtta ttttattttt aatgtttgtg 480ggtacatagt tgtacatatt
tatggcatac atgtgatatt ttgatacagg catatgtgta 540atgaccaaat
caggataatc gggatatcca ttacctcaaa catatcattt ttttgtatt
5995599DNAHomo sapiens 5aggggattca agtcaagttc acccattact gaaaatagag
aagacagtga ttttctaaga 60gcttctctgg aaaactgaat cccatcacaa gtcttaagtc
cctgggcttg agttcctgat 120catgggtcaa aggaaccagg atttaaacaa
ctgactctct gaatatacta ttactataaa 180tcctttattt gacttctgtc
tgcctaagtt tggaagcacc cttctgcttc taaaacccct 240ttactccaat
tttcaatcat aattggcagg atttctgaaa atgtacagca tttgaattay
300ctaggggctt ttgagatatt tcctggcccc catctatcaa gtcatctctg
ggggaggggg 360ctaggactct ttatttttaa caagctctta cagatgttct
tatacccaca aacatctgag 420atccactgag gtgtgtaaag ctcctagcac
agtgcatggc aaatttaatg ttccaaatgt 480atatctgcag tgtcactcca
gccctccaat tagagcacaa acaggaaaag ggggaaaaat 540actgacaaat
atttgctttg aaatgaactt tggtggagat ctatttaaca aacagctgc
5996599DNAHomo sapiens 6tgctgagtaa taaaccaaag aaaatgaggg aaagagcatt
tcaggccaag tgaatagcat 60gtgggaaaga gcttgaacta aaataaaatt aaagaccagc
atggctggaa aataataatg 120ggcaagttaa agagatgcag gggctgaggt
gatcaagttg gaaaagggct agatcgcgta 180ggacttctag gactttccat
ttcatttgag gcacggtatg agcccttgca ggattttagg 240aagaggagtg
gcataacatg aactgcattc tttaaaggcc acatgactga acatgtggar
300ggagccagaa tggaagcaag agacaaatat taaaggcaca taaatgtggc
agatagggtg 360atgtgataga aattgatgta agagagacag aatgctggag
aaatgcaatt gaaaacgaaa 420tctcctccaa acccaaacac ttctccacaa
aggtagaaaa caattttaat gttcaataag 480tatcaaacca gactgcaatg
cacattatag gcagactgct aagagatttc aaactggaaa 540gtaatctcac
ccttttatat agccaagccc attcaacctg ttacatgcct attcttaag
5997599DNAHomo sapiens 7gaccagcatg gctggaaaat aataatgggc aagttaaaga
gatgcagggg ctgaggtgat 60caagttggaa aagggctaga tcgcgtagga cttctaggac
tttccatttc atttgaggca 120cggtatgagc ccttgcagga ttttaggaag
aggagtggca taacatgaac tgcattcttt 180aaaggccaca tgactgaaca
tgtggaggga gccagaatgg aagcaagaga caaatattaa 240aggcacataa
atgtggcaga tagggtgatg tgatagaaat tgatgtaaga gagacagaay
300gctggagaaa tgcaattgaa aacgaaatct cctccaaacc caaacacttc
tccacaaagg 360tagaaaacaa ttttaatgtt caataagtat caaaccagac
tgcaatgcac attataggca 420gactgctaag agatttcaaa ctggaaagta
atctcaccct tttatatagc caagcccatt 480caacctgtta catgcctatt
cttaaggtaa gcaacaacta cagacagtcc ccaacttatg 540agtttgtgac
tttccaatgg tataatatgg atacattaga gaccatatgt caagtactc
5998599DNAHomo sapiens 8acttaaggac tatagatgct cctcgtttta tgatccggtt
atgttctgat aagctcattg 60taagctgaaa atattatgtt aaaatgcatt taatacatct
aatctaccaa acatcatagc 120ttagtcaagc ccaccttaaa cgtgctcaga
acacttttat tatcttacag ttgggcagag 180tcatctaaca taaagcataa
taaagtattg aatttctaat gtaacttatt ggacactgta 240ttgaaagtga
aaaatagaat gtttatatga gtacttgaca tatggtctct aatgtatccr
300tattatacca ttggaaagtc acaaactcat aagttgggga ctgtctgtag
ttgttgctta 360ccttaagaat aggcatgtaa caggttgaat gggcttggct
atataaaagg gtgagattac 420tttccagttt gaaatctctt agcagtctgc
ctataatgtg cattgcagtc tggtttgata 480cttattgaac attaaaattg
ttttctacct ttgtggagaa gtgtttgggt ttggaggaga 540tttcgttttc
aattgcattt ctccagcatt ctgtctctct tacatcaatt tctatcaca
5999599DNAHomo sapiens 9aggatgaact atctgtaata aatgatgctg tgaagtccac
ttaaggacta tagatgctcc 60tcgttttatg atccggttat gttctgataa gctcattgta
agctgaaaat attatgttaa 120aatgcattta atacatctaa tctaccaaac
atcatagctt agtcaagccc accttaaacg 180tgctcagaac acttttatta
tcttacagtt gggcagagtc atctaacata aagcataata 240aagtattgaa
tttctaatgt aacttattgg acactgtatt gaaagtgaaa aatagaatgk
300ttatatgagt acttgacata tggtctctaa tgtatccata ttataccatt
ggaaagtcac 360aaactcataa gttggggact gtctgtagtt gttgcttacc
ttaagaatag gcatgtaaca 420ggttgaatgg gcttggctat ataaaagggt
gagattactt tccagtttga aatctcttag 480cagtctgcct ataatgtgca
ttgcagtctg gtttgatact tattgaacat taaaattgtt 540ttctaccttt
gtggagaagt gtttgggttt ggaggagatt tcgttttcaa ttgcatttc
59910599DNAHomo sapiens 10gaacataacc ggatcataaa acgaggagca
tctatagtcc ttaagtggac ttcacagcat 60catttattac agatagttca tcctagattc
acctggtaat tagggtggcc atctgtgttt 120gctaatcagc tttatcaaaa
ggagattttt aacttctcag atctttatga aaggaagtag 180ctttgtaact
cggagtaagg tactcctatc ctcccacaga gactgggaga taaagatgca
240atctctctgg atatttacat ttcaaggaga tgatctcagg tccttgaaaa
agacattcck 300gggtcttaaa gctgataaga gactattcag ctttttaaaa
ggtttacaca catttcaaag 360agatagagaa ataacttata attacaattt
tcttaagtaa ataatctaag aaagggaagg 420gggggaatgg tctcttccct
tattttcaac agggagagtt aaatctcttg tttttaattt 480ttatttgctc
tttttcaaga gatagataaa tggatttgag actactgtac attgggttat
540atgtgaagat tggaggagga gaaactaaaa tgatgaccag tttgagcaat tacatcagt
59911599DNAHomo sapiens 11agacctctga ggcggagtca ctgtcttgct
gctattacct tggaagaggc tcagtgagac 60tgtttgggaa tacggaaaag aagttgaaga
ttgaaattaa ctgcccctgc caggttgaag 120gggccttgct caggctattt
gagaagaaca ggaagcaaag caaaaaggag tatttcagtt 180cctcctccag
ccttgcagtc ccctctctag tacctttatg gtggcagaac ctaacaggaa
240gcctccttgt caaaggatca gtggaatttg gtaagccatg gccccagcat
cacacagcas 300agtgcagagg actaggtttg ttggagggag aacattgttt
aatagctgga acaagtcctt 360tgtctgcttt agcaatagac cctctgatgt
gcccacatct ctgcaaatgt gtgactgctc 420tgcttggggg ctggctgcct
gcataattgc taagcttggc acttctgttt gttgacatta 480aatgctatta
gggaacaact ttgtgaaaca atatttttgg tgatgctgca ttttcttaac
540ataattttca ttacattcac gtggacattc acgacaaacc tacaggcatg cccttatgt
59912599DNAHomo sapiens 12aataaataac taaagcaagt ggctgccatc
gctaatgttg ggggaataga gagaaggggt 60tgggttgtag gaatctagaa gcttaaaggt
ggggccctag tatactggga ctcagacctc 120tgaggcggag tcactgtctt
gctgctatta ccttggaaga ggctcagtga gactgtttgg 180gaatacggaa
aagaagttga agattgaaat taactgcccc tgccaggttg aaggggcctt
240gctcaggcta tttgagaaga acaggaagca aagcaaaaag gagtatttca
gttcctccty 300cagccttgca gtcccctctc tagtaccttt atggtggcag
aacctaacag gaagcctcct 360tgtcaaagga tcagtggaat ttggtaagcc
atggccccag catcacacag cacagtgcag 420aggactaggt ttgttggagg
gagaacattg tttaatagct ggaacaagtc ctttgtctgc 480tttagcaata
gaccctctga tgtgcccaca tctctgcaaa tgtgtgactg ctctgcttgg
540gggctggctg cctgcataat tgctaagctt ggcacttctg tttgttgaca ttaaatgct
59913599DNAHomo sapiens 13ttgtgtcagt gaaacaaaac tcatactaga
tattttgaca gagaaattaa ggtgggaaat 60tggctaagtg ttggagtact gaaaaatcag
agaagacact taggaaacac agataataaa 120taactaaagc aagtggctgc
catcgctaat gttgggggaa tagagagaag gggttgggtt 180gtaggaatct
agaagcttaa aggtggggcc ctagtatact gggactcaga cctctgaggc
240ggagtcactg tcttgctgct attaccttgg aagaggctca gtgagactgt
ttgggaatay 300ggaaaagaag ttgaagattg aaattaactg cccctgccag
gttgaagggg ccttgctcag 360gctatttgag aagaacagga agcaaagcaa
aaaggagtat ttcagttcct cctccagcct 420tgcagtcccc tctctagtac
ctttatggtg gcagaaccta acaggaagcc tccttgtcaa 480aggatcagtg
gaatttggta agccatggcc ccagcatcac acagcacagt gcagaggact
540aggtttgttg gagggagaac attgtttaat agctggaaca agtcctttgt ctgctttag
59914599DNAHomo sapiens 14ataaaatact taaaatgctg agataagtaa
ccatggaagc aaagttttaa agatgcataa 60ttaattcatg cattaaatat ttattgtgtc
tgctatgtgc taggtgtagt atgaggtttg 120ggggaaaact acagtgaaca
agataaaatc tctatcaata caggtttcca tcttccagga 180gagacctgaa
aatacagaga ccataactcc atggggaata tggagagcag tatctccaga
240aatccctagg cagcaggaag cctgtctgct gaggccctga aaactaagga
gcctcagacr 300aggtctactg gcagtagact tgacttgaaa tcctggctgc
atactattta agctctcaaa 360gctttgcttt ccttgtctgt gaaatccact
ccatcttcag ccacaacttt cagtttttct 420aatgcaatat agggaaaaaa
cagggtggaa gaaggaagat aatgctatag ttcctttctc 480tttttttttg
cccaaattac acctatgtca atgaatgcta tgaatactta tttgattgaa
540tcctttgagg aggaagagtt tggaataaac tgcccctcta tgagagacag ttttaactt
59915599DNAHomo sapiens 15catttctcct tcctggacag agaacttgaa
cactagatag tcctaaatta ttcttttgaa 60gtttgaatta gccatagttg aataatacag
gggaataata aaatacttaa aatgctgaga 120taagtaacca tggaagcaaa
gttttaaaga tgcataatta attcatgcat taaatattta 180ttgtgtctgc
tatgtgctag gtgtagtatg aggtttgggg gaaaactaca gtgaacaaga
240taaaatctct atcaatacag gtttccatct tccaggagag acctgaaaat
acagagaccr 300taactccatg gggaatatgg agagcagtat ctccagaaat
ccctaggcag caggaagcct 360gtctgctgag gccctgaaaa ctaaggagcc
tcagacaagg tctactggca gtagacttga 420cttgaaatcc tggctgcata
ctatttaagc tctcaaagct ttgctttcct tgtctgtgaa 480atccactcca
tcttcagcca caactttcag tttttctaat gcaatatagg gaaaaaacag
540ggtggaagaa ggaagataat gctatagttc ctttctcttt ttttttgccc aaattacac
59916599DNAHomo sapiens 16actccctctt gctgtgttta gttgccaacc
aacagtgagg agtttgtaaa gtgtcttttt 60catttctcac atccactgta ttttaaacaa
tgagaatagt atgcccttac ttcatctgca 120ctgggaaaat acctgaaagt
aagctaatga tgagatttct ccagatgaaa catgccaggt 180gatatcttaa
acacaatttt taagtcttgt ttagtttcat gcagtgcatt tctccttcct
240ggacagagaa cttgaacact agatagtcct aaattattct tttgaagttt
gaattagccr 300tagttgaata atacagggga ataataaaat acttaaaatg
ctgagataag taaccatgga 360agcaaagttt taaagatgca taattaattc
atgcattaaa tatttattgt gtctgctatg 420tgctaggtgt agtatgaggt
ttgggggaaa actacagtga acaagataaa atctctatca 480atacaggttt
ccatcttcca ggagagacct gaaaatacag agaccataac tccatgggga
540atatggagag cagtatctcc agaaatccct aggcagcagg aagcctgtct gctgaggcc
59917599DNAHomo sapiens 17ggttggggta tgaaaagggg caatttcccc
atctctggct actggcaaat ttattttgca 60atgagccctg caaacgatgt gtagtggccc
tgattggaac ctgttctccc aaggtcacca 120taactttcat tccactgtgt
gttgactgca actgccctgt ccaatcccca tcttcagctc 180agacctgagt
ttcagccatg tctatgccac tgtatccagt gaccgcatct tacctttcct
240cctattctca caggttccca catgttcttc tcagctagct gaaaagctca
tctttgctar 300taatagctgc tgcttattca gcacctccta aaaactaggc
ttggggttta tatgccttat 360ttctgtgact cacaatgatg cttcaaggta
aatatgatca tctacatttt ttttgagacg 420gggtctcact ttgttgccag
gctggagtgc agtggagatt tcaaatgttg gttaatttcc 480aaaacatatc
tctttttact tcagtcacaa agtgtctaaa tgattttgta gtagatacta
540atgaactatt ttgttacctc ttctagatag aaatagtaag cactgggtat gtgccagat
59918599DNAHomo sapiens 18atgtacatat atacatacaa catgatgtat
gtgtatgagg gtatatatat ttttatattg 60aatatatata cacatatgta gtgctaaaat
gagaatatag ttaggttcag agagtaaata 120atgttcatta ttgccataaa
gtgactctat aatgattaat aaagatataa aatcaaatgc 180atttaagagg
aaaggcatta attgaattaa gtactattat tatattggca tctcctttat
240gcctgtgcta tgttactggt gtgggaaata tatatgcact taaactattt
tgcaacgtay 300acccaaaatc acactgctgt ttttgaaaag cccataaaaa
gcctgaattc tccacacata 360ttccatacat gagagcagaa aagaagaatt
tgccaacttg taaagtttct atgcatgtac 420ttaatttctt cccaaaggtc
caattcacta gttattcaga ctcaacattg ggaaatggac 480ataaggaagt
acagttggag caaaacatgg ctacactttg gccagcaaaa tcttcctcac
540cagcaatatg gatactacag acagcaaaat tatcaatcag cactggaaaa agaaaatga
59919599DNAHomo sapiens 19tgttctacat tatatgaatt tctcaaaagc
agatggctga ataacttaca gaattgaatt 60tcagctccat tagattccat tcttacctaa
aatgtgtgta ccacattata tctgctagtc 120agaacagtct tttggcaata
atataaactg tgagcactca gaccagatca gaatatattt 180attgttttgt
tagaaagcac ctagttcatg ttaactttca atggaagtta tattgtttag
240caacttgagg aaaaaaattt taaagatgtg aataggatac tttaggtagt
atctctttty 300cagatagtag agataaatta taaatggcag ggataaaaac
aaagatgaaa ttttggcctt 360aaattgtcat atgcaaaaac atccccaatt
tatttaaacc tgtttaaatt taatttccaa 420ttatttaagc ttttattgca
ggttcagcat tcctaatcta aaaatccaaa atgctccaaa 480atcaaacttt
ttgagtactg acatgatagc acaagtgaaa acttccacac ctgacatcgt
540tgctttctca tttcattgca cacgaacttt ttcatttact aaattattaa aaatagtgt
59920599DNAHomo sapiens 20agaattctca ctctgtcaac agagtgtctt
gtccagcctt tggatttttg cagatacagg 60aggtgagaaa tggtatctga gtgaaggatt
aatttgtgct tcttattatg aagtcaggca 120tcttttactt tacttaaggg
ccatatctac ttcttttgtc aattgcttgt tcatgttgtt 180tgcctatttt
tgtctgtttt tgtgactttt tctttctctt cttccttttc atattcactt
240aatatttcaa tttttaaagt acttttcatg ttgtgaatag ttttgtataa
acccacgaar 300tatatttgag tagtgttgtt tgaactctaa cctgataaag
tttcacttcc tcaacctgcc 360ctcaaaatat ggccagggtg gacatgttcc
aaattgaatt actccataaa aacagtcaga 420atctcagata aacagtgact
tccaaatatt aaaaataaat atgtgaataa ttttaattaa 480tgtaacatag
tttggcagat tttatatgag ctggccacag ctttttaata ggtatgtaac
540tcccttttaa acaaaggatt tcatagacaa aatgttctac attatatgaa tttctcaaa
59921599DNAHomo sapiens 21tcttgaatgg gattgtgtct gtgttgttat
aaatatttta tattcagaac aagagcttga 60atctagtcta ttgtgaagga tgaaagagaa
gtattttatc agggaagcca cttatcagat 120ttatgttttc taaaaatcaa
tgtggttgtt ttgtttaaag caccacagat tctttcacat 180ttctcctact
aatgggtggg atctatgttc cttcctcttg aatctgggca ggcttgtaac
240tgcttcaacc aatatggatt gacagaagtg atactatttc actttcaaag
cccaaggtcr 300tatatcttct acctggttct ctttggaggc tcactctgga
ataagccaaa ttccacttaa 360ggattccaat tacaccattc tggagaagtc
tgtaggtaca tctgtcagca gttcaaacct 420tctagtcatc tctgccaaga
caccagacag gtgagttaag gagcttctag aggatttcag 480tctccagcca
tttgtcaccc ccagctgttt aaatatcccc aaatgaaacc tcacacactg
540aggagtagag acaagccatc cctactatac cccatcccag tttctgactc ctagaatcc
59922599DNAHomo sapiens 22aacaatctgt ttgccaagga gcttcctgag
agcttcaaaa gcagtggtag ttaaggcctg 60cctcttgaag atagtcctga tccaggtgta
ccaaccacat aaaaaagaca gtccacaaag 120gtctcagtga tttatgctca
gtccctttca ttaatattgc caatcatgta atccattctt 180taccccttga
aaagaaggga gggtagaagt gggggtagtg tagaagaaat agtgggagct
240ctgttcccag ttcttctgaa ggagctgttc ttgttttgtg agtctaagtg
aaaacattay 300gtcaaaaaga atatagcttt ttctttgctc tctgctctgt
ggagccaggc agggtaggaa 360aaggagattc cagggagcta agaatttaaa
gccagagtga ctgtcaacat tcccatagtg 420aaacgcagct ccccttcact
agtcctaaat ggtgccctat agaaccctgg aagaccttcc 480cgggggcacg
tcacaacctc actgacgcaa aatgtcctct ttgggactac cagaagacac
540catgtagtaa cctttgtagg tagatggctg ctgagtcact ataatgaaca tctaaaatt
59923599DNAHomo sapiens 23cagctcccct tcactagtcc taaatggtgc
cctatagaac cctggaagac cttcccgggg 60gcacgtcaca acctcactga cgcaaaatgt
cctctttggg actaccagaa gacaccatgt 120agtaaccttt gtaggtagat
ggctgctgag tcactataat gaacatctaa aatttaacat 180cttctccttt
tactttgtat taccaatgat ttatttttta ttctttttaa aaagaataca
240atataacttg gaaaagaatt ggctagatac agctcagtgg acttaaaaca
atgtgctatr 300tttgaacaac atcaaattat ttttgaaaac cttgccaagt
gacttcaata agatgagaac 360tattaacatg aacttttaaa acagcaaatt
tcaaacattt tttagatgtt ttctgcactg 420gatgttgtag agtactattt
agatcctccc tgaagaccaa ggcattcttt tcctcaggtg 480ctaagaatct
tgcctactga tgactcacag ctgagtccac ctacaggcat ttcccttcac
540tgaaaaaagt tgtttccccc aatcctgcac aaactatgtc ccatcctgga aggcagcca
59924599DNAHomo sapiens 24ctgccaacag tcgtgttatt aaaacaataa
cttgcgaatt tcaagctcaa aattcttaca 60tgatttctca ttcaatacaa aataaaatac
aatctcatca acccagaatt caaagtcctc 120taccatatga aatagtcttc
ttaacaacta tttgctgctg gacacacaca aacatccaca 180caccatactc
ctcttaattc cttcagtcta cacttttaga actctgtgtg gcttttgtta
240agctattgtt taagctaaaa gctcttcttc caagccatct cttccttaac
agttcaaatr 300ccactttttc ttacatccat tagttgattt ttttcttgaa
tttttattgt actttaattc 360ttcctttatt ttgatgctga acactgcttt
ttctataaca tacgtgagtg catacatatg 420tattatatat gcatttttta
gctccttaaa agttaagaac tatgtcttag taatcttgac 480atagaagatt
ctaaaaatag tatttattaa tttctattgc aagttggtaa taaggcaatg
540atattttcca taaagaaaaa tgagagtaga actttatttt agtttgttga tattttgac
59925599DNAHomo sapiens 25aatggtagag ttagaaaaca agggcatggg
atgcatccca agtctttcat ccttttaata 60ttcatagaca accaagagcc aactacatac
atcaattcaa gattaaaaac atgaaagttg 120aaaggaaaag aaatctataa
gcaattacca ccttccaagt
cttatgttga tattacagag 180tatcttggga gttggtttga ttaaggaaat
acgtggtgct ccattaaaat ttcttactta 240tttttattac actctcactt
gccctaatga aaataatttt ctttctgttt caggcctgts 300catcttttgt
taaagttaaa tacgccatta gtaatataaa atcaaataac cagatagatg
360ataaagccat aaagagacag acagagagat aacagtttca aatgctttta
gagtctacta 420acattggtga atttctaaga tttagttaat acatcaggaa
actgagaaat tagaccacct 480cttcattttc tttgaaacct agttggcata
ttgatctgtg ttgggttgca ggtttaaaaa 540ggagccatac gccaattagg
actgtgacag tggaataact cttcctgtat accccatta 59926599DNAHomo sapiens
26tctaatatac cactggaatt aaataaatag tgtcatatag aaggaattac attggtgtag
60aggcctaggt tcttgcccca atctacagtt gccatctaac tacattgtac acattaccat
120catgaaactc gataaataac tactcagatt gataataagt aaaagccatt
agactttcct 180tcaaaaatac attgagtact ctttttcaca ctcttcaatc
ttcaatgttc tcaccagttg 240ctctgtgtct tgcagatgaa tctttgtttg
ttttagttct ttttagttct tttcttctty 300ctaggatgtt tgtccatatt
aacaattcct tccttttata acagctccct aaagaaactc 360tttggtcttt
tctcccattg caccctcttc acattggaat caaattgcct ggttttccat
420ctgcataaaa ttatctctga aatctgaatt ctacatatca cccaggaccc
gttcctatgc 480tatatttttc atgagatttt tactggtcct cccagctagt
gcttcctcca ctcatggaac 540ttccatagca ttcaatccat gcctctttta
agataattac aattttctgt gaatatgca 59927599DNAHomo sapiens
27gcagaatttt aaaaaataaa agatggccaa taaactagac caaaggacaa aaagataatc
60ggtgaaacct cacctcaaag atggcagagg acaggagttt aagaaaacaa agggacagtt
120gaatggacac taaggagaaa gagaggttcc caaagaaggg atataaacac
ttcctgagaa 180atccagagat gttcaacccc tagaaataag aagaaagaca
cattgggaat aggtgtttaa 240gatgtagatg aggcaagatc aataaaatag
aggcacatat gtgccacgaa gggacactcy 300atgtgaatta taataggcaa
cttatggctc acctcaagaa cagttatgtc cattgttctg 360aactttgaca
tatgcaccca cattattgaa cttacaaagc ttaaggagtg gaaagagatc
420aaatgcattt ggaactgatg ataaacgtat gtgacagaat gtgcctgtac
tttgggtgat 480atcattgagt gaatacacat atagaagaaa gctttaattt
tcattttttg ccaaaactca 540tgtcaacttt aaaatatgct catatttcat
taacaagaaa acaaaatatc ctgtcataa 59928599DNAHomo sapiens
28cagtctaatt caaccccaag gcaggtgaat gttaagagat tgaaggctgc tgccaacact
60tacagctgag aaatccttgt atctgcctcc tgtgggaaaa gagaaatgga cccagagtga
120ttctatttct ccttccaaat cttgagcaag ggcttcctat tggcagaact
ctaaatgcat 180ttagaatact gagagcaggg gagttcagga gttgcagttc
cttggcttct agcctctgtg 240atacagagaa gagcctaaaa gagattgtca
gtgtgatggt tgtggtggtg gggggaggar 300gaaaatgcga cttgccaaaa
gaacccaata tttagcaaaa ccttcccttt cattctgata 360agtgtgttta
accaaagatg aatacgtctt tttctaggaa ctagaaagag ggaatagttt
420ggcatattga atatgcttga tttaagttgg cattaatatt agatagcaac
tctctggctt 480aagtgatgaa aatactgaga tatacattaa aaacacaccc
aaagctaagt taaggcatag 540attgcttttt cataaagagg aattgtacaa
ttttataagc tattacattg ttatgctta 59929599DNAHomo sapiens
29cttagattat agaattatat gtgaatatgc ttttggctct tacaccatta atgttacatg
60taatcaaaag taattaaatt ttcaaaatta gtaaaaccac tcagttaagc aatgtaagca
120tacattagct gataatcatt tacaatgcca attgcatcct gaggctgtta
ttgacatgtc 180agcagagcat atgatagagt tgtttttctg ccagtactaa
tccagaaaca atgtaaggtt 240gccaatgcag atgggattgt atttgtagaa
tggagcaatt cccataagag atttttgccr 300tactaacagt cgctaggact
tcctcagttt tctcctgtgc caggtggcag tagccaccaa 360cagcatttgg
gcactctgcc ccaccacctc cctcctctcc tgtggggaca tccaataaag
420atgagaaaga cgtgctttgg gcaccaataa attagggaca acaaaatgtg
atattctgga 480agaaatgtca agtcaaaaaa tactgggaaa tctcagcatt
tcttcacatt tatttgtatg 540gtctattaat taatataagt atcataccat
ttggctgtgc tttgatgttt gtcagtgac 59930599DNAHomo sapiens
30cccagagaca tgcacctcca gaatactcag agccaatgat tggcccaact gaagacaatt
60ttgaggggcc actgggcttc cattgtagtt aaaaatctgc agaattctac ttagttctcc
120tgctttccac atgcattcca tgggcacttt tcaaataatt ccctgaacac
taaactctgt 180cccagagact gctcctaggg aatccaactg gcaatgcttt
tcatgcaact ccatccattg 240ttttcttcat ttttctctta ttgggcccaa
aaatatgcct cttgcatttc cacttaccar 300tccttcttct gtcctcagaa
ccaacacaaa taggaatatt ctgatgttaa tttgaaaatt 360cctttaaata
tttgtttatt ggaatttctt gaaacatacc tgatcaatgc aatgacaaca
420gttaactagg tcaatattta taccaacata taacttgcaa ttctttctcc
aagaattaaa 480atacaaattc attgaaaact gctaaaaaac taatcgatac
tttccaacat atttatactg 540ttataagacc tatttcatca cttggaccct
ccttttctaa catagctgtc aaaagaatg 59931599DNAHomo sapiens
31ttataggtgt caatagattg agtgatgtgc cttaggcaca tgaaaaccag gctttccaga
60tgcagctctg aggttaatgt ttcactgttg tatagcaact ttccatccga gggttcctaa
120gagctttata actttacaaa caatctaatg tctttgaagt caatactctt
cctttcctaa 180atgaacataa attcttctcg aattcaccag ggaaaaaaag
cacaatgact gctccattgc 240ttcatcagtg ttagctgtgc ctgacactgg
actccagctg cactttttta tataactgty 300atagctctta tcacattatg
gcaaaattat taatttatac atctgtctcc ccaaatagcc 360agcaggcaac
ttgatggcaa agactgtgtc ttattcacct tggtacagtt tcagttcaac
420aaccatttaa tgagcacgta ctctgtgcca ggattcaagc tagatggtgt
caggttataa 480agacaaatga aacacagcac aggcccttga ggatgctgtg
gacaagtgga ggagacaggt 540acattaattg ttcatttcag cagagtgtgg
aagaaactac aatggatatt taaagccct 59932599DNAHomo sapiens
32aagcacaatg actgctccat tgcttcatca gtgttagctg tgcctgacac tggactccag
60ctgcactttt ttatataact gttatagctc ttatcacatt atggcaaaat tattaattta
120tacatctgtc tccccaaata gccagcaggc aacttgatgg caaagactgt
gtcttattca 180ccttggtaca gtttcagttc aacaaccatt taatgagcac
gtactctgtg ccaggattca 240agctagatgg tgtcaggtta taaagacaaa
tgaaacacag cacaggccct tgaggatgcy 300gtggacaagt ggaggagaca
ggtacattaa ttgttcattt cagcagagtg tggaagaaac 360tacaatggat
atttaaagcc ctgcatagac tttcttctgc ctctaatact ctacccccat
420cttctaatac tctccccatt gcttactgga ctgtaggtac attggttttc
ttgctgtttt 480tttgaacata accagcatgt catcacatca aaatatttga
actttccttt atggaatagt 540gttctcctac atattcacgt ggcttacccc
tgcacatctt tgagtgtttt taattctgc 59933599DNAHomo sapiens
33tatgtatatt gggtttgagc caagtaacta gtatgctgcc cagataatag acccttcagt
60ctcactctca agggcagcag ttgggggaag gagttgtttc tagggcagct ggagcgctga
120tgtgatgggc attggaatac actgagctag agcatgggct ttgcagtcag
gaaaatatgg 180ctctgctagt ttaaatgcta tgtaatctca gttaggcaag
ttagcatctc taaatatttc 240aattcccttc ctgtgggaaa aaaaatgaat
actttcattg tgtcataccc attaaatagy 300gttagatctg tgaaaggctt
agcagagttt cagactcata gcaggtgcct aaggagagag 360aattagctaa
ttaaaagtat tataagcata ttacaattat aatacactaa tgaagtataa
420aagtaatcta gtcgttcata tattctttga ctttttgcca cgtaaaacta
taagacagat 480ctgagaattg ccctgagaga taactcagca tgctgtgaaa
atgaaacaaa ttggtatagg 540ttgataatct ccctgaaaaa aaggattccc
aagcaccata ggtgagaagg gcagtgtaa 59934599DNAHomo sapiens
34aaatatgaca cattatttga aagatcctaa tgtgttagtc aaaatctttt tatgacagca
60aggattttaa ttagccatac attggtaatt tcagttagtc atacattttg taaataaaaa
120cggaagtgag gatggccaaa taggaacagc tccagtctat ggctcccagt
gtgagtgaca 180cagaaggcaa atgatttcta catttccaac agaggtacca
ggttcatctc actggggatt 240gtccgacagt gggtgcagga cagtgggtgc
agtgcaccga gcatgagctg aagcagggck 300gtgagctgaa gcaggcaagg
aatcgcctca cctgggaagt gcaaggggtc agggaatacg 360ctttcctagc
caaggaaagg ggtgacagac agcacctgga aaattgggtc actcccaccc
420taatactgca cttttctcat ggtcttagca aacggtatgc caggagatta
tatcccacgc 480ctggctcgga gggtcctacg cccagggatc ctcactcatt
gcaagcacag cagtctgaga 540tcaaactgca aggtggcagc gagggtgggg
gtggggcgcc gaccattgct gaggcttca 59935599DNAHomo sapiens
35tgatgaaaac acctaactca ccttagaaga aagtatttgg catgaggaag cactcaaaac
60ccatcactaa ttgctctaaa atcatatgtt caataggcta tgaattaagc taacttgtca
120caattcctcc tatcatcact tccacatttc tcttgatgat attaacaact
tcatagaatc 180attcctctgt aatagtttgg tggaagaatc tgctatataa
ataaatgcat gttatagaga 240cactttgaaa agctcatgtc gcctttatct
gacagcacct ctgttcagaa aagtggaaam 300ctggctctat gagtatatgc
attcatgagc tcttgattga aaggggtcag tttcagaaat 360ctctgagttg
gaggtcttgg gcctgagcct attaagataa ataactcccc cagggtaact
420catcaatgag gagacttcag cagttaaatt ccctagacta agtctcatgt
tctcactcag 480cacactaacc catgcacagc taaattatct catccacaat
ttcaattttt gattcaacta 540aaaaatacat gcctataaag ataagtcttc
aagtaagcca gacacacggt agtaggaag 59936599DNAHomo sapiens
36tcatctgaaa cttctgtaaa tgctgtgaga agagcttggg gaagaagaga cattgaactc
60tcttcaaaca taaccatgaa atgtgaagtc accctaccaa aaggagcctc tcatctatat
120aaaaatgaaa aacaaccagg caaaaaagaa aaaaaaaaca ttttgctctt
caagttaaaa 180taataagaat caaaaggtaa ggctgagtcc tgggaagtat
gttatataaa tatacaacac 240aagagagacc attatgttaa gaaggctcca
gcaagaatta tagctgcttt cctgtttacr 300tgacaatcta cctatgacaa
aagttttcca ccctttctct tattgtagac ttttaacaaa 360atctcatgct
catactcttc tccatcattt aaaactcaac tcactggcat cctcactaca
420atgccttacc tttgaaatgt acatcatgta aacttacagc caaaacgttg
tggaataagg 480agtgcagatt agaaaacttc ttaatttcaa tgcttgtcct
aatactgtta ctaaaatgaa 540tgaaaagtat attcctgggc aggcacaggt
gggcagatca tttgagtcca ggggtttga 59937599DNAHomo sapiens
37gagcccactt cctcattcat agacagctgt cttttccctg tgtcctccca tgatggaagg
60aacaagacag aaccccgctg tctcttttat aagagcacta atcccattca tgagggctcc
120acctttatca gttaatcagc tcccaaaggc cccacttcca aataccgtca
cactggggat 180tagatttcaa catatgaata tggagcaggg aggggacaca
aacatttagt atattgcaag 240aactattttt cttgctgttt catgatgtaa
ggtaagttct cttccgctgc tcctgtggas 300agtacctcct actggtggtg
tcatggtggc tgaggatgtc tgttatgaag caaaacagag 360aagagaagag
gcctcttttt tggctgtatt cagttaaagg agtcctacaa cagtgttgct
420catactacaa ggtgttaaag aagttaatta aatagtcctc tcagcattca
ctcataatct 480tctctggaac cagaacttag acaagcatcc tgagtgatgg
aaacattttc atggaggaag 540gaccagacat tttgagaaca ttttatgtct
atagtaaaag agaagagaaa acaggaata 59938599DNAHomo sapiens
38aaacactgac aaaaaaaaaa aaaaaaagac ctggcttcct tggctctgca tgtagataat
60ctccctcagc taattacagt aaatgccaaa gatctaacat ctttcctgca gacccacaag
120gaagatatat gagaaaatac tgtaggatgc ttgcaagact gaatttccaa
agcagcttta 180aagggaatta taaggaagat gttagaacat taggggaaaa
tcagtgctgt attgcaaagg 240aaatgtttaa ttgtaaagag ataactgttt
ttttgtacat gtgttccaac aggagattcr 300tgaaaactta actgaactta
acatggttat atgagacagc aagtgacatg aaggagcaga 360ccaccaagat
tttggtagta tatcccagtg ttcctttgtc attggcaact tgttctcagt
420aaaatatata tatatatata tatatatata tatatatata tatatatata
tgtttattcc 480tcctccctca taattattaa gtgaaactcc cagttaccaa
agttagttat tattttgatt 540aatttggcat taaaccatta ggagtgatat
acttaactct tcccatggga atttttcct 59939599DNAHomo sapiens
39cattttgccc ctgccctaga gatctgtgga actttgaact tgagagtgat aatttagggt
60atctggcaga agaaacttct aagaagcaac gcgttcaaga ggtgacagag cataaaagtt
120tagaaaattt gcagcttgac aatgcagtag aaaagaagaa cccattttct
ggggagaaat 180tggaaattgt gttttattaa tagacttcgg agtatgtatg
gaaatgcctg gatgtccagg 240gagaagtctg ctgcaggagc agacctctca
tggagagcct ctgctagggc agtatggaar 300ggaaatgcgg gattggaacc
ccaacacaga gtccccactg gggcactgcc tagtagagct 360gtgagaacag
ggccaccatt ctctaggccc cagaatggta gatccaccaa tggcttgcac
420catgcacctg gaaaagctgc aggcactcaa caccagccca tgaaagcagc
caggttgagg 480gctgtaccct gcaaagccac agaggcagag ttgcccaagg
tgtaggagcc tacctcttgc 540atcaacgtga cctggatgtg agacatggag
tcaaacgaca tcattttgga acttaaagg 59940599DNAHomo sapiens
40agatgagttt gaagggttaa aatgtcagac attatttgga aatcaaaaaa tcattatttt
60cttgataatt agaaaataga ggcagggtta aataatgact tatttatatc taagataact
120taggctcatt ttctccttta ttgaaataat acctgcagtg atagatattt
ccagaagtga 180gagatatatg tgtatttgta tatatttttc ccagagctta
ttattttgca tattaccact 240acatagagat gttgtaaaag aactaagagc
aaactatggc aaaggcagat aatgaagggr 300taaaattaat gtttaaaata
gaatcctcaa caatcggtga caataaaggt aaatgataag 360tgaaattgta
tatttcagta atgtaagcat ataaaagaag atagcttttg aaagattgaa
420ttaccctcat tcattctgaa gaaaaaaaat aaagttttat tatacataga
tgctatggag 480tggaactcaa ttgtgggtga tcataaaagt atcttttact
tgctgtccca agcatttgga 540agtgtaacaa attccaagat tgggctgcag
agcctcttta aaaagggtat ccacatagt 59941599DNAHomo sapiens
41aagagtttat ttgggacaag attgaggact gtggcctggg acacacttcc aaagtgcctt
60gggaagtgct ctggcaaaca aaggagagac tcaagttttt aatgaaaaac gaggcaaatc
120agcagaaggg gaaactataa aagtagttca tcaggaattc tcactggttt
acagaagtaa 180ctttgattag caattggcta tacattgtta aattacaggg
taagagttat ggtggtaaga 240gtatgttatt ttatggctac ttggtattag
ttagtagcca caaaatgctc acacagcaas 300tggtttcaag aggtaatggt
actcagttca atggggagtg aaatttgtta cattttaaat 360gcctctttgg
gactgaaaat gtaaaggagc tctcattgct cagataattt ttttctttct
420cacattcaat atttattcaa caaatgccta ttgaatgaac ggatggatag
atggtgaaag 480ataaaatgaa aaaaattcaa tggtgtgcaa tatcaaagaa
acatcagctt ggagccagac 540atacagggat tcaaatttcc tatctgccac
taactagctg tgtaatcttg ggaaataac 59942599DNAHomo sapiens
42gagatgtatt aatggtgttg gttttatagg accctttagc tttgattctg ggtgcatatg
60gcaatgtagc ctctatatgg tttctttggc tgtaaacagt atgagtaaca tctgtggttt
120cctaggtggt ttaggctcta attattagtg gaggctatgg tgaagttttt
ctgggggcag 180ggatggcagg tgggtccata tctggtcccc attggtggaa
gcagtgggct gagcatgctt 240actcttgggc ccaagcatag cagatgctgg
cacttgtgtt agtgggataa agtaggccar 300ttcttgagcc tgtagtggct
gcagtgggct gggtgggtaa atgggttccc atgtccccga 360gaagtcaacg
tggtatcagt gaagccagta gcagtggtgg gatgactctc tgggtcctga
420gcactgcaca ttggtattgg tggtggttgt atgcaaggtt gccagtcaca
gccccagaca 480tacagttctc aaatgttcct gctctccaca gcagcagcac
cacagcatca cacagaagca 540ggtaggaacc acacatttca tgtgctagcc
tgtgtatata ggctatgcta ccaaaatat 59943599DNAHomo sapiens
43tgctctccac agcagcagca ccacagcatc acacagaagc aggtaggaac cacacatttc
60atgtgctagc ctgtgtatat aggctatgct accaaaatat gtcatatgat aacaagtatt
120agtgaaggta tgaggaaatt ggaagtattg tatatcatca gtgtaaatgt
aaaatgacac 180aactgctata gaaaacagta tggtggttct gtaaaaaatt
aaaaatagaa cagcatatga 240tccagcagtc ctagttttag atatttatcc
aaaagaattg aatacaggat ctcaaaaagw 300tgtttgcatt ctcacgttca
ttgcagcact attcacaata gccaatatgt ggagacaacc 360taaatgccca
tcaacagatg aatggataat gaatatgtag tatatacaga aaatcctgtc
420atatctacaa catggatgaa ccttaaggtt atgctaagtg agacagctca
tcgtattagg 480acaaatactg catgcttcca tttatatgag gtatctaaag
gagtcaaact catagaagca 540gaaagtagaa tgacagttgc caggggttat
ggggagggga aaatgaagag ttgctattt 59944599DNAHomo sapiens
44atagaaaaag aaagtagatt agttgccatg ggatctggag aaggtgagat tgagactaac
60tgctaataat taccaggttt cttttttgac atgatgaaaa tgtctggaat gaaatagtgg
120tgatgtttgt acaacatata agtaaactaa aaatcactat attgtgcatt
ttacaataat 180gaatgttgtg tgaattgtgt ctcaatttaa aaactttttg
aggtatattg tttaatttgc 240aaaaacagat ggtctctggc ttatggtagt
ttaacataca attttttgac cttatgatas 300gtttattaag gtattaagta
catttttgac ttatgagttt atcaggatgt actccatcat 360aagtcaagga
acatcgatat gtggtgatgt ttgtattatt gtttgaaatt tattttcata
420ttaattctct tataatcaaa gaaactgtgt attatttaaa tcttttgaca
tttgttgaaa 480tttaatttat atactagtat atgatccatt tggtcgatag
tttataatta taaaaatgtg 540cattcagttg tagttcatta tagtgatcta
tatatgtcat ttaagtcaag tgtcttaat 59945599DNAHomo sapiens
45gaaagtagat tagttgccat gggatctgga gaaggtgaga ttgagactaa ctgctaataa
60ttaccaggtt tcttttttga catgatgaaa atgtctggaa tgaaatagtg gtgatgtttg
120tacaacatat aagtaaacta aaaatcacta tattgtgcat tttacaataa
tgaatgttgt 180gtgaattgtg tctcaattta aaaacttttt gaggtatatt
gtttaatttg caaaaacaga 240tggtctctgg cttatggtag tttaacatac
aattttttga ccttatgata cgtttattar 300ggtattaagt acatttttga
cttatgagtt tatcaggatg tactccatca taagtcaagg 360aacatcgata
tgtggtgatg tttgtattat tgtttgaaat ttattttcat attaattctc
420ttataatcaa agaaactgtg tattatttaa atcttttgac atttgttgaa
atttaattta 480tatactagta tatgatccat ttggtcgata gtttataatt
ataaaaatgt gcattcagtt 540gtagttcatt atagtgatct atatatgtca
tttaagtcaa gtgtcttaat cacgttaat 59946599DNAHomo sapiens
46cagttgtagt tcattatagt gatctatata tgtcatttaa gtcaagtgtc ttaatcacgt
60taatcagaac atttataacc tgattttttg tgtccatgct ttactaatta ctgaaaatta
120gaatttccca caatttgtat attgccatta gatatgtcat ttttgtttta
ttggttttga 180tgctacgtta ttttagtcac atacaaactt agaagtgttc
tatctttcta tttgaccatt 240ttatcattag aaaacattct acccttattc
ctgataatat tttttgccat aaaatctacm 300ttgtcagaca ttagctttct
tttgctaaat tttacatgct gtttattgtt ccattttcta 360cattcaaatt
ttgtctttat gtttagagtc agccttttaa aagcagcata tagttgattt
420tctaaaaata tgagcctgac aatcattgcc tttcacttga aaattttaga
ccatttatgt 480ttaatatacc actaatatat ctcaacttaa acatatcatc
ttattatttg tcccaccttg 540tctattttct ctcttttctc accttctttt
gaattaatca actattttat tatttcatt 59947599DNAHomo sapiens
47cttataagtc catgtctgat tcactcaata tttgtttgtt tttatgtgtt ttttctcgtg
60tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtacatgtg tgcctggtct tttctttgat
120atgggtaagt tttttattca aaaatgagtg ttttgaaaga aaagttgcat
aaataaattg 180aagccttaga gaatgttatc tgcttccaaa gagtatttag
tcatacttct gttagaaaga 240gtagaagctg attgccttaa tccaacagga
ttaatcactt ttaaaagaga gtttccaacy 300ttgtgatggt ttatttctag
tttcccatga ctcatagaat atagtccctc ccatatgaaa 360gcctgggagg
tttaccaagg cttctgctca tttttttaat gtaaatgtat tacaatagaa
420ataattcaaa gttctgctcc acttcctagt ctcttaacca caattttctg
ctcagtctca 480gcttctaaac tgctggttcc aaataagcaa atctctcaag
gaaaaggcat tgcagaatat 540tgggattatc tcaatgcatt tcccatctca
ggaatcttgg ccttcaagcc ccattgcct 59948599DNAHomo sapiens
48aaatttgcca tatgtgtatt atcttttgta aaattttttc tgttggtaat tatctatgtc
60ttttgctcat ttaaagaatt atatttataa aataaattca taggatggta aattctgttg
120ctgtgcatgt atgaaaagta gttactatgg aaaattcctt tacaaacaat
gctgggaaat 180ttgcttcata aatgaatcct taattagctg caaaacttat
ttgttaacaa tactggatac 240tgtattacta gcattgagaa ttaccattat
tctttagttg caaaatttct tatggtctgr 300caacataata aattattcat
tgccatggtt tgatgaattc tgattattta tacttgaata 360tatatgttat
gttactgcaa tgaaaaggcc atttattcag tactatctca tcatcttctc
420tttctaggga ttcatcatga atatccataa tatggtttct aaaaatgcat
gaaggaatca 480gaggagacct gctaaccatg aaaagaagag catagcaata
gagaaccaaa gtggcacaag 540aatgatcatc tttgaataat ttagaatcaa
ataacatcaa atcaacaaac acttattga 59949599DNAHomo sapiens
49caaacaatgc tgggaaattt gcttcataaa tgaatcctta attagctgca aaacttattt
60gttaacaata ctggatactg tattactagc attgagaatt accattattc tttagttgca
120aaatttctta tggtctggca acataataaa ttattcattg ccatggtttg
atgaattctg 180attatttata cttgaatata tatgttatgt tactgcaatg
aaaaggccat ttattcagta 240ctatctcatc atcttctctt tctagggatt
catcatgaat atccataata tggtttctam 300aaatgcatga aggaatcaga
ggagacctgc taaccatgaa
aagaagagca tagcaataga 360gaaccaaagt ggcacaagaa tgatcatctt
tgaataattt agaatcaaat aacatcaaat 420caacaaacac ttattgaagc
tctccatctt tccatccttg attcctgtgt tattcagcat 480ttttggtagg
tttccagcag gcagccttct ctcaaaagta ctgttaggtt gtaatgtttg
540caagtgctgt cttcaggctc tcttactgct gatgagtatc aatcacataa aattgtgta
59950599DNAHomo sapiens 50taaaaaagtc tgaaattttt tactcctaaa
gcaccctatt tcttatttac ttctaacata 60acctacaagt cactaaagca gttaggttag
aaagaaaatg tctgcagtgt ctcatagagc 120aaagacccct ccaaagactc
cagactctgg gtgaagatta agagcaggcc agcaatatta 180cactgtaata
aatgacaact gtcaataaga agtaaaagta aaagggtagt aatggcatct
240taaaaaggca actacatttt gctttcttgc tttctttata tgttatatcc
tgccttttaw 300cttttcctat cgaccctggg tttatccgta tgccaacctc
acatattaaa agcactctaa 360tgtctccaca aagaagtact tgtgtgcatt
tatttatcta tgtatattaa acgaaactgg 420ttttctttga cttcttaatc
cttctcgtta ggtccttaat tctcaataaa gaatatcctt 480taaaacaaaa
ttggtctaca caaacataca ggcagtgcca cctaatggca gctaccattc
540attttaaggc attcaaaccg gagagactgc tgtagtattt agatgtcttt gtgaacaaa
59951599DNAHomo sapiens 51tagcataaaa tgaaagcaca ggacctcttg
tttaaaatgc tgggaaaaaa acagtgctgt 60tgaagtccta aaatataaag ctgtttcctt
tcttccatga tctctctctt gacttcttgt 120ggtgtctttt atttgttact
tgtgacaatc taagttttaa aaactctgtt tttttatttt 180ttaaattaaa
aaaatagatt caggggccca tgtgcaggtt tattacatgg gtatattttg
240tagtagtggg gtttggactt ctagtgtacc catcacctga atagtgaaca
ttgtagcaaw 300aggtactgtt tcactcctca ctccgttccc actttcctcc
ctcttggagt ccccagtgtc 360cattatttcc ctctgtagct ccatgtgtac
ccattgttta tctcccactt ataagggaga 420acatgcagtc ttgggttttc
tgtttctgag ttattccact taggataata gcctccagct 480ccatccatgt
tactgcaaaa tacatgtttc attcttttgt gtggccatag caattttaaa
540atataaggac atttaactag tatacaggat agtcaaaatt acacaatttc tcagacata
59952599DNAHomo sapiens 52cctgtgtgac tgcacaggtt gtgaacctag
ccctgtttgt gaaatgtagt aggacaaaaa 60aaatcactct tctttaatca gggataaaaa
caagacttac atttattact tcccacatgc 120tgaatggtag gttaagtcct
tcacatacac tatctcattt aaccatcaaa taacagtttg 180gggtaggtat
tattaccttc atttacagag aaggaaatag gagattttag aaactaagtg
240atttacccaa tatctattga ctaaaaggta gtggagtagg gattttaacc
cgggtttgas 300tgaccccaaa gcccagttaa tctactactt ccataaaacc
atttagtgca gattttaaat 360tacaaaatat ttttaaactg ttagtattag
atatacacat ataataaata cctacatgct 420aataagacca agtatgaatt
aatgaaatag catgattcac agattaattt tttaaaatct 480cttctggcct
tctaatgtaa tatgacaagt ggaacacata tgtttatctc ctttacctcc
540tgaggcttca ttaaaatgat gatagtgctt ttttaaggta taagccatca actacaaat
59953599DNAHomo sapiens 53agcccagtta atctactact tccataaaac
catttagtgc agattttaaa ttacaaaata 60tttttaaact gttagtatta gatatacaca
tataataaat acctacatgc taataagacc 120aagtatgaat taatgaaata
gcatgattca cagattaatt ttttaaaatc tcttctggcc 180ttctaatgta
atatgacaag tggaacacat atgtttatct cctttacctc ctgaggcttc
240attaaaatga tgatagtgct tttttaaggt ataagccatc aactacaaat
atcacaggay 300agaggctatt agtaaatgag caatttcaat aaatcaaatg
agcaattcac taaaaaatgc 360attacaaatc tatttataaa gtttaaaagc
aggcaaaact aaataataat tgtttagtaa 420tacatacata ggtggtaaaa
ctatttttaa taacaaagga atgattatca caaccttcag 480tgtagatgtt
acctctggag gggaggggca catgatgaag agggagaaca caggaacttt
540tatgctgttt aaccaaggca agaggtgcat gggtattcat tttgttatac atttattgt
59954599DNAHomo sapiens 54tacagaaaaa acgaagaggg aaaagattat
cacagaaatg ctaatagata atttccctaa 60gatggatcca gtcttcagac taaaagaact
cattctgtat ccaggactta aatgtgtcct 120ggaaaaaaat gttatatatc
taaggataaa gagaagaccc aaataactgc caaggagaaa 180atacagctca
catgcaaagg aataagagtc aaagacgtta gctttctcat cagaacacag
240aatgtggaaa gtcaatgaag aaaggtcgtc aaagttccca ggaaaaaatt
attttcaacm 300catatttcta taactaacct tataaccact gaaaagaaca
tcataaaaat gttttttaac 360atgcaaggac tcagaagttt actcaaatgc
accatttctt agaaataaaa atgtatctca 420agaaaatagg caagtattcc
atcaaaacaa aggaagaaag cataatggcc tcagaaacag 480tgatacccaa
actaagagag gaatgaagca aaattccagg atgacatcca cactgctgtt
540ctagagagtg ctagtaaaga ttggggccag agaacagaat gttttgcatg ggaagttca
59955599DNAHomo sapiens 55aaaacaattt tgaaaaacaa caaagttgta
ggatttacac tccctgattt caagatttac 60tataaagcta tagcggtttt tacaatgtga
tctttggcca agaatagaga agtaaatcaa 120tggaacaaga tgaggtccag
ccataagccc acctatacat ggtcaattgg ttttcaacaa 180aaatactaag
gcaatttaag aaagaaagat aatgttaata aatggtctgg aacaactgaa
240tctccataag aaaaaaagaa gaatcttgac cactacctct taccatgcta
aaaaaaaaar 300gggggaggcg ggtgaatatc ttcatgagtg tggagtaaag
atttgtttac actaggccaa 360aatatgtgtg tgtgtgtata tatatatata
aactttaata aattttactt catcaaaatt 420aaaaactata actattcaaa
aacaccatta tgaaaatgaa aaggtgatcc acagattggg 480aggtaaatct
ttccaaaaca tgtatctgac tagtattaaa gatatacaaa gagttctgta
540tcaatcaggg cttgattaat gaaacagaac cactaagagt cccatacata tgtgtatgt
59956599DNAHomo sapiens 56tctcttccta ttcagatgcc ctttttctct
ctctctcttg cctggttgtg ctggctagga 60cttccaattc tatattgaat aggagtggtg
agaggagtca tccttgtctt gtgcttgttt 120tcaaggggaa tgattccagc
tttccccagc taattaattt tttttttctc agagattagg 180tctaattatg
tttcccaggc tggtctccaa ctcctggcct caagtgatcc tcctaacttg
240gccttccaaa gtgctgggat tacaggtgtg agccactgtg ccctgctcaa
atccatgaas 300ttttgagagt ggagatgtac gtgactttct tatcagaaag
ctaagacctg ttccatgtct 360gagtctcact gctcataatt tctttgagtc
atttgctgac atgatcctgc tcacacccag 420agaaagctgg gtggcactgt
ggaaggaatc atggagtgag agcccagaaa cataaggtgt 480agactgtctg
ggccctgtga gcaactggtg atagcccaga tgctggactt ccctgcttta
540ttttatctgt aaaacaatct taatagtatc tacttgtgtt aacttccaat ggctgatgt
59957599DNAHomo sapiens 57caatattgtt aaaatagcca taccgcccca
agcaatttat aaattgaatg ctattcctat 60taaactacca acgacattct tcacagaacc
agagaaaacg atcttaaaat tcatatgaaa 120ccaaaaaaga gcccaaatag
ccaaggcatt cctcaacaaa aaggacaaag ctggaggcat 180cacactatct
gacttcaaac tactgtaccg ggctacagtc acaaaagcag cacgatactg
240gtacaaaaac agacacatag acaaatggaa cagaatagag aacccagaaa
taagaccatr 300caccaactat tatctgatct ttgacaaatc ttacaaaaac
aagcaatggg gaaaggattc 360cctactcaat aaatggtgtt gggaaaactg
gctagccata ggcagaggtt gaaactggtc 420cccttcctaa cacctatatg
aaaattaact caagatgaat taaagactta aatgtaaaac 480ccaaaagtat
aaaaactctg gaagataacc taggcaataa cattcaggat ataggcacag
540agaaagattt catgtcaaag atgccaaaac aattgcaaca aaaacaaaaa ttgacacat
59958599DNAHomo sapiens 58caatgtgaga gtacacttat cttgctttgc
ccaaagatgt gtcagcaaca taaccttcag 60actaaaacca aaaatttcaa tttagagtat
ttatcccagg acctaaaaga cactaaggcc 120taccacacac atcaatcatt
ttaaacaatt ttataggagg actatgtgaa tttatgttat 180tgagcctctt
gtggcttggt accaggagtc tccttttgta agaaatcaaa taaatgaccc
240tgaccttctt caagaattga aaagtggttc agagaagtac tttgttttat
ccgggtagcr 300ggttaagtat caaagtatca tcccttagag aaactgattt
aacacattaa attatgaagc 360aatctagagt gtccccaggg ctgctgctta
ttattgacaa cataagtagg tggtctagaa 420gtaaatgaat atatgggaag
agcacagcag ctacacgttt cccaactcca tgggggcatc 480attcacataa
aagacatgtg agcagtgacc tctagaattg tacattaccc tcagtccctg
540agggtttgag attttttgag actgtatact cttcagcctg tcacactcat aaactgcct
59959599DNAHomo sapiens 59tgcctacctg tttaatacag tgacacagaa
actcccattc gtctctaaat atttccacca 60ccaacctgct aaaagagttt aaaaatccaa
tctctagagt catcctttgt attaataatt 120attactgaaa tgattatttt
aaagtgtaat ggatacttgg aagaggcaat acaatctata 180taatactgag
cagaaaataa ttaaatacta acatctcttc cattcttctt agagcttctg
240taagatatgc agaagaagtc aatgatgtca gagatgttat cttcttgcta
caaattgagk 300gatcacatac tcaacgtata cactaagcag gaaggaaccc
attccaccag gaagaactta 360gtcaatcttc ctactgatat agcccatgca
ggtcctaagt gtagcaaaca atgcaaatca 420tggtagagaa cagaaaatgc
aaccagtagt gagagaaaga agaatcaaga caaacagaac 480ttgggctaca
gagaaaacac aatggccaag gaatccataa aacctatttc ttttacaggg
540aatttggctg cctgaactcc tcagactata taaaaaagga gcaaaccctt ttttaagca
59960599DNAHomo sapiens 60cactccagcc tgggtgacag agcaagactc
tgtctttttt ttttctttat tactatactt 60taagttttag ggtacatgtg cacaacatgc
aggtttgtta catatgtata catgtgccat 120gttggtgtgc tgcacccatt
aacttgtcgt ttagcattag gtatatctcc taatgctatc 180cctcccccct
ccccccaccc tacaacagtc cccgctgtgt gatgttcccc ttcctgtgtc
240catgtgttct cattgttcaa ttccttaaaa aaagaaagaa agaaagaaag
aaagccttay 300cttatcttat gggaaatcaa tggataacat gggtgaaaat
actacaagaa atggctgaaa 360taaataaaaa tgattgcctc tgggaggact
gggaatttgg aggggcaaga caaaggacag 420cagtttttca ttattatgct
attttatatt tcacatttat gaaatacttt gagatacaag 480tgagaataaa
tgaaacagtc aaactctgta tgttcaagaa gtatttgtgc cctttactct
540gcttgaaaaa tctaaaattt tgatttagta aaaattgagg atgaatatat tctacaaat
59961599DNAHomo sapiens 61gctaaatttc cttaactaca aaaaggtaaa
atacagtctt acatcaggca aatgaaaaac 60aagcagagga aacactatac aaagggaagc
actataaaga ccatgcaagt atcacagaaa 120ttagcacttt ataactttat
aaaacatgat ctctccttta agtgtctaaa ttgtgactaa 180ataatttaat
acttacctga aaattatatg tttaatctgt gcaatcattt tttggcatac
240aactttctgg actgtttttg ttttttcatt tgattagttg gctgggctgt
tgttttattk 300tgtgtgtgca atgaaaaatc tcatgtattt tagtgagttc
atctgtacgc caagtactcc 360aaccatctct caacttttca aacaaatccc
caatggcctc cctgagttaa atcagcagaa 420caataatatt tcatggctca
ttagtgcatg caatcaagca acagatcctg atccagtagt 480ggaaagggag
aagcaatagt tggtttcaat tttgttaata ccacaatatg cccataggcc
540tcagccaaaa ggtgtaaatt aaggattgaa cataaccacg aagcaattgg ctgacaaca
59962599DNAHomo sapiens 62tgactaaata atttaatact tacctgaaaa
ttatatgttt aatctgtgca atcatttttt 60ggcatacaac tttctggact gtttttgttt
tttcatttga ttagttggct gggctgttgt 120tttattgtgt gtgtgcaatg
aaaaatctca tgtattttag tgagttcatc tgtacgccaa 180gtactccaac
catctctcaa cttttcaaac aaatccccaa tggcctccct gagttaaatc
240agcagaacaa taatatttca tggctcatta gtgcatgcaa tcaagcaaca
gatcctgatm 300cagtagtgga aagggagaag caatagttgg tttcaatttt
gttaatacca caatatgccc 360ataggcctca gccaaaaggt gtaaattaag
gattgaacat aaccacgaag caattggctg 420acaacaaaaa aggggggaaa
aagactttta acagaaagag ctactgcaac ttaaattgtt 480ctcacatttt
aaatgtgtta acaatatcta tttttatttg taagccaact ttgtgttgca
540actctgctga gtttcatctt ttaagcctct tttgcctctc tgagccagtt ttatcttcg
59963599DNAHomo sapiens 63atccccaatg gcctccctga gttaaatcag
cagaacaata atatttcatg gctcattagt 60gcatgcaatc aagcaacaga tcctgatcca
gtagtggaaa gggagaagca atagttggtt 120tcaattttgt taataccaca
atatgcccat aggcctcagc caaaaggtgt aaattaagga 180ttgaacataa
ccacgaagca attggctgac aacaaaaaag gggggaaaaa gacttttaac
240agaaagagct actgcaactt aaattgttct cacattttaa atgtgttaac
aatatctaty 300tttatttgta agccaacttt gtgttgcaac tctgctgagt
ttcatctttt aagcctcttt 360tgcctctctg agccagtttt atcttcgtat
ttgaggcttt acattcaggt gacttctttc 420attgcatttc aagggttctc
taacccaaaa aaaagatgga agcagcacac gacaatcctt 480tggggtgagt
aaagaaaaat attagaattt ctatttccat tttctctaaa tataatatga
540gtctacattt gatatatgga ttttcacagg cattcttgtt cagtaactat atcagagga
59964599DNAHomo sapiens 64tggaattaca ggcatgagcc aacatacctg
gccaatctct tcttattacg agtaactgtt 60agccaagacc atcacttatg gccaaagtta
ccacaataat tcagttaaca gctgcacaga 120actgacaaga agaatgcatt
gtgaaggcaa atcacagcaa aagcacacac agttgagaag 180agctttgagt
gggaggtagc ttttgcttga catttttgtt ccagagatct agaagcttat
240ctttctttta ctggcctccc tccaaggttc cagccccagt gttagcaaca
aaccagactr 300tttgccattg ttcaatcaca gaatgttctt tcaaatctcc
aaactgttct tgctttctgt 360gcctgaaaac agctcctcat cctccttcaa
ggcaaagttc ccaaatacgg catttgaatt 420taattacaat ctattgatta
tattggcttt ttcctttggc aaaacttagt gatcctactg 480aaatagggat
tatagtgtag caaagtaatt aggagttaaa tagaaaacct tcttctaagg
540actgatgttc ccagaaagga ctcttgtgat ctcagtacaa atggtcccta aatgaatgc
59965599DNAHomo sapiens 65tatacttcta tgtgtacaaa atcaggaaga
acctcttatt ttccctagag cagatcttgg 60ggatgttgca taccagttca catttattga
gcacttgtag gtgctatacc aagtgttgaa 120tggatactct ctcatttaat
cctctcaaga gtcctcagac acaaccatta ttatcacact 180tctgaagttg
tagaaacagg catggagaac gaactcactt gtgcaaagtt acacagcatc
240agtcaggatt cagattgttt tctgttgact ctgaagttca taccattaac
tgctatactm 300caaaaggtgc ttgcctaaag atggtcctat acttttgact
ttgtagtctc tgaagcttaa 360gtacctctgg gttttgcagc agctatggac
atagaagcat gtatggtaat aataatgata 420aagctatcaa ttgtaataat
tataatggtt aataatataa atgatagcat ttataacaat 480ataattagat
aatatagtaa ttaatatttt tataatgtgt tatatgttag taatattata
540aaatagctat cttcaataac ccttacaata tgctagacaa tgttctgtgt gttaaacca
59966599DNAHomo sapiens 66caaagataga taaaattaga tttaacaata
ggaaacatat tttcaagaag tatagttcag 60ttttactctt gggaaacata tttttataga
gctaaaagta aataatgtcc taatctgaga 120ggcctgaaat aacactgctg
aaatttacat gctttgttga atgcgacttt tagaaatgtt 180tactcccaag
aagtctaggt tcaagatgta tataaaatga tattgataat tcacatgtat
240taattgttta ttatttgcta agcattgtgc tagatgcctt cctcttacag
tcttatgagr 300taggcacagt atttgcatcc ttgttttaaa gatgagaaaa
ctgaagctta gggatgttaa 360gtgacatgcc atactcatac ctcggcagga
tttgagtgaa agtctgactc tcaaatttaa 420gcttttaatt agtatcctat
acagatttta taggacaaat ttgttaagtc agagatacaa 480gccctctgtt
gttgtcacct tttaacaatc tttcttcctt cagagaactc ccttaccctt
540caagtacaca gcttcttcct gatttctagg gatccttctt tattgagaaa tttcatgct
59967599DNAHomo sapiens 67cacctaagtt tccttttttt cattcaacaa
gagctgcaat tacagtctga gaagtcagct 60tttccaagtt tctgctgtgg taaaaatcaa
cccccaaatc ctgttgtttt acaaaaaagg 120tttatttcca gcctatgttc
catattgact gcaggtgggc tgtgactctg ttccacgttt 180tcttcattcc
aggatccagg ctgaaggaac attctctatg acacaccatt cttgtgccac
240agggaaaaaa gcaatggtga aatgactgat ggcaagtaaa gtttatggtt
agacaacatr 300taagtcactc atgttcccat tagtcaaaga aaagcacatg
gccaaccctg gggctgggaa 360gtacaatcct cctatgggga actcagtgaa
taattgggga aaataataac aacctagcac 420atggaccctg gggaagcaag
ttctttaata cacatctaca atcatgtgaa gaaccatgac 480atttaaagaa
tataacttag aaagtaacta ttttgggaac tactgcttaa gaatgtttgt
540ttaaggtctc ttaagtcacc agataatctg aagaagtttc tggtcagcag gaaaaggta
59968599DNAHomo sapiens 68caagcctagg ggaggtgtca catcaagtag
tatctgaaaa attgcaaaag tgaatcagta 60tttttttttt aaggtggagt ctcactctct
gttgccaggc tggagtgcag tggtgcgatc 120ttggctcact gcaacctccg
actccctggt tcaagcaatt ctcccgcctc agcctcccga 180gtagctggga
ttacaggcat gcaccaccat gcccagctaa ttttttgtat ttttagtaga
240gacggggttc accatgttgg ccaggatggt ctcgatcagt tataatgagc
tttttttcay 300atacctgttg gccacacgtg tcttcttttc aaaagtgtct
gttcatgttc tttgcccact 360ttttaatggg gttgtttttc tcttgtaaat
tggtttaagt tccttataga tgttggatat 420tagacctttg tcagatgcat
agtgtgcaaa tactttctcc cagaatgtag gctatctgtt 480tattccattg
ataatttctt ttgctgtgca gatgctctta agtttaatta ggtcccactt
540gtcaattttt gcttttgctg tactttattt tggtgtcttt gtcattaaat ctgcccatt
59969599DNAHomo sapiens 69gtcactattc aagagctagg agagagagat
gagatcaatg atgttcaaca gaaatctgat 60ccaagccaca tacttgattt aaaattttct
aatagtcaca ttaaaaacgg taaagaaaaa 120accaggtaaa atgaattttt
tttaaatttt attattatta tactttaagt tgtagggtac 180atgtgtgcaa
tgtgtaggtt tgttacatat gtatacatgt gccagaattt taatagtata
240ttatttaacc taagatttct aaaatattat ttcaacatgt aataaatatt
atttgtatts 300ttttttggtg ctgattcgga aatcagtatg tgttttaaac
tgacagcaca tctcaattgg 360actagcctaa tttcaagtgc tcaatagtaa
catttatata gtggctacca tattggacag 420ttcaacaata gataattcag
aaaagagcta ttactacagc tgaaagaaac aagaaatgtc 480aaagtcacgt
gccaccaata ctgggttcgc cacattttct ttgtacatga aggatagctt
540atttttattg ttctggggaa acagatgagg atcacatcac caggatgctc atccaggag
59970599DNAHomo sapiens 70ctggctcctt gcttctagcc ctcctaggct
cctagatcaa ttgtattccc attatctgag 60gtagcagaac atattccata taaatgctaa
accatcacag ctgtagatca tgtgcctgcc 120cttttgaacc ccacattctc
accaactgtt tctttgttag attaccaata aatagcatgg 180gctcccagag
ttcagggcct ttgcagcctc cacgatcgtg atggccccct ggtcccactt
240tacttctcaa actgtctttt tctcaatcct ttgactccac tagactttat
cgcccccacr 300acgtggtgtt gggtctgatc accccaacat tcctggctgc
ccaatgtgga gcaacaaaga 360cctggtgaag aaatgctaga gcgtgtgaaa
gcggacgatg cattgtcaaa ggatacccaa 420gtacgtctaa aagaagctcg
gtgggaaagc tgagcactcc ggaagaacca gggtaacaat 480gggacaaagt
gaaagcagac attctgcttg tttaaatttc tgaaggcatt tactacaaag
540agatgaagtg aaagttagca ctcagaattt gttatcactc tttattgcag taaagcagt
59971599DNAHomo sapiens 71tacatgttac aggggaaaaa tatccttctt
tcagttctgt ctgacaagga cctaaagaat 60cctattgatt ttattgctcg gctccaggag
gctgtgtata aaaccataac tgataaaata 120gctcaagatt tgtaatgcag
cttcttgcat acaataatgc taatgcagac tgtcaaactg 180ctattagacc
cctgagaggg aaggctcatt tagctggata tactaaggct tgcgatggca
240ttggaggtaa cttacataag gctactcttt tagctcaggc tatggctgga
ttaagagtcr 300gaaataatat gccccatttc tcaggctctt gctttaattg
tgggcaattt ggacacagaa 360aaaaggaatg tagaaaagga aatcaaaagg
caagagctac catcaaacaa cagaaaagtc 420ccagtgtatg tccccgttgt
gaaaaaagcc atcactgggc aagtcaatgt cattctaaaa 480gtagcaaaga
tggacaacct ctctcaggaa acaggaatag gggcccgcct tgagcccctc
540aacaaaccaa ggcatacctg gcacagccag tgcccttaca aatgtacaat tgtcccctg
59972599DNAHomo sapiens 72aaaaaagcca tcactgggca agtcaatgtc
attctaaaag tagcaaagat ggacaacctc 60tctcaggaaa caggaatagg ggcccgcctt
gagcccctca acaaaccaag gcatacctgg 120cacagccagt gcccttacaa
atgtacaatt gtcccctgcc acagcaggca gtgttgtcgt 180agacctctgc
agcacaattc ccctctcctt acttcctggg gagccacacc aaaaaaggtc
240cctatgggag ttaggggacc cttaccagca ggaacagttg gtctattact
tggaaagtck 300agttaaattt gaaaggtgtc actgtgcata tgggaataat
tgattctgat tataccggag 360aaattcaatt agttactagt tcctcaactc
cgagatctgc ttccccagga gaaagaattg 420ctcagttgtt gctgttacct
tacataaaac taggaagcag cacagtgaag agaacaggag 480gctttggtag
tactaatcca acaggaaagg ctgtatactg ggttaatcaa atgtctgaca
540aaagacctat ttgcacagta actattcagg gaaaagatta tgaaggacta ctagatact
59973599DNAHomo sapiens 73gttagctttg acactattaa aatttggaat
taaatacttt tgggaggtta aaatatctgt 60gggcaaagct acctctaatc cactgctttc
aaggagagac atcaagaaga agcagtcttt 120atcaaagtga gagtttcaca
gcttaaatct gaaaagaact gtcaaacatt tcttagtctc 180ttggatacga
tgtaaattag ttaagatata attacaacta atacttgtta ctattactac
240catagcttca tttataaaat attacttctc cactaattaa atgaagcatt
cagtgcttcs 300cataaccaat taaaatgtta agtagttaca ttatgcagct
agatatgtga aaaccaagaa 360taataagcca gataatacaa aagaaaaaca
gtgatgtgaa atgagttaca gcgaaaatga 420gcaaagtgaa aacacattta
aaccataaac ttttctgaaa atttgaggtg tccaagagga 480cagtcaagca
tgtacacaga atcaggtggt atgaaatcta
acagcaaaat atagggtagc 540ccagtctaac aacaaaatga tatagtggat
tggctgattc aggtttattt tcactcaga 59974599DNAHomo sapiens
74cagtctttat caaagtgaga gtttcacagc ttaaatctga aaagaactgt caaacatttc
60ttagtctctt ggatacgatg taaattagtt aagatataat tacaactaat acttgttact
120attactacca tagcttcatt tataaaatat tacttctcca ctaattaaat
gaagcattca 180gtgcttccca taaccaatta aaatgttaag tagttacatt
atgcagctag atatgtgaaa 240accaagaata ataagccaga taatacaaaa
gaaaaacagt gatgtgaaat gagttacagy 300gaaaatgagc aaagtgaaaa
cacatttaaa ccataaactt ttctgaaaat ttgaggtgtc 360caagaggaca
gtcaagcatg tacacagaat caggtggtat gaaatctaac agcaaaatat
420agggtagccc agtctaacaa caaaatgata tagtggattg gctgattcag
gtttattttc 480actcagatat caagatacac ttgagagcac ttttcctgga
ctaaattgta actttcaagg 540tgaagatgta atcatgagac tagaaccctg
tgtaaggggg cagcagagac aagtaaaca 59975599DNAHomo sapiens
75cacagaatca ggtggtatga aatctaacag caaaatatag ggtagcccag tctaacaaca
60aaatgatata gtggattggc tgattcaggt ttattttcac tcagatatca agatacactt
120gagagcactt ttcctggact aaattgtaac tttcaaggtg aagatgtaat
catgagacta 180gaaccctgtg taagggggca gcagagacaa gtaaacaaag
ctgactggca aaaatcccca 240tggtccacac agcatcctat tctacctgta
tcatttaagg tgccagaaga taaacaaccr 300caacctatta agaaagcaag
aaacaaacct ggaaataaaa taaaagccta gacggaaagc 360tatacccagt
gtctgggtta tttgtgagat aaaataggat aatacctcac ttcatttctg
420gaaagtctaa atccaattac ttaaaaaaaa aaactcacta tagagaacat
taacaaatat 480ttatctcttt ctacttttcc caatcacttt tccttaaccc
tttgctatct ggttaacagt 540aaaacatttc tttgaatggt cactaaaaat
ctgctaaata ttacatgcaa taggcatgt 59976599DNAHomo sapiens
76agagcacttt tcctggacta aattgtaact ttcaaggtga agatgtaatc atgagactag
60aaccctgtgt aagggggcag cagagacaag taaacaaagc tgactggcaa aaatccccat
120ggtccacaca gcatcctatt ctacctgtat catttaaggt gccagaagat
aaacaaccgc 180aacctattaa gaaagcaaga aacaaacctg gaaataaaat
aaaagcctag acggaaagct 240atacccagtg tctgggttat ttgtgagata
aaataggata atacctcact tcatttctgk 300aaagtctaaa tccaattact
taaaaaaaaa aactcactat agagaacatt aacaaatatt 360tatctctttc
tacttttccc aatcactttt ccttaaccct ttgctatctg gttaacagta
420aaacatttct ttgaatggtc actaaaaatc tgctaaatat tacatgcaat
aggcatgtct 480tcatcttcaa gtttttgacc tgtaccatga cattatggat
cacctctttt tgacaattat 540acaaactttg gttccacaac attgtactat
cttaatcttt cccttacccc tttgagcct 59977599DNAHomo sapiens
77ccacacagca tcctattcta cctgtatcat ttaaggtgcc agaagataaa caaccgcaac
60ctattaagaa agcaagaaac aaacctggaa ataaaataaa agcctagacg gaaagctata
120cccagtgtct gggttatttg tgagataaaa taggataata cctcacttca
tttctggaaa 180gtctaaatcc aattacttaa aaaaaaaaac tcactataga
gaacattaac aaatatttat 240ctctttctac ttttcccaat cacttttcct
taaccctttg ctatctggtt aacagtaaar 300catttctttg aatggtcact
aaaaatctgc taaatattac atgcaatagg catgtcttca 360tcttcaagtt
tttgacctgt accatgacat tatggatcac ctctttttga caattataca
420aactttggtt ccacaacatt gtactatctt aatctttccc ttaccccttt
gagccttttt 480tctgttcctt ttggcttctt catttaccaa tatattttcc
ataagtattt aattataaag 540tgtaacaaag tctaaagtga ttttagtaca
tctgacatct ttttgaacaa ggcaaggac 59978599DNAHomo sapiens
78gcaggtggtg gtgcgagtga gcagcaccaa ggaggcggca gccgaggcca aaaagagcgt
60ttgtcgccgt ctagattaca tcacgcagag cctccagcag cagggcgtgc aggtgagatc
120tccgcggggg aggaaataag agccggaaga cacaaaaggg ttggcagatg
gtcgggcccc 180acaggccccc ctagcgggaa gggagatgtg gagggtctgg
agcgtttagg acgcgtttgt 240tgcaaaggta ctccgggacg ccaggacctg
gcagagtgaa tatttgaccc attcttctcy 300tagacgaagg taattattgg
cctcaggcaa attaaaaata aaagaatgca aattgggtag 360gtttttatct
ggggatattt gcttcagtga ttttgttttt aaatttaaag tgatgaaatg
420ttaaaacttg aaatgttagt tgtaaatact tgcccacgtg gagtgctgga
cactaaatat 480tttgttttgt tttgttttta ttccgcacca tggaattggc
aagtgaagag cacgacctgc 540ttccttccga tcatgtaaaa ctttgcatgg
aatggttctt gagtatgttc cgcaaacag 59979599DNAHomo sapiens
79aatagtcttt gtttcctgca accatattta ttttaaaaaa tcctacagtt cactctaaat
60agacaaccta aacttatttt tgtggccaga gaaatgccag accaattagc ttagatatgg
120atttctgtcc atcttttaac ctaatcctat agcaaatcag atgtgatcat
cctaagtagt 180ttaaacctat tacggcttac cctgaatcac atagttactg
ctcagaggta gtaggggaag 240agtgtatgac atgaggattc tgtatttctt
gttttaccta ctgctttgaa atgttactgk 300ttattgctat ttgtaatctt
cagatgttct tgaattagtt acagaattaa ttagttcatt 360tgatccttgt
tacggtcctg tgccagtact atcctgttta aattattatc ttcataaagc
420atttgtaggg caagttctcc cctcattact cttctgaaaa aaattccctg
tctgcaagga 480acagagggac attttaagtg acaacatgaa attatagtca
gaaattccag agggtggaaa 540atttctatac aaaaaatttc tatttatatt
ttgcattcag tttacaaatt aatttcagg 59980599DNAHomo sapiens
80cactatagaa tgggagaaaa tatttgcaaa ctatgcatct gacaaaggtc taatgtccag
60aatcctataa ggaataagca ggaaaaaaaa caatctcgtg aaaaagtggg caaaggaaat
120gagtagacac ttctcaaaag aaaccataca agcagccagc aaacacatgg
aaaagtgctc 180agcatcacca gtcattggaa agatgcaaat caaaaccaca
gtgaaatacc gtctcacact 240agtaagaatg gcttttatta aaaagtcaaa
aaataacaga tattggcaag attgtagagm 300aagaggagtg cttatactct
tggtggaaat gtaaattagt tctgccactg tgaacagcag 360tttggagatt
tctcaaagaa ctagaaataa aattaccatt tgacctggca atctctttgc
420cgggcctata cccaaaggta aataaatcgt tctaccaaaa agacacattc
acttgtatgt 480ttattgcagc actattcaca atagcaaata catggaatca
acccaggtgc ccatcaacaa 540tggattagat aaagaaaatg tgatgcttat
acacaatgaa atactgtgta gccataaaa 59981599DNAHomo sapiens
81ctgccttttg tatttagaaa taaacagtag cttaatcaag aaaacttagc agagtaggct
60gatatatttc aatatttttc agttttgtgc cccttatagc aggctttctc aatcttggca
120gtattaacat tatggattgg ataactcgtt gttgttgggg gctgtcctgt
gcattgtagg 180atatttaaca gcattcctgg cccctaccca tggggtgacc
agcatgtcct cctttacctg 240aaactgttca agttttaaaa ctggcaggtc
catgtctgag gaacctcctc agtttgaggw 300tcacagggac acttgatcat
cttgtgtatc cacttagtag tgtattcctc ttccccagct 360gtgacaataa
aaaatgtctc caggcattgg cagatgtccc ctagggcaaa atcatctggt
420ggagaaccac tgccctatag ataaacaaaa aatctcatac tctgtgttgg
aacccaccag 480ccagactatc agaaacgtat ctatagtgaa acaaagttag
gtttatttag catgatgcaa 540caaagaataa tgcatcccaa aggaccttag
gagtgtttca gaaacaggta ttcaggagg 59982599DNAHomo sapiens
82agaggattac agttaggcta ggtgtgcctt tagtaaaggc acagcaatca agcagaaaaa
60gaatgttaat tatttcttgt ggttgcaggt ctgttagttt ctgttagaaa ctttggctct
120gttaaaaact ttcttagatt ctatgtcctc tggaaacatt gtttatgttc
tgcttagacc 180ttctccatct gattgtcaac aggcaatttt tatttctcca
ttccctgtaa tattatttag 240aatttcaaaa tatatcagat attttactat
atagagaagc aagataactg tcttcttatr 300tgggttgttt tcagactgca
cacacttccc tttaaaaact actgggctgg cataggttcc 360aagatggcca
aataggaaca gctccagtct acagctccca gcgtgagcga tgcagaagac
420gggtgatttc tgcatttcca actgaggtac tgggttcatc tcactagggc
ttgtcagaca 480gtgggtgcgg gacagtgggt gcagcccatg gagcgtgagc
cgaagcaggg cgaggcatca 540ccttacccgg gaagtgcaag gggtcgggga
attccctttc ctagccaagg gaacccgtg 59983599DNAHomo sapiens
83gaagcaattc gataaagaaa ggagtctttt caacaaatgt tgctgcaaca gtcaaatgtc
60tgtatgcaaa aaaatgaacc tccacactca cctcacacct tatacaaaac tttgttcaaa
120attggtcaat attgagcatg tagcatctgt tgcctgttac caggatagaa
gtccaagcac 180ttctgcccac tgcattttgg tatgagagtc accaagaaaa
cacaatgcag tcaagcactg 240gatggaacaa accttactta tgtagagaaa
agacaagagt gacatcagag tcagtagtas 300atgtcagtcc cccatggcca
gcaactgctt cccagcagct aatgcagggg cagttgacct 360acatgcacat
ctcttgtgct gcaacagaag gactcagtcc ccttcctgca gggtacagat
420atagtagtga ggttggtcag gtgtcatatg acatacaacc tttaagtaga
agcaaaaagt 480acatattgag tctgaaatgg ggaaggtatt cccatacaag
gaaacaagcc cagcacaagc 540tctgaaagat actttatctc ttagtaagca
agtgttccag ggccacagcc cattcctgg 59984599DNAHomo sapiens
84tttgagcttt tcgaattttg gattttcaca tttaggatgc tcaacctgtg ttaccaaaaa
60gcacagtcca tgaaacaaac aaaaagataa attgtatttt atgacaatta aaaactcact
120ttgtgaaaaa cattgttaag aaaatgaaaa gtcaatctat agactgggag
aaaatatttg 180taaattacat agctgataaa ggacttgtat ctgttaagaa
aatgaaaagt cagtctatag 240actgggagaa aatatttgta aattacatag
ctgatgaagg acttgtatca agaacatatr 300tagacctcaa ttcagcagta
acaaacagct caataaaaat gcacaaaaga tcttaacaga 360cacttcgcca
aggaacttat acagatggca aataggcaca tgaaaagata ctcaacatta
420cttgtcaata gggaaatgga aaataaaacc acaatgaaat actgctatgt
acctattaga 480atggcttaaa tacagtaaca ctgataccaa atgctgggaa
ggatacagag caacaggaat 540tctcgttcat tgctggtgag attgcaaaat
tatatggcca ctttggaagg tagtcttat 59985599DNAHomo sapiens
85ttggaagcat gtcactaagt gcagcccaca ctcactcaat aaatactact ttatttcttt
60tgttgctcaa ttgttctagc tttggccatt gggacttctt tcaggttggc tcctttatct
120gtttgacata cccctttcct ttactttttg agcactttct tactttctgt
tgcaagatat 180tataggctta tgcagtttcc ttgccccagt cctagaataa
gccctttctc caagaagcat 240agtacctttt ctttgagatt tatgtagaac
caagatctga atgctgagac tgctcactgy 300tattggggtg tcattccttc
taggctctct cagtggacag agctaggtta catatatata 360tgcatagaca
tatatatacg cacacagata ctaacttaca tgtaaaattt tctgtatttt
420tccacctgta caatatacaa aggtaaacat gagttcacac tgatgttttc
aactctaatc 480ctgaatcaca gaattcattt taaccttcca tttttatctg
taacttccct ctctgatagt 540gagaaacctg gctcccacca tccactatcc
acttatttat ttgtttaacc ccagtatat 59986599DNAHomo sapiens
86tttaccgtat tgtgataaat attgtttaaa aatgaaaacc attcaacctt tatacaaatt
60gaaaagaata aaactatttt caaattataa aaggagtgac atttatgaaa ttttaagcaa
120aatcaatttc tgaattcatt ttatgtcact tttaggaaag ttttaaaaca
tcaggcaaag 180ttctttttgc atattttatg tttttctgat tttaattagt
gtaggtttct aatttatgtt 240ttagagtaat tgcatcaaat atttagtaat
catactcttg gactttttct gtttcaggcr 300gaaaatataa ctgtgacaaa
ggattttagg agagtggaaa atgcttatca catggaagca 360gaggtatgta
cttaacaaat aattggaagc agcatgattt tgtggagaca gtcattttta
420ttcttgaact gaaatgaatg gtgaaaaatg cttctcatga tattaataga
agattatttt 480tctcaaaatc atcttggtgt tatatatcta tttcggcttt
taaataaact tgagatttaa 540aagaaagttt aaaatggaat aaaaacagca
agtgggaaat agcagttaat tgccactaa 59987599DNAHomo sapiens
87aaatgcaaga tttgaatttc catattcagt ggacccagtg ggtgcccagc gcaatgaaca
60acaacaacaa caaactcatc aaagcatatt ggaaatgtta gaaccccagg aataaaagga
120ctccaaaagt tctagagaaa gaaaaatagt tcacaaacca agggtcagaa
atctgaacag 180caattggacc tctcagtgtc aacactggaa gctagaaact
gaaaagcaag acagcaacat 240cttccaattc tgagagaaaa caatgtctaa
tctagaaatc cttacctggc caaaaaacar 300tgaaggagac ggtaatacaa
ggacaagcag acagggctga ccagaagtgt cacactgttc 360tttatttggc
caggatctga tggattaatg ccctctgaaa gatgttaaaa atgtgaaaca
420tcactcctgc atacaaggtc tcaaaacatt tccctaccat acgtgaggaa
gcaaaccaag 480aaagagaaaa acaggagttc ccaggtaatg gcaaaggaat
gtccccagat tcaggggaca 540ggaggactaa gggcttcagt aaaatgcctc
caagaaaaaa ataaaggaac tcatagatt 59988599DNAHomo sapiens
88ataaaattta aaatttagtt cctcagtcac actagccata tttcaagtac ttgaaggcca
60caaatggctt gagactacct tgctgaacag accaaggtca aacactgaga taataatgat
120tcttaaggcc atttgaaagt taacagcaag tatgtattac tgctatctac
agtaagaatt 180acattttatc tacaggcaat cataagccat gtctgttatg
cagcataggc tttccattct 240ctatacatct aggtcataga gtttttccat
tgataaatct ggatgtttat ataccaacak 300tactttctta caacatattc
cagtatatag tgtccagctt cacccacttt ttaaagtggc 360cctgaaacaa
ttttattcat cttattggag tgttgctgta ggggaagagt agaagctaag
420aagagtttga gttcaacacc attatatcca aatcctgacc ttactactgg
aatgtaagct 480ccttgaaagt ggagatcttg tctgtcttgt tcacagttgt
gttcccagcc ccagaggtag 540tctcagggcc aatatcaagt atgctctcaa
atatttgctg ggaaaattta ctagctgga 59989599DNAHomo sapiens
89atacatacat acatacatac atacatacat acatacataa aatgcccagt atcttacaag
60actgtagttc acagtgggta attcaaatca gacactgctc ttcaagagag gtaatattaa
120tagaaatctt tcaagaagga ttgttttcta ctattaaaac aataaaactc
ttataaacct 180gtttatcaga aggatatttc tgtttcagca actcctggaa
tccttcttca acatcccaac 240caacaattac tcccagatag ccatgtcacc
tgtgaattat catgaatccc acatcaaatr 300aacaaatact gcctctggac
tctgaatgta agttggttca ttataagagt gagaaaaaga 360agactaagaa
aaagcatact gtattctttg ctacataggg tttaaacttt attaggaggc
420caggcatggt ggctcacatg tgtaatccca acacttcggg aggccgaggc
aggtggatca 480cttgagacca agagtttgaa accagcctgg acaacatggc
aaaaccccgt ctctactaaa 540aatacaaaaa aaaaaaaatt agctgggtgt
ggtggcacac gcctgtaatc ccagctact 59990599DNAHomo sapiens
90ccatttttca gaataagaca ctttttcagt gtctttcaaa aataaagatt ctgtctccta
60tcctgctcct tttttcaaag aacaattttg ggcaaagagt aaaatacaga catatagttt
120cagtgcttca tatggacatc agttttacgc tggtcacatt aattatgccc
taattatttt 180ttatcttccc cttcacaaga ctgtgaactc ctcaagagta
gggctatgct tgaaacagtt 240tttttcccaa ggtttgggta ataaaaggct
aaggaggaaa aaagttggct gtgaggtaty 300gtgctttatt ctcaaataag
acagatactg tttatggcaa agttacctga acattggtac 360acctggaagc
agggatggga aatgcaggac acatattcaa actgtgtttg cacattttgc
420agtccaataa gcatgctttt atttctccag agcttagctt tctcaaaaag
tagtttgtgg 480ctatgcaaca acatacattc tgttgtgtaa acaagcctct
taaatcattt cagaacctat 540gttcatttca agcttattgg atcagctata
agtgtgtatc tttgcccttt acctcctat 59991599DNAHomo sapiens
91aaatacaacg ctttagaagt gttttctcta aaagattaga cacttcattg accaatatta
60attaatgata tttcatattg tttggtgata actctggaaa cataacactg caacagccac
120ctaaataact atgagaatac atgaagctct gagttttgga cagatttcag
ccctcagttg 180atcactgtag ccctgatgac aggaaaagtt gaaacatcag
caatgttcaa agagccatgc 240aattactgct tctctatgtg tgaattagaa
tattcagaaa gggacagaga catgcagttr 300aagaaacagt aaattccttg
aaaaatagtg tggcatgata gggcctataa tattacttcc 360agaatatatg
gaggtaatac tttgaatgct aagttttcag tctgctactt gttagaaatg
420ttttttttga gattgaatct tgctctgttg cccaggctgg agtgcagtgg
tgcgatctcg 480gctcactgca acctccgcct cctgggttca agtgattctc
ctgcctcagc ctctcgagta 540gctgggacta caggcacatg ctaccatgcc
tggctaatgt tttgtatttt tagtagaga 59992599DNAHomo sapiens
92acaaaaatac aggaaaaggg tggaagggaa acaatgaaaa agttcaggtg ggtcacaaac
60atggacacaa ggagtctgaa aggcaggcct tgacatttgt ctgaataata ctaacgatga
120cccttcggag tttcacggga gaggagggtt gccagactgt aatggagaga
aactggactt 180agttgctaat taggatgatg gtgcaaggtc catgacaggg
gatgagggaa tgcctgctcg 240gggaggggaa aaggggactg gacggagggc
acggcaggat ggcctaggga ggacgggcgr 300gggcctatca gttacaagag
gaaggagaaa gaggatactg gttttcctct gcataaaaaa 360cgcgatggat
tctcaagaat ttattgaaag tctgtgtgtc caccatagtc caggatattt
420tggaatattc aagggaaata caaatccaag aatttagctc aggaatcagc
atcagaacag 480aatccccgaa gagtaaacta ttcatggaaa acagtagact
gataacattt gaaaaactga 540tttcccatag aaacaatagt tactgtttga
cgaattatac aacgtagacc taggtcgtg 59993599DNAHomo sapiens
93ggtggcatgc acctgtagtc ccagctactc gggaggctga ggcaggagaa tcccttgaac
60cctggaggct gaagttgtgg tgagctgaga tcacaccact gcactccagc ctgggcaaca
120gagcaagact ctgtttcaaa aaaaaaaaag tacaagtcat tactggggcc
gggcgcagtg 180gctcacgcct gtaatcccaa cattttggga ggccgaggca
ggtggatcac ttgaggtcag 240gagttcaaaa ccagactggc caatgcggtg
aaaccccatc tgtactaaaa atataaaaaw 300tagctgcgca tagtggcaca
cacctgtaat cccagctact tgggtggctg aggcacaata 360atcacctgaa
cccaggagcc agaggttgca gtgagccaag attacacact gtactccagc
420ctaggtgata gagcgagact ctgtctcaaa aaaaaagtca ttgctgagaa
gatgactgca 480tctttaaaat acagtttaga ctaaaaagtg atgagagtga
actaattaat ggctatttac 540agtgaaacct ctactttttt cactccagga
gtatttcaac tatttatatc aaaggaata 59994599DNAHomo sapiens
94tcagcagaaa gctaacagca ggagatattg ggtgcctatt ttcagcattc ttaaagaaaa
60gaaattctaa ccaagaattt catatcctgc caaactaagc ttcataagtg aaggagaaat
120aaaatctttt ccagacaagc aagtgctagg ggaatttgtt accactaggt
cagccttaca 180agagatcctc acaggagttc taaacatgaa aatgaaagaa
tgataactgc taccacaaaa 240cacacttaag tacatagccc acaaccacac
ctaagtacat aggccacaca gtagaaactw 300caaagcagct agctaataac
ttcatgatag gatcaaaacc tcacatatct tgcttgagcc 360caggtatttg
ttaccagcct agccaacata gagggatccc atctctataa aaaatacaaa
420attagctggg tatggtggca cacaccggtg gtcccagcca cttgggaggc
tgaggtagaa 480ggattgcatg agcctagaag tttgaggctg cagtgagcca
tgattatgcc actgcactcc 540atcctgagtg acagagtaag accctgtctc
aaaaaaaaat tatttttaaa atatcaata 59995599DNAHomo sapiens
95gcacacacca agcctggcta atttttgtat ttttagtaga gacggggttt caccacgttg
60gccaggctgg tcttgaactc ctgacctcag gtgatccacc caccttggac tcctaaagtg
120ctgggattac aggcgtgagc cactgtgctt ggcctacaac atgtatttct
taaataacaa 180gacttgaaaa tcaaaattac tccttgatct gtgaggtgca
gaacggatgt tgtgttagca 240ggcatgaaag caacactaat caccttgtac
attgccatca gagttcttgg gtgaccaggy 300tgtcaatgag cagtagtgtt
ttcaaaggta tcttttttat ttttttattt tttttctgga 360aagcaggtct
taacaatgga cttaaaatat tcagtaaacc atgctataaa cagatgggct
420gtcatgcagg ctttgttgtt ccattgacag agcatggtag ggtagattta
atataattct 480taagggccct agaatttttg gaatggtaaa gaagcactgg
cttcatctta acaccagctg 540cattagcccc caatgagagc ctgtcctttg
aagctaggca ttgacttctc tctagctat 59996599DNAHomo sapiens
96ggagaaaaga acaaagactc aggaacttct aagtgtttag gatgactggg atacaaaaga
60gagaaagaag gtaaaagaac ctggaatgtt aggcaagagc caagtaataa agagtcttgt
120gtaacaggca aaaaatttaa aatgtttcca tatatgattt gaaggcaagg
aagtgttttc 180tctgtgtgta cgtacacaca tccacatgtg ctagagagaa
ataaaaagat cgctttggct 240gcaatatgag agagggactg gttaagaaag
agttgagaac tgaggcagga agaccagttw 300ggaaactagg aaaatagtcc
aagcaagaaa ttatgtaggc cttgaaataa tgtcatggag 360gtgagaatgg
agaggagaga atagatttaa gagatgttat ggagggagaa acaacaaaaa
420caaaaagctg ttgaacagat tcagttgctg aagagaaggc taggatgact
ccctgatttt 480aagtttacac gggtagatcc caatgccatt aacaaaaata
agatttcagt agagaaatta 540aattttgaga gaggtttctg aagacaacaa
tgaagaaatg tcttagacac actttgaaa 59997599DNAHomo sapiens
97ttcaaagctt tggaatgttt cacagaattc tctagtacta aaacatacaa acaaaattta
60aaaattaaga gttattgaac ctaaagataa gaaaaaaggt taacctgaat tatttgaatt
120agccaagaca acaaaacctg aaggatgctt aaagctttct taggaaagct
actttctaat 180aggaaaaagg cgtatccaac tagaaactct taatagtttc
agccctttta gaagctgtcc 240catcatttca aaatttcgaa ggcaagtctt
ggcaaattgc tagctagtgt gggtactgtr 300atttaaattc aggtagttta
gatcagagtt gccattttta agcattagtc tataatgacc 360taaacctcaa
tttaattctt cttattaaaa actttttttt aaaataggaa attaataaag
420aaggcaaaaa caacagtgtc tgctaggaat tactaaaact cagtatattg
catttggcaa 480agtaaaagct taaattaaga aaatcatcat atacatttca
atttagaaag tgagtcttac 540ttgttttccc tggtattgca gatgcattag
cttttgtaat aaaagtcttt gcagctgaa 59998599DNAHomo sapiens
98gttttgtctg tatgagccat ttgaatttag agtcggactt ttctttaaga atctcaaaac
60ttggaagatt tctgttctaa
acacaaaaat acataattgt taaaatgctt cagtttacct 120tttcatcaaa
agattaggaa aaagggatgt aaaaaacaat aattaaattc taaatatttt
180ttactggaaa aatatttaca ttacagtatt tactgaacaa aggtattttc
ctccaaggaa 240tggttgaaca cttttttttt tccctcacag atttacagca
tgagtttgcg cctgtctgcw 300ttctttgaag aacacattag ttcagtttta
tcagattata aatctgctct tcgttttcat 360aaaagaaata ccataaccaa
aaggaggaag aaaagaaaca gaagcagctc tgtttccagt 420agtgctgcat
caaggtattt aatttctttt aaataccact agctgatcta taactttcat
480ctaaatgata gaacttggtg ttttttaata cttcctttac tattccctat
attgcagaat 540gataatttga catgcaagtt cctatgatgt ggaggatttt
taatctttta actaaagct 59999599DNAHomo sapiens 99gacaataagt
tttgtctgta tgagccattt gaatttagag tcggactttt ctttaagaat 60ctcaaaactt
ggaagatttc tgttctaaac acaaaaatac ataattgtta aaatgcttca
120gtttaccttt tcatcaaaag attaggaaaa agggatgtaa aaaacaataa
ttaaattcta 180aatatttttt actggaaaaa tatttacatt acagtattta
ctgaacaaag gtattttcct 240ccaaggaatg gttgaacact tttttttttc
cctcacagat ttacagcatg agtttgcgcy 300tgtctgcttt ctttgaagaa
cacattagtt cagttttatc agattataaa tctgctcttc 360gttttcataa
aagaaatacc ataaccaaaa ggaggaagaa aagaaacaga agcagctctg
420tttccagtag tgctgcatca aggtatttaa tttcttttaa ataccactag
ctgatctata 480actttcatct aaatgataga acttggtgtt ttttaatact
tcctttacta ttccctatat 540tgcagaatga taatttgaca tgcaagttcc
tatgatgtgg aggattttta atcttttaa 599100599DNAHomo sapiens
100tgattgcagt ataagggggg ggagtatgaa ataaataaga attattagaa
aaaagggact 60cttgataagg ggaacaggag tgattattaa gagttctagg acttgcagtc
atcataaaaa 120tcctgtgcga atccctgcac tgagaagtga tgctttgtgt
agtaataatc ataacaccac 180ctgttttccc tctcctagga ctacagagac
atcattgaca ctccaatgga ttttgctacc 240gttagagaaa ctttagaggc
tgggaattat gagtcaccaa tggagttatg taaagatgty 300agacttattt
tcagtaattc caaagcatat acaccaagca aaagatcaag ggtatataat
360tacattattt tcttttatga ctagattaag ttagaggagt gtgttaaatg
actaaatgtt 420gctttactta aaatttaggt caaagttaac tttctgttac
attcttaatg ttgtcctact 480ggaaaaagaa attatacctt tctactcagc
tccttgtatg aaataacatt gatgttatct 540ttgatgtctg ggaatggtta
cttttcttga agtagtgcgg ttgatgcaaa ttgtcctgg 599101599DNAHomo sapiens
101ggaagttttc ctttgttccc ggttttctta ggggttttat aatgaattaa
tgtctcactt 60cttcagattc tgcatttgtc tatttgccat ctattcacag gccaatgatg
atctggtacc 120tggggggcct tacagacctg ggaaaagatt gccccttcct
gggcagtctt agtgaggggt 180tccactgaga acatgtcttt catatacata
ccaatgaatc ccaagtataa agccacaatc 240agctcctttt ctcactctca
cacactaagc cagtatttcc ctgttttaaa tcatctcagr 300gctgggacca
gacaactaga tacctgtgcc ccagggccca ctggaattat tcaaactagc
360caataataag ctgttaactg tgacctgcct tgcatttcct gcagaaaccc
caataaagga 420tttctaagct tttccctggt tttggtctct cctacccaac
caaaacctag cacttcccct 480gtggccctgt gtggcatgtg gtaagccccg
acttttctgg gactcttttt tacttttttt 540tttttgttgt taatgagata
gggtctcact ctattgccag gctagagttc agtggtatc 599102599DNAHomo sapiens
102aaatcattag ttcattcagt taaggattaa cattttttcc ataatggatt
tctacacaag 60ggtggtgcaa atttggattc taagtccatg tatagtgtaa gtttaggaaa
atttctcctc 120tctgacacta gaaccactgg gggaaacatt ctttgttgtg
aaaggaatta ttcaattctt 180cttttcattc agggtacagt tcttcaatat
ttctggttta gggttgggtt tcagctccaa 240attccttttt caccactgcc
caaggactca attatctctg tatagtgtta atacttgtgm 300ctctagaata
aaaacattgt cttatttcta tctcttcttt tctgtgcaaa gcccagaata
360caaacgctta aaacaatgaa taaactgcaa cttatttttc aaaagaatac
atagctgagc 420ttgcaagaac caaagcgaaa tccataagtt gtgaaaacac
agagagaaat gaaagccaga 480acattatagc atcagctcag tcccaggttt
tttgaaaggt gaggttctaa ttagctcaat 540ttatcacgcc gctggaatta
aagatttctc ttccacattt aacattctat gtttctggc 599103599DNAHomo sapiens
103ataaggctat tcctataaag tgttggcatt ttataaaata cttcagattt
gaatattcct 60caatctccgt gtccatccag ctcttcttac tcatgttaat ttctctctag
actctttgca 120gctgattctt tattgagaga gtgggttgct acaaaccacc
acataatcta gttacttcag 180aagcccagaa tttagataat caagttttgt
ggtcactgtt ttcttttaac aaggcagagc 240aattaatata ccctctcctc
tccccttaag aagatcctct tttgtgtgtg tatattaagy 300tgggggagac
cagtacaagc tacccatata attataactc agctttcaat cctcctcctc
360caattcatat catgtcagcc tgaatatgtc aagtgtttta aattgggttg
tggaggaccc 420agttttttca gagatgcctc tggcacttct aggaggccct
tattctaaaa ttcagctaac 480ataacctaat ttataactgt tttaaatagt
taagtcctgt gttaagacca cattcaaaaa 540gagattccac ttaaaatgtc
tgaaaccact gacttaggat attgtgaaaa aaaattttt 599104599DNAHomo sapiens
104tcttactcat gttaatttct ctctagactc tttgcagctg attctttatt
gagagagtgg 60gttgctacaa accaccacat aatctagtta cttcagaagc ccagaattta
gataatcaag 120ttttgtggtc actgttttct tttaacaagg cagagcaatt
aatataccct ctcctctccc 180cttaagaaga tcctcttttg tgtgtgtata
ttaagttggg ggagaccagt acaagctacc 240catataatta taactcagct
ttcaatcctc ctcctccaat tcatatcatg tcagcctgar 300tatgtcaagt
gttttaaatt gggttgtgga ggacccagtt ttttcagaga tgcctctggc
360acttctagga ggcccttatt ctaaaattca gctaacataa cctaatttat
aactgtttta 420aatagttaag tcctgtgtta agaccacatt caaaaagaga
ttccacttaa aatgtctgaa 480accactgact taggatattg tgaaaaaaaa
tttttgttgg agaataacag tatttttcca 540ttactttgtg ttctgccagt
tttttctata ctcgcgtgtt gctttactta cctagtgtc 599105599DNAHomo sapiens
105tttttggctt atgcaattgt gcatgtgtgt tgtatttttt acaaacaaac
aaaaatgggc 60aatgaagtgg aaagaaaata taatctccag gctttggtcc caacgtcctt
ttctcagtgc 120aaggaagatg tcatactcac tgcctaaggc taattattaa
atcctgaatg tgtcaggcca 180tatgcataat gacagttata ttatcattat
taattacaac tatatcttca ttgagctctt 240atatgtgtca ggctctacaa
taagcacttt acacacatga tgctatttaa tcttcaaagy 300agccctataa
ggaaggtatt agctttgacg gtttctaagg ccgagtacta aaaagttggg
360gtgtgaggct ttatggaact tgccaagatc acataaaaaa tgacaagtca
ggatatgaac 420tgatgtccgt ctcactcaaa agcatgacct cttaactatt
atgttacact ttaaacactc 480tgctaaagtt acaaaagtgt ctctgcctcc
caaatgcaca ctttcttggg tgaatagtaa 540ttaataaaac aatttcatgt
tttgctgtaa taaattaatt tcaatcaatt ccaagtagg 599106599DNAHomo sapiens
106agcctaacac acacttacca ttattaggta taagctccat atcccaagga
ctcatctttt 60ctgtatctcc attgtcccag cttaaagaaa gaaaaatcat tatattaaaa
aatctaaatt 120attgtatcac aattttaata aaatcaatta tcaaaataat
tgcttctgtg tttaaaagaa 180gtctctttat ctcttaatag atggaaaaaa
aaattcaaag caagcctagg tgaactaaaa 240tacaacaaat atttccttac
caaacattgt agcattgaaa cagactatca gggtactcar 300gttgaagagg
ttcctggctt tcgattgttc caaaccacca ggcatcatct atgacagacc
360tgaagcggtc acctggccaa gaacaaaaac taactcatca ttctgaaatg
catggctgct 420gtcactgctt tttcctaacg ttaaccttta agtacctaaa
ctgcctgtat gatttcagaa 480gacaaaaagt gaaccacaaa ctccaaaaat
aagtaagtac aatcagcaat accaagagaa 540aaaaggaatt tagtaagcat
acttgaagtg tgacttaaca gttttcaatt ctatttttt 599107599DNAHomo sapiens
107gaagcggtca cctggccaag aacaaaaact aactcatcat tctgaaatgc
atggctgctg 60tcactgcttt ttcctaacgt taacctttaa gtacctaaac tgcctgtatg
atttcagaag 120acaaaaagtg aaccacaaac tccaaaaata agtaagtaca
atcagcaata ccaagagaaa 180aaaggaattt agtaagcata cttgaagtgt
gacttaacag ttttcaattc tattttttat 240atttcattaa ggtatacaga
aattcacttg ttttaggcat ttttaccaat ctagcatttr 300aaattcatca
ttaacactat acccaaactt ttcactgaaa taaaattata attgcggcaa
360gttccactca acaattactt agtcttttaa tttcttactt tctgtaagca
agtttcccca 420accaacaatc aatcaagact ccacgctaaa aacaacaaac
aacataaaat ccaacctgtc 480ttccttcatc tcaatcaccc ttaatactca
ctcactctcc ctttcctgta aaaggaaaca 540aaaaagaaac aaaaataaaa
caactattct ttttaaaaca gaggacactc cttgtgtct 599108599DNAHomo sapiens
108cagatgtacc aaaggctgat agccaaaacc aagaaaaatg ttttcatcta
ttttacctac 60tacttcttga cttacagatt tcttcactca tcaatttttg acagtaagta
tcagagttga 120ttcttgaaga catgggtttt aactgaccag gtctacttat
acacagattt ttccaataaa 180cagatttggc cctctgtatt ggcagattct
gcatcagcaa ccaaatgcag attgaaaata 240cagtattagt gggatgtgaa
atccatgaat atggaagggc caacttttca catcgggggr 300ttccgtagga
tcaattctgg aacctatgta tgcaaagatt ttggtatcca tggaggtcct
360ggaagtaatt ccctgtggat actaagggac aactataact tcaatacaac
tgtgcataaa 420aagtatgtgt attatattta atccatattc aatttttaat
catgactgtg taaatactgc 480ttgctcctaa gcaaaacagc atataattcc
ttccttatat aattttgttt tccctaaaat 540taataattgc ttcatttttt
taatgcttgg ttttcagtga atttacaatt aaatcttcc 599109599DNAHomo sapiens
109tttaatccta gttatagtaa gttacaacta aataaggtat tctcatagga
gttgagtagt 60gcaacatgta gaaagctaat tatttccata agctggacat tacacttcta
cacagcatga 120gaaactatgc ctctgagaaa gttccttaac tttgctggtc
acccacaagt ggccacaatg 180gtcttgatgt tgttacctta gactcaggaa
aaaaatgaac tttctaagaa catttgaaac 240ctaatatttt tacaagtaaa
aaaagttatg caattgatta aagtcttttg tgaatcacay 300gtaaaacatt
aaaaatgatt gtacactaag actgctacat tttacttgtt tttttaaaaa
360caaggtagtg taattatcag tataaaataa tacttgttta ctaaaagaag
caatgccata 420acatgatatc agagaacact acttgcaata ggtaatacta
ctacttccca actgtagtag 480ttgtcatttt cctctttttc ctattagcca
cagccacact gagtgtttct cagtcaaaca 540tatcaagagc attaccctgg
agagttaggg taaaggtctt tggaatttac tgtacgtga 599110599DNAHomo sapiens
110ttaaagaata gaccctaggg agaaacaagg agaaacagga agacacatga
gatgctacca 60cagtaatata aatgagagtt cagggtgatt cacaccaatg tgatggcagt
ggagtggtga 120aaaacagtaa agtgctgaat atacttataa tccattagat
aattaattcc ctgatggact 180ggatgtggaa tatgagagaa aaagaggaat
caaagatatc tccagggttt ctggtataaa 240caactaagag agtcgtcata
ttactgagat aaagagggct ggggtacagc gggtttgagr 300aaaaagcttg
gtaaataagt tttgtaggtg ttggatgtga ggagtaaaat gatatccaaa
360cagtaatttg atatatacac agttatcaaa taaagtagcc attatgttat
gcactgagta 420tatcacagag atcccacaac ccaggaactt ccactgtgct
ttattcagag cagctgctat 480cagttttgta tactgaggag ctaaaagttt
gtttgaaaaa ggtttccttt gactaataaa 540aaggaaaaga aagacagaaa
agtttgaaaa tcataattct agcctcaata tggactatt 599111599DNAHomo sapiens
111cagcgggttt gaggaaaaag cttggtaaat aagttttgta ggtgttggat
gtgaggagta 60aaatgatatc caaacagtaa tttgatatat acacagttat caaataaagt
agccattatg 120ttatgcactg agtatatcac agagatccca caacccagga
acttccactg tgctttattc 180agagcagctg ctatcagttt tgtatactga
ggagctaaaa gtttgtttga aaaaggtttc 240ctttgactaa taaaaaggaa
aagaaagaca gaaaagtttg aaaatcataa ttctagccty 300aatatggact
attaattgct aggcaaggat ttctccccat aaggaattta tctatgttca
360atggggaagc taacaacttt tacatcaaga caggtaagtt gtatattaaa
taagaataat 420catatgtatg actgaaagac tttgggcatc accaaaaatc
attatgagga catatcttat 480tccccaataa ttcctgagga acttagaatg
tttggttgag gaagatttct gtcacttatt 540aattataacc attaaggggt
taagaatgca ttgagtattc tttaacattt ctagctcca 599112599DNAHomo sapiens
112agatagttaa ctcaggaggc ttgcattgct ttcttaactt catacttttc
aaaaccagta 60atgaaactgg tttgcaattc aacattataa cggtattcag aagaaacaat
actaagatga 120taaagttaaa agcatcattt tgcagatcta gttgcaatca
ccaaaaaatt attttctata 180gagaacatat atcagaaaat ctacatttca
tacaacttca aaaactctct gaagaacttt 240gaacttacag agactttgaa
acgtgttgct ggttaaaaaa aaaaacacct ttctaaagay 300tttatataac
atttggaaaa ataaaaagca ttcatttacc tagaactgcc atcactgtgc
360catgctctct cttcttcttc ggatgttcca ccactgacag caactacttc
gccttcctaa 420gatatgttga atacatgtct tattgcataa ttttataaaa
taacatttta tgattacaga 480aaatatcagt gatatcttat aatatcagtc
atattgggat atttaaaatt tgatttaaat 540tagttgcaaa gggtgttgtg
gctcacgcct gtaatcccaa cactttgaga ggtcaaggt 599113599DNAHomo sapiens
113ctcaggaagt acgtatctct ctcaattagg ccatgaccaa ttgaaatcta
ctgggtgcaa 60cagtttttcc agagtaggat gacagaaaag ccaataagtc aaaactatta
gggacaatct 120acctctctta atgaagaaaa tgagaaatat tatctatagc
agcattagct gacttgatta 180tctagaataa tgaatagatg caagacacca
caaaaacaca tagaaaaaca taacaaaatg 240ctatttttag actgtacaaa
gatggcacac aagattatga agagctaaag aaagttctts 300atgaggcttc
agtgtaattt attagaattt catgagtatg taagaattgg cactttggga
360aagggtatgc tacaaagcag aaatggaatt aaaaatttta aatagtaaac
aatagataat 420ccagagataa ccaagattta ctatgttaat ttttatcatt
aacctgttta taataccatg 480ttaaattaca aaatggagcc ttaaaatggt
cactatactt aagaagcaaa tattaaacat 540caaaataatt aatatgtacc
tttgagacag tgggtatttt attctctttt ggaacagtt 599114599DNAHomo sapiens
114ctctcctcag gcctcactat tccctgagac agaacaatat taaagttagg
ccaattaaaa 60accctaactg atccagtgaa aacatctctc actttaaatc aaaggtagca
acgattaaac 120tctgtgataa aggcatgtca aaatctgaga caggctgaaa
gctatgcctc ttgtgcccaa 180caaccacgtt ttcaatgaaa aggaaaagct
cttgaaggaa gttaaatatg ctactccagt 240gaacacagga atgatatgaa
agtgaagcag gcttgttgcc gatacagaaa tagtttttgy 300ggtctggata
gaagattaaa ccagctacaa cattccctta agccaaagcc taatccagag
360caaggctcta actctattct cttctatgaa ggttggaaga ggggaaaaag
ctgcagaaga 420aaagttggaa gctagcagag gttggttcat gaggcctaag
aactacctgt gtaacataaa 480agtgtagggt gaagcagcaa gtgctgatga
agtagctgca gcaatttatc cagaataact 540agctaagatc actgaagaca
gtagctacat taaacaacag actttcaatg tagtaacag 599115599DNAHomo sapiens
115gaagaatgca gtgatatttc actgtggttt caacttgtat ttccctagtg
gttaatgaca 60ttgattatct tttcatgtgc ttatttgtca tctatagatc ctctttggta
aatgtctgtt 120catgtctttt gcccattctc cggttggatt ctgttgttta
ctattgagtt atgagaatta 180tttctatgtt acttagcccc ctgttgggta
tgtcattgga ttccatttta attaatggat 240gaggctgacc catttcagag
agccttttta aaaggaaact ttagactacc cactggagas 300attcttagga
agattcccat aggatgagta caaagtttta gagacaaagc tccaggaagc
360ccaaagaaag aatatctgtt aaagttatgg ccacagtctt gcttgaccat
aggccaatga 420atagttaagc ccaatgataa aggaataaaa ggatgaagaa
tatttgaaga gaaataaatc 480ttcctcactc ctcaggttcc cttccatgtg
caggagcctc aacctacaac tagcaacctt 540atctcctgac tcattcctct
ccagaggagg agtaaattag tcaactgata tgctctgga 599116599DNAHomo sapiens
116cgtactgaga cacattaatc tcacaaactc cagataagtc cactggactg
cactactcta 60ggagtagcag caggaatgat tcctctaatg cttcttctca ccctccattc
taagtggacg 120tgtctaattc caagaggagc cccttctatc cagtatgtcc
atctttattg caacttcatg 180ctaaatcctt taagaaaaat aagatgcacg
tttgaggttg attttttctg tgctccttac 240agaatctaat ttcattattt
aaaagtcact caacacaaaa gctacttaga agcttttgty 300gattgaagtc
tagaacttaa aatattttca taaatatttt tctagtctaa aaatatagta
360gaagtattca taatgacaaa actggtttaa ccttctttac agaacctttc
cttattttta 420cttaatacac tagtgctgca tttcttgtca aaagagggaa
agcagtttgt agactttgac 480tccattttaa ctctcattta attcttcaac
actccattat acttcactaa aacagctctc 540aacactttcc atgtcaatcc
tcttataaac ctttaaaagt tggtaacttt ttaaaacat 599117599DNAHomo sapiens
117agaagccaag agagagaaca aaaaagcaac tactttataa atctactcta
ataaatgttt 60ccagaagtat aattacaagt ctaagattac aatttgaagt agagtggaga
cttgaaagta 120gtccaattta gcaatttcaa aggaaatctg ataaatgttc
ctaagcatgg tatccttcat 180gtgttgttta aacaaacatt ttttcttttt
gggggtgagg gttgcggggc aagtaggact 240gatcaaccct tgaccctatt
atttatcaat gttgccacat ttacagttag tagatctctr 300aaataatctt
ggggacagtt gaagcttata aagctctaaa agagcaaaga aaaaatagca
360atcatattta agatgcctgt gtgtcctata taacacattt cattgtgaat
atggcaagac 420agtattaatt ttcttggtat aaggcatctg tttaactcca
aagtgacttt tatatggaga 480aaatgaaagt atatttcaat catatcagaa
aaaagaaaag gatattattt ggattaacca 540tttgtttact aaaggaggca
ttaaaagaat ctgctttact catgaaccag ttagaaaag 599118599DNAHomo sapiens
118tccacatagg tagttcaacg caataaacat tattacaaat gaactgaata
aagaagtcag 60ttctccctta tgtctttcat atttccacta ataaaaccat tgttctcaag
gtcacccggg 120cttaacactc tataaaccca tttattaaat ctttcctccc
tgtcatccta tagcccaaat 180cctaatatag tcacaaaaca ccaagtcatt
tatgtatttt tttctttaca aatttcctac 240caactacccc tataatattt
catgactaat taaagtagtt gtcctcacac ttattcaatk 300tcatacctga
aattgtacta ctggcaacca aactattttt ctcttagctt ctcgaccatc
360ctataaaata atttactaaa gcccccacaa ggttcatagg tatttatgcc
tatgagatca 420tttgaagtca ctgacagttc atctcaattt gtttttcgtc
attatttcca aaatctactg 480caatcaagct tcctaaatat ctaaatttct
atgaacatgt cttgacactt agctttttat 540aatgttcctc ttgtttataa
aattcattct ctttcttact gactcgattc ctatttatc 599119599DNAHomo sapiens
119tagttaaact cgtagttaaa acttagctgt ccggtgctaa tttaatgggg
aataaaagac 60cataaaacaa tttatattta ggaacattta aggttataat taacttctaa
acctggcgac 120ctctttcaca gaaggccctc agcttcagtc ctgagagttg
cacacatttt caagctattt 180ctgggaatta tttatctgcc ttttagcatt
taatgggagt atagagcctt tagagtttag 240aacaactctc atcaaaacaa
agctattctg atgtttacct cctgccaatg ccaaacaaaw 300gtgggcttac
taagttatac ccaactatta tagtttggaa tattcttaat atacactact
360tgcttcagta aaatatccaa atatatacta catttcctct gaatactcaa
gttatgtaag 420gactgttcag ttgattcgta aagaaataaa agtactgaag
gcctagaatg tagtttgttt 480gtttttaaag aataaagttg tctcataata
ttttctacaa aattctcttt ggtttcttct 540cctgttcact taaaaaagaa
aaacaacaac aacaaaaaga accacaaagg ctttcccaa 599120599DNAHomo sapiens
120attttagtaa ctgaaaaact tattgattag ctacagagag ccaaatagct
ataattatag 60ccaaaactca acattcatga tagcaagcag tgagaacgca ggccctccct
cgaattgttt 120ctctttattt tcttaatagc aatgctggat gctttatctt
ccatttgccc ataaataaaa 180caagcaatga aaagaacaaa agagtgaaga
gcaaaaagaa ttagggcaat tagataactc 240ataaaagaca gacaggaaaa
aaaatcaagt taaagagtaa gatgtcaaaa gatccactcr 300gatttattac
cattatgaaa acatttcttc atagacatat cactaactga gtattgttaa
360aagttagcta tgcagtaaca ttgacaaaag ctcaaaaagc caaccatgac
aagatttgag 420tacaaccaga gtcatgggtt tatgctccaa gtgcccgcat
aatagctgtg tgaactcagt 480aaattggggc aaagcacttt atctctgtaa
tgtacagttt ctccattcct aagaccaaga 540ataataaaat ctatcttgat
catcttacaa ggttttcatg agacccaaag gaggtaaaa 599121599DNAHomo sapiens
121aggtatctct aatatacaga aagtagacat ttaaaaaata tgactacaca
aactgcagta 60gttgaggaga ccttaatact tcatacagta aatagaaaca ctgctcggta
agttgtatgt 120gatatattaa aacattgtaa ttcaaatact tggccaatta
tgttaacatc taagaaacaa 180aatgtgaaga gaagagtata aactcaaata
tttaatatac taccaattga ttaaaagcaa 240gaaatgcttg attctttggc
cttaatttta aaatcagtgt acttgagtaa aattctattr 300tgctagaaga
ctattaaaca agtacaataa tacgagtatt tatttataat ttcttcacat
360ggttttccaa gtattttttc ttctctatat tgtatcttca tacttgtgaa
tttccaaagt 420ttcactgcta aaactgataa aactgtatca gttatcacaa
tgtacaggca ctgtaatatg 480cacaattaat tttcttttaa attcagcatg
tcaataaaag tgtggaataa atcattcttt 540attgatggga atttaaagtc
aaaataatga accaattttt aaatggattt cctttgtga 599122599DNAHomo sapiens
122aacatctaga agttagaaaa tgaacatgtt tggatattag
tatggcaaag acagactcac 60ttcattagtt tgctatccct tatctcaggt aatactccta
tccacaatta taaaatgagc 120ggaaaaagta aaactgaaaa taaaggtagg
aggaacaggt attagacact atttggatct 180actcatgttt catttaattt
tcttatcaat ttactacaaa taaccagatt ttttttataa 240cttgtttaaa
aataccctaa catccattca aaatgctgct gcataaacac aaatctgaak
300tggaatctta gcactgctat acaatcactt tttaaagtgc aaataagaac
aatatgtagc 360gaattaactg ataaagatgt acaaatatga atcaaattta
ttttacttaa ctatagaata 420ccttcaaaat ccatgaaaac ataaaccaga
tttaaaatac cattcttaca atgaaacaac 480tatttaaaca ttcattcttt
aacagggtcg attttgaaac tatttattct ctcctactag 540aacattatag
tcttcttaaa gaaaaacagt catgtgatta tataaactaa actcttgca
599123599DNAHomo sapiens 123caggagaatg gtgtgaaccc gggaggcaga
gcttgcagtg agctgagatc gcgacactgc 60aatccagcct gggcgacaca gtgagactcc
gtctcaaaaa taaataaata aataaataaa 120taaaagatat ggtatagaaa
gcatcaaagg gcagagaagt gctctagtcc tggccttgcc 180aatttttaaa
catagtttta actatgggaa agtcatttaa ccatttcagt gcccttaatc
240caaagataat actatccagc caacttgttt tgataaaccg aagtattaat
atgggcgacy 300gcacaaatgc aaaatgttat tatggggagg gaggggaata
catctatcta ccttgatgca 360gtttagtgaa acttcaatga ttctgtctcc
ctacattttc ctagatctaa aataaaatct 420aaagtttata gattcagtag
catcaataat taaaattatt ctaaagaaca gcattagaaa 480ttcttaagat
taagttctga gcatcaaaag cagctattaa aactatgcag cacatagaaa
540ggagtggtaa taaaacaggt aaatgctgaa ggaaagagct aggattagga taaagagaa
599124599DNAHomo sapiens 124tgtgacctcc acctcccagg ttcaagtggt
tctcatgcct cagcctcctg agtagctggg 60attacagatg tgcaccacta cacccagtta
atttctgtat ctttactaga gatggggttt 120cgccctggtg accaggctgg
tctcgaactc ctggcctcaa gtaatccacc caccttggcc 180tcccaacgtg
ctgggattac aggctataaa tgtgttttaa ataaatgagg aagaatgaat
240taaaaatcga taaatatgat tattttaaaa aagaccaaaa tgtctaacat
aatttgaacr 300gatacactct cttttccata agcctacctc tagttccacg
aatgttacta agatcaataa 360gccaaagagt aagatattat agtcttttga
ccaaagaaaa ataaaatgtt aaaaccaagt 420tatggatatt aaaaataatg
ttacgtaaat ggtgaaaagg ggcaatgaca taagatatac 480ctcttctaag
gtgtatgaaa gaaaaggaag tagggagaga tcatgtaacc tcagcaaaaa
540caaaacaaaa caaaatctga ggattaaaag tgagagggag agaacaacaa gcgaatgaa
599125599DNAHomo sapiens 125catttgtgtg ctcactggag tagcacgttt
aatttccttc aagaactttt gctttacatt 60cacaacttgg ctaactcttt taacatgcat
tcctcactcg ccttaatctt ttctaacttt 120tgaattaaag tgagagacct
gagactcttc ctctcacttg aacactaaga ggccattgta 180gggttattaa
ttggattaat ttcaataggc aggcccaagg agagaaaaat ggggaagggc
240cagttggtgg agcaatcaga acacatgcaa cattcattaa gttcgccata
agggtgcagk 300tcatggcacc ctaaaaagac ttacaatagg aacatcagag
attatagatc accataacag 360ttataataat aatgaaaaag cttgaaatat
tgtgagaagt atcgaaatgt gaaagagaca 420agacttgagc atatgttgtt
agaaaaatga tgctgacaga cttgctttac tcagggtttt 480cacaaatata
caatttgtaa aaaatacagt atttgcaaaa tgcaataaag gcacaatgaa
540acagggtacg tctgtattag catttttcat aaagcctagg cagtgtctag taacacatt
599126599DNAHomo sapiens 126ttaaagaaat caacgactaa cattgattaa
cactgaatga ctaatattct ttgagtgtgc 60gggatggcaa ctaagaaaca acttgtccaa
acactgaaac tccctctact tatgagatag 120aactggctga aatcagttgg
aaccaagatg gccaactgga gtctgcacag aacaagcttg 180ctgacatcat
agcctgacta tctaccacat ttcatactaa ctaccctaga atttgcacat
240gtgacccatg aggtatcata atgagttaac tgtgcatgcc cagggacatt
ccagacctcm 300cctttccttc caccaaacac ctactaatct cagaattcac
ccctactgaa cctgtaataa 360aaatactgcc ttgaaaccag catgaggaga
cagatttgag cttgacccct gagtcttctt 420gggagttgac tttcaatata
aagcttttct tttctcaaaa acccagtgtc atagtattgg 480cttctagtac
actgggcagc aagccccctc tgctcaataa cacaagcaga aaactgtaca
540cattgggaaa cagtttactt ctgttcagat aacttgagaa accttaaaat taaaatatt
599127599DNAHomo sapiens 127tgtgacccat gaggtatcat aatgagttaa
ctgtgcatgc ccagggacat tccagacctc 60ccctttcctt ccaccaaaca cctactaatc
tcagaattca cccctactga acctgtaata 120aaaatactgc cttgaaacca
gcatgaggag acagatttga gcttgacccc tgagtcttct 180tgggagttga
ctttcaatat aaagcttttc ttttctcaaa aacccagtgt catagtattg
240gcttctagta cactgggcag caagccccct ctgctcaata acacaagcag
aaaactgtay 300acattgggaa acagtttact tctgttcaga taacttgaga
aaccttaaaa ttaaaatatt 360gacctatgta cctaaaagag aggcataaat
tatacaaaga ttactacttt gacatgaaaa 420taaaagaaat tatgtgattt
tttaactaaa aatatcttag agaatttggc attccttgaa 480aacctactgt
tatctggcag agtcaacaag gagaatttta atttctcttg aggctacttt
540acagcttttg agtcagagat ctcatctctt attgccatta gaataagcag tagaaatga
599128599DNAHomo sapiens 128actgcttaaa acagtggctg gttcataaaa
ctctgaagtt cattaaagga atgcataaac 60tcattttctt tattatacca tattaattag
aatcagagag acaatttatg tttctgaaaa 120ggggggaaaa ctctgctttt
tatatggcgt tccatgtact tttgagtgcc ttagttgtga 180aaattcatta
actctgcttt tctccgttaa atgtcactta aggaaatgat tttaaaacca
240agtaaaaaac attaaaaggc taaaagagaa ttagtgaaca aaatctgact
tggcaattay 300gctatttccc tccttgggtt tttctcatta aaataattgg
gaaagcaccc attcttaaaa 360tactgtcata caaaataatg atacattttc
ctaatacaga atttcattat caattacaat 420gatttccttt ttaattcttg
tataccattt ataaataaga ttttatttgg ataaaaaata 480aaagataaaa
tttacttaaa tctataagta gcagtaggaa aaacctaatg actgctttct
540attttgttca gtactaatta tatgcattat ttcatgtaat cccacaaaaa tcctatgtg
599129599DNAHomo sapiens 129caagagaatc ccttggaaaa agctttcaaa
tatatataca caaatatctt agaaataaat 60ctgcaaggtc ttaaaatacc aattatataa
aaaggaaata ctggttgatc cattaccaaa 120ttgttacctc caaaaataat
aacagtatgt tctctcacag gagtgtttca ctggtcaatc 180atgatctact
atcttaaagg ctgattctat ctattttcaa gactgatttc cataggacta
240gttagcgtct agtctgtgcc tagtgaaatg caaaaaacac tcagcaccca
ctttattaay 300gagcaatatg aatagtgaac atatgtgtac cctaccacca
cttgaagtga aaataataaa 360aatacaagaa tttttcaaaa aaatagtgcc
ctcatatctt cgttatttct tattgtaagg 420taacattctg aaatctgtaa
ctccaaacca ccagtaaaaa attacaaatg agactgaatt 480tagcaaaaca
aattctatca cattcttaaa aaataaacat ctttagactt tggtaagacc
540atataaaata gtacagtgct acttttcttc tcttaattga tgtgctttca actaaagaa
599130599DNAHomo sapiens 130ttcacctata agcaatattt cctcaattac
atatatgaat ataaataata ctttagcaat 60tacttacagt aaatatccgt ctgccagttc
gatcaaaagt tacacagtac acagatgaca 120agtgtccaag aattcgttta
tgcattttca tgtgctgata cactgcagtt ggaacaagtc 180gctcaagtct
gtatttccca ttcagcttcc ttgaaaacag agtatccgct accaagaaaa
240agaaggaaaa taaatgtaat ctggaaatta attttcttac atgatcacct
tttaagaaty 300cacatactcc aatttgtcat gtgcaggtaa aaataaagaa
gctttctgat atatatggct 360tctagttaaa agtctttaaa gtaatgaata
aaaacattgt ttcacctgaa ataagtcagg 420cactatcatt ctcactttat
aacttaattt gtaagttaaa tgacctgtcc aaaaatcaca 480aagtaaggca
tgaagctagg attaaagctc agatttattt actctctggc tagtgctctt
540taaaaaccta aagcatttat atgttatttc cttaaaagct gtctatgaaa tagtttttc
599131599DNAHomo sapiens 131caaaggcact taaaactgga acccagtgta
cttttcataa atcagtaaca cttgaacact 60cgaaatctga catgcagaat gatatttaaa
aacatcttta taacaagtga agataaagga 120atacgtcatt tgcattatta
aaaaataata attaaactgg gaatcttgcc aaacacctgt 180ataatgattc
cttctctgga atctattagc tctcccttag ttctcccttt caactcattc
240attctaatca ttattcaaga tctgactgaa gtttatcttc tgtcccaaag
cttgatacay 300tgactccagc tgaaaatgtc ctcttccatc taaattacta
ctgtacttat tttctatact 360ggtaacttat ggacaaagaa ggtgctcaat
aaatatatgt tgactgatct gcaggcacat 420tattaaccta cagatgatct
tctaatacag gctttttttt ttttttctaa cagtgactgc 480catctacatt
gggtaattag cactagggtt tctcggtcga atttagccct aaagaaaact
540aaatatatat acaaaatact acttagccaa ggtacagagc ccagtaatta tgccctaaa
599132599DNAHomo sapiens 132aaaggaagat ttatctcaca gattaaaata
ttcaaaatat ctctaaatag tgcttcattt 60taactgccct gctaaatgaa tttaattggg
aaataagggg agaacgtatt cacttaattt 120tctgaatata gaggataaat
gaaataaaaa ttccagaaat cactgttatc catttgaata 180aagtctgaag
taaaaaagga gcaaaatact gaagcatgtc atttgcagca aatcattcag
240aacagccttt gaaataaagt atatgtgctc aagtctacaa agccaattag
tagagatcar 300caaaaggccc acaacttctt aaacattaga tgtgactatg
cgcatattca gcccttgggt 360tctcatccat tacttcttta ggtgctagga
taataagtca aattccccca taagtcactt 420cttacttcac acctagttat
ttttcgagaa ctgatttact tatccaatca taatactaat 480gcatattcaa
tttagaaaag aacataaatg aaagaaaaac ccataattct attgtctata
540gcaatcactt ttaaaatttc gcaaaggttt acctcaaaaa cagcatttta acagctatg
599133599DNAHomo sapiens 133tttaacttta ctaccaaact gacatctttc
tatctagaac atggtgcttt cttcctgttg 60ttgggcccaa attttcaatg cagatgattt
tttaaaaaga taaacataat aaagttacct 120cattttctct cactacatca
tttgaaccaa gttcacaaag aaagaaaaag gtagctgcca 180taaaagagta
tctgtaataa ccttagtaaa tacatttttg aaggcactag aaaaatacat
240gataaaaaaa accctgcaaa taagtactat agcagaaata ccattacctc
cctacaaaak 300gtttagactt ttttctcctt ttgcaaagat ctttgtaaaa
tgaacaagca cacatgataa 360agctgcaata aattacccaa gatcaaaatt
aaccatggtt aaaaaagatg acttggaaaa 420aaatgaaaat gactatgaat
taacaaaata caaaggttag tgttttttgt tattattgtt 480ttctaactgt
taataacaat ataatatgct atataatacc tactccagtg taggaaagct
540gttccctctt aatcagaaat ggaggaccac aaaaacagtg cttacaactt ctgccaact
599134599DNAHomo sapiens 134ggttctaaac acgttggggc tgaggggtgg
atatctggga gtctgggaaa acttctctga 60aaaactgaca tttaaactaa gacctgaaaa
atgaacagcc acagaatgct gatgtgagcg 120cagcatattc caggttgagg
aaacagcatg tgcaatagcc tgaggctgga aagagcatag 180cattcaagca
acatgaagaa gtcaagattg acttgcacac agagtagaga aagggcaagt
240gtcaagagaa gagactgaga aggtagggga gcggactata tagagtgctt
tctaagctar 300gttaggtatt ttggactaaa ttccagtaat aacgggttga
agttttgggg gagaaaagaa 360tggagtaata tacatagtaa gatttacttt
gggataactc attgcagttt tctcttgacc 420acaatgagaa tgaattggaa
aggatataag taaaagcaaa agctaacttt gcaaaaaaat 480caaagggttc
tgaaaacaaa atttcatttt agaaaaaatt taatcagctt gacaccaaaa
540ttatcaacac tttcccaagg aattaaatac ctgatctcat aagtatctgg cactatata
599135599DNAHomo sapiens 135cctagagata aaaagtttac tttgctaaca
tgtcaaatgt aagaaaaatg caaacaaagc 60aatcagcaga aattgcttta atttaatgta
ttacaatctt tttcacaaga taaacatgca 120ttaaaccaac ttccaaattt
aatcttaaaa acccctttaa tgtatttagg tctcttcttt 180cctatctccc
cttactcatg cacatttatt actgaagtat aagcaaatat agaataaact
240atatctgaaa acaggcataa tgtgggtatg gaggtaagag aaaggacaat
actaaagatw 300cgctaatacc tttggaagta aatgctgcta tgccaagtac
acactcacat ctctcttcca 360caataaaaga atcacaagct agtaataaca
acagatcagt gggatctttt gtctttgctt 420ttgaaaacag tattaaagga
ggttctagag cactggaagg caggtgaacc actttgggtc 480tcttgctgag
actgagttct agttcaattt tcacaactta catcaaagac caaaaggttc
540aaagtagttg ggaattctaa gcacataata aaataaaaca ggataagaaa acactgaga
599136599DNAHomo sapiens 136gcatttaaaa gaaaacttac caaaatgagt
ttttaaaatc gtatactttt ctttaatctt 60ccccaaaata atttactcaa aaataaaatt
tagaagtcta gaatacttgt aaggttgctt 120ccagttctaa gcttgcaaat
gattatttta atgtgactta attgatcaaa attcctttta 180aaaattttac
tttaaagaag atggaagttc attacttatt aacttcagat gtgtgatgat
240cctgttttag tatcctctgg caaaatatat tttcaggtag tgaaactgaa
aatccttack 300gtaatattct atctttcaat aaaatattat gaatccactc
tgactcaagc tttctttggt 360gatttagaat gtttgaattt ttcaaaatca
actttcattt taaagttaga agagatactt 420ccagttctta aattccttgt
gctttctctg gcttttgaga ctttatacaa gctgatgcct 480ctgctggcaa
tcttgtctta cctgctcacc tctacacctc attctccttc atgtctcagt
540ctatgtctca ctcactgcct tccatgacct atttacacca cctgtgcccc tttttggac
599137599DNAHomo sapiens 137tttctcagta atctgccata caatattatt
tcaggggaaa aataacccct caagatcccc 60aatttctgat atacgagtta ctttctgtga
ccctaagtgc tttcaaattc ttaacattca 120agacataaaa agtatgacca
gattataaag tcagtgtgat aaattatact aatatagcta 180acacatattg
gctgcacact gaatgccagg ccctatggta agtgtggtaa gttttacatg
240gaactactca taactctgag aggtatatac tatcattatt cccattctat
aaaaaaattr 300tagaatttat ttaaaaagat attgagacct tcccaagttc
aaacacagca cataagagag 360tcaaaccata gcaatctaac tctggaccct
acaattcata ctatcacaca aatgacctat 420tacctcaaat atgtgtatat
atcaatgtgc aagatataag caagtcatac aacagacatt 480ttgaatagtt
ttcaacagac attaaactga gccagaaaaa gagaaacatt tcacagttca
540cttgcactac taaggaaact agcataaaag cataaattcc tataggtaaa agggaacac
599138599DNAHomo sapiens 138caatttctga tatacgagtt actttctgtg
accctaagtg ctttcaaatt cttaacattc 60aagacataaa aagtatgacc agattataaa
gtcagtgtga taaattatac taatatagct 120aacacatatt ggctgcacac
tgaatgccag gccctatggt aagtgtggta agttttacat 180ggaactactc
ataactctga gaggtatata ctatcattat tcccattcta taaaaaaatt
240atagaattta tttaaaaaga tattgagacc ttcccaagtt caaacacagc
acataagagr 300gtcaaaccat agcaatctaa ctctggaccc tacaattcat
actatcacac aaatgaccta 360ttacctcaaa tatgtgtata tatcaatgtg
caagatataa gcaagtcata caacagacat 420tttgaatagt tttcaacaga
cattaaactg agccagaaaa agagaaacat ttcacagttc 480acttgcacta
ctaaggaaac tagcataaaa gcataaattc ctataggtaa aagggaacac
540tttaaaaaat tctaagggta aaagtagaag ataaaactac aatatttata agattatac
599139599DNAHomo sapiens 139gcctattatt tctttataat tataataaaa
ttaatataga accttattaa gtgtaaaaat 60cttgatggtc tatttgctca agtaattgtg
aataaacaag cttcaaagaa tatgtcatat 120tcagaattta cttaactgtt
aagaattcat ttagataata attcagttta cattatcaat 180acaaatacca
acacaaattt gtcatttaaa gaaaatgcaa tactataaga aaaacaaaca
240aaaaaagaaa atgcaatact acgcttccaa attttattca tcataaacca
attacatctk 300gctaaaaaaa agagactcta ttcagaattg aggtttccat
aaaccaaagt agggatgctc 360cataaaaaat aatttaaaat acaacaaaat
gacaacattt aactgcttaa aataacaaat 420tttcaagttt tgatgtttaa
gtcgtcatat gtgctaattt gtgtaatttt aaaattctct 480ttaaagcatt
attagtaaaa cgttaaactc aaatctagga atctgatgaa aagttactgt
540gtattaattt aaggacgaaa catcctttaa ctgcttatac taaggccaat gtaaataat
599140599DNAHomo sapiens 140ctagattcac tattcaaact aagaaataaa
caaatgacaa agctttcctt tcgtccaaaa 60aaagtttttt attctacagt ttaagaattc
tgatacttgg aaaaagtgcc ccttttcttt 120aaaataaatc tcatatttta
aaaaatgtaa aatctaatta aacgtatacc atagtaccaa 180aaacaacttt
tagcttccta tccaattcca tttactttgt taaaaatgtt ttaaatctta
240aggtagatgg tgataatcag tcatgtttta taccagagac agaaacaacc
ataagatacs 300accatttcct ttctcaatca cacttgaaat gaacgcatca
attttaacct gcaaactttt 360aaaactgctc ttaaaattct actttcctct
tgattaaaat tcaaccattg cgattgtaac 420tagactaact acagatgatc
agtgactatt tttaaattca catctacaaa tattacaccc 480cattttaagc
agcaataatt tgaggtttcc tagaaatttc aatgcgatgt gatatatgag
540ttctcccatt taaaatattg ctcagtttat tagttaatac aacaaatcat ttccaggta
599141599DNAHomo sapiens 141aattaaatta actcaaaatc aaaattgata
gctcattttt actgaaaaaa aaaacaaaaa 60aacaaaatga tattcctacg aggattagcc
attaccataa tttagccaga taacattaag 120ctgcttcatt taaaaaatgt
aacattacca aaagattaag aaaatgcagc attcctcagt 180gacttaaggt
ttgtgggttt ttaagagatg cacagatgta aaagcagatg caaagacgag
240ttttgtaaaa cctgccccat cttaaaaatg gagtattata atctttgcga
taatttttty 300aaatatcaag gaagacatgt aaattcactg aagacttcta
tcaagtattt gtaaacctaa 360aaattaattt caaattagta aatcttggag
tttacttcca gctccattca ctttggccaa 420gaattgaatg aaagtaaccc
aaatcactcc ttgaaaatta acacacgttc agtgtgaaaa 480tgaatacact
aatacactgt taaatctcca ttagatgtat taaacctcag tacccttgct
540tatttcaaca gccttgagcg gttatcaaca tcttatatta aaccacaaga gatttatac
599142599DNAHomo sapiens 142gccctatact aaaacatcca gaaatcatca
tacatatgag gaagaagaaa taaagcctca 60aaccctttgg aataatagga tataaaattg
ccttttgtaa ctgaatctta aaaatggaag 120gttaccatga cttgtcctat
tgcaacctgg ttatcagaat aacttatttt ttttaagata 180gctattctca
aatactgaac atatttgcat ctttaaagac actttattct attcaattat
240aggtaaagta gcctatttct aggtggttag gcttgaaaag atagactgaa
aagataggam 300attttgtatg cctttttgca aattgtattt acttctaaga
ccgatgctgt tttagcttaa 360cttttaaaaa agtgttcttc aaataattgt
aatattttac acgatcttga agttcttcaa 420ataaacagag tttagaaact
aaaaattata gtgggatttt ctggttttga aggcttggaa 480tgtatgattc
ttactaatag atgttttatt cttgtgattg aaaataaacc aaattatgac
540atggaatata atattactct gggtaaagtt tgtgatatat atcttctgtg tgttttgta
599143599DNAHomo sapiens 143gttaatcacc caactttttt cctgttatta
ttttatgatc ttttcccttt ttactactca 60taatatttta atagaaattt ttttaatgtt
aaaaaagatg aaaaaaataa gaacttctgt 120cacaagttct ggtgttctgc
attgctgtga agctgtgttt tttttttcct gggcaaaatt 180atttaagatg
acataaaaac ccaaagtcaa cctctaacat ctgtccttgg cccttatatg
240tcattcctac tactatagta ttctcattgc agcgttattc ctttctctct
gtgtgtcagy 300tgaagaacca tcatttaaac acttgcagtt tgaccctcat
tatgtacttt gtttcaacac 360atggagatgc ccagcttact agaggctgat
aatctgaagc agcagtgacc cctctaacca 420caacatctgg aaaacaaagg
ttgcataatc tggctagtct ccagaaattt tcagttatta 480aaatctgact
ttgtttaaca gcaataactc aatttattga atggattgca agagatatga
540atcaatggct atatatacca ttcaaattta actgcaaaga attcacattt ttgaaacaa
599144599DNAHomo sapiens 144aaactgctaa caaatatcat tcaactgctt
aaaccccatc catgatgctt catgagtcct 60ggacagtcct tagtatgata tgtgagatcc
ttcatgatct gccctccctc gaactctcca 120cactcagttt tatccaccag
agcataatca ttctaaattc tttctgtatg gaaatattta 180gttttccaga
tatgtctcct ttattttttt gcacatactg gcctctctat aatcttcatc
240tccaaaccag gccaattcca atgtggtttt caagagacag cccattcttt
gcctctttgr 300gaaaccttac cctgtgtctt tcctcccagc aaacaaacaa
ctaggtgttc atcctttgtg 360cttccagaga atcttctgta tatctctaca
gtggtatagc attcagatag tttattgttt 420tatagtgctc ttcctcacta
actaaactaa gaggtttttt ttagaatagt tcctgaacgt 480tagatttctg
tattatgtgg cacaattcag aacatacaat gggtatttaa taaattcagt
540gggttttttt ccttggaatg tgttggttaa ataaataaac tatggtcatt tctggagat
599145599DNAHomo sapiens 145gctaacacat atcaaatatt tagtatgata
catagtacca tgggatatgc cagacactgt 60taactactta ataaatatta cctaatttaa
tcttcataag gcctgtataa ggaaggcaat 120gttacctccc ccactttaaa
gatcaaagag actgaggcaa agaatgataa aacatcttgt 180cctaagtcat
gaattagtga ttaataaagt caggaataaa acctaggaag gttgctccag
240agccttcact cttagccagt caatctcctg actcctatgc tattaatatg
cataaacccw 300tttccatgca cagaactagg tacataataa gggcttaata
aatgttggat aatactattt 360ttatactttc tcatgtggac aaagaaaggg
atgcctaata ttgactaaag gtttactcta 420agcataaggt attctcttta
caactaacct ggaaggcaca cagaggccca gggaggttcc 480atggctcaac
cacagtcaga agccagtaag gacacaacca ggattcagaa gacattggtc
540ttggtccaaa gcccatggtc ttattactac attccaacat gaactcttat
ttggatcaa
599146599DNAHomo sapiens 146tttttcttgg ctgaataata ttccattgtg
tatgtggtgt gtatgtatgt gtatatactt 60acatacatat gtatacatat acacacacac
atacatacac accacatttt cttttctatt 120catctgttga caggcactta
ggctgtttcc atatcttgtc tatagagaat aatgctgaag 180caaatattgg
agtgcagata tctctttgac acacaaattt cattcctttt ggatatatac
240ctagacgtgg gattgctgga tcatatggta gttctatttt aattttttga
ggaaacctcm 300tactcttttc tacaatgtct gtagcaattt acattcccac
caacaatata aagagaatgg 360gtttcttttc tccactttct caccaacact
tattatcttt tgactttttg ataataatct 420tcctatcagg agtaagatga
tatctcattt tggttttgat ttatatgccc ctgatgatta 480gggtattagt
cagggttctc tagagggaca gaactaacag gatagatgca tatataaagg
540agagtctatt aaggtgtatt gacccacatg atcataaaag ttccacaatc tgctgtctg
599147599DNAHomo sapiens 147ttttctattc atctgttgac aggcacttag
gctgtttcca tatcttgtct atagagaata 60atgctgaagc aaatattgga gtgcagatat
ctctttgaca cacaaatttc attccttttg 120gatatatacc tagacgtggg
attgctggat catatggtag ttctatttta attttttgag 180gaaacctcat
actcttttct acaatgtctg tagcaattta cattcccacc aacaatataa
240agagaatggg tttcttttct ccactttctc accaacactt attatctttt
gactttttgr 300taataatctt cctatcagga gtaagatgat atctcatttt
ggttttgatt tatatgcccc 360tgatgattag ggtattagtc agggttctct
agagggacag aactaacagg atagatgcat 420atataaagga gagtctatta
aggtgtattg acccacatga tcataaaagt tccacaatct 480gctgtctgca
agctgaggag caaggaagcc agtctgaatc ccaaaacctc aaaagcaggg
540aagccaacag tgcagccttc agtttgtggt cgaaggtcca agagtccaaa agctgaaga
599148599DNAHomo sapiens 148gtgaggactt tctggcactt cagataggaa
aataggggta caaatactat gattatattc 60aataaacaaa atggtttatt tcaatggtgg
gtccctgaca cattctgaaa ttttgctctc 120caatactaac ttttgaaggt
ttaaaaagtc actaaatatg acaaaattat gttgatttaa 180aatatttctt
ctttgattct ggggtcattt gctccatttt ctacagcttc aaaaccacaa
240atataagtga gtagaaatat ttaatgcttt ttagtttttt gtctattttc
tataaatatm 300ttgagactgg cctgattata cagtctaagg aaggaaaacg
gtgtcagagc aaatcttcat 360tttattaata aaaatctaag aaataagagg
aagtaagaaa tgttgcttca agtaaaacag 420aaataaaaac caagcaacta
aaaacaacaa aaaagaacat attttcatga aaaataaact 480ggtgatgtgg
gagcagaaaa gagaaggaaa ataatcttga aataaccttt taaagtcaga
540tgtattcaac tcatcagaac aaggaaaaga tgacaataaa agtttagaga gttgattac
599149599DNAHomo sapiens 149gcaagttatg ggaacctctt tgcactttac
attactcatc tgtgcagaga attatggcat 60ctttcctgtt gttattgagt tgttggaaga
aaaaatatga cagtgctttg taataataaa 120acttatacat ataaggggat
tgtaataatt aaaattcata aagaaaatgg ttgatgagat 180cgcccagcca
ctgttatctt tgaggactca tgaaagcaat agttggaaat aatttctctc
240tcttgattag acacactgtg gagttagtgt tgcacccagt ttttgtctcc
ttaccttaay 300aaggatgctg tgaagttaag gagtttggag tagattaata
atatgattaa agtgttgaat 360aaataagacc catgagaaaa ggagtttgaa
ttaattagtc tggaaataat aactgccttc 420taatacatga agcattatta
caagaaaaat atagaccatt tctcttctct gagaaatgac 480ttgaaagtaa
ctgtggacat ataacacaga cataagaagg aattcactga tagggttgag
540agttaaatat taaaacagga tataagaaga atatttggca tctcctttgc tgctaacta
599150599DNAHomo sapiens 150ggcttctgcc attttgaaga aaaatctggc
aaagtcattg tgcatatatc atatgattat 60ctgatctcac tcttaaagag aaagggggag
ataaaaattt tataaaagaa tgtaagataa 120tatgtttttt cacaacattg
tttatgaagg cagggaactg gaagcaacat tgttgtccat 180tattagagga
ctatactaaa ataaggttgt ggaggcatac tactgaatac cacatggtag
240ttagaaacaa catagatctt aaaagtgtaa tgctttgtga aaaacagaag
aaaatgaatr 300ggttccattt atgtaaattt aaaagtatac acaaaaaaat
gacactacat gtttctaaag 360atacatataa atttgagaat gtatatcaaa
cacattagag cagttacctg tttgggaggg 420agtagaatat gataacaaga
agaaatcagt ttaaaattgc tttttttttt tttgctttgc 480tcaaatcaat
gatgataatg tgccatgaac cagagtctgc atctatctca ctctcctctc
540tttttcttta aaaaaaaaaa aaaaaaagga aagaaagcta catacattgt aaaatagta
599151599DNAHomo sapiens 151gtcatttttt tgtgtatact tttaaattta
cataaatgga acccattcat tttcttctgt 60ttttcacaaa gcattacact tttaagatct
atgttgtttc taactaccat gtggtattca 120gtagtatgcc tccacaacct
tattttagta tagtcctcta ataatggaca acaatgttgc 180ttccagttcc
ctgccttcat aaacaatgtt gtgaaaaaac atattatctt acattctttt
240ataaaatttt tatctccccc tttctcttta agagtgagat cagataatca
tatgatatay 300gcacaatgac tttgccagat ttttcttcaa aatggcagaa
gccaaatatg aagaaatact 360catttatcca ttaacaatta atattatcaa
aatcagcaat tttttcccat atgatggatg 420taaagtagta tctcattgtt
aaatttattt tctatttact gagataatat actaattatc 480catatatttt
ccatctttct aggtttttag tcttgctgat tctaggagtt tcttccatag
540tacctttatc attcctttgt ctgtttctta tgtctgttca attcatctat ttgtctatt
599152599DNAHomo sapiens 152aaaaaccttg gaatatgctt ggcttttcta
ttgtcttgtc catcagtaaa atctaacttg 60tctattgcca caattctagt tcaagtcatc
attatctttt gcctatactc tcctaattgg 120tgtccctggt tctgcttttg
tctctctaca ggatacttta tagcagccca ggtgatttat 180ctaaaacata
attttaataa tatctgcttt aagttttcca agggcttcct acttcactct
240caataaaaat aaaaatcctt gccttgactt ccaataaatg atctggtccc
acgccaccty 300tcttacctcc ttttctaaca ggcttccctt cccatcctac
ctctcaactc cacttcagta 360gcactaggct tcttgttcct tgaacagaga
aagcatactt ctaatttagg ggctttatca 420cctgcagctc cctccatctg
gaatgctctt atttcagatt tttgtacggc ttagttcctc 480acttttttca
gggttctgct tgaatatcat cttatcttga ggacattccc ttaacactct
540ttaactcaca ggcaaagatg gagaatcaaa catgtgcatt tcccttagca ccctcttca
599153599DNAHomo sapiens 153atggcagtta atgattgtat tttaagccta
taaactcaca aagacaaaaa gaacaaagaa 60gactctaatg acaaaatttt ggaaggtgga
gagaagagat aacaaaacac acacacatac 120acaacacaca cacacacaca
cacacacacc atgactatcc attcctctta cctagcttta 180tttttcttaa
tagcacttca cctagataaa tgtaagtaaa tataaacaca agatatatat
240tgatttttac atttgtttgt tgtcgcttcc tttttgcttc cagaacataa
gctgcatgay 300agcaatcttt tcagttttgt tttggtgttg cattctcaag
ctttggaatc atagcagaat 360caaattcagt ataaattttt gactgaataa
ctgaggtgga ctggatgagt gtagtttgtg 420tgaggtgtgg ggttgtggga
atcaagtgtt caattttgaa tgttaacttg aggtgtctat 480tagacatcta
agtgatgata tcaagtgaaa tccgcatatc tgaggctaag tcatggctaa
540aattataaat tttagagtca tcaacattgg ctctaaagaa gatcacctgg ggggactat
599154599DNAHomo sapiens 154agccaagctc caagccttgg aggacaacac
catttagaga tcaggcagag cagaggtctt 60tgaaccttat aattatacac tacaatttgt
aagaagaaga aaaactaatt taaactaagc 120aatgtgatat gtagatattt
atctataaat aatatatatg tatctttgca caaatatatt 180atgtacatta
caaaatacac agacacagat attaaaaaag aatgagctga acaacttcca
240gttaaagagg aagtattgaa cacatgcatt tttcagctcc ctgctaaagg
cccactacar 300tgatagtaaa tggattttaa aaaataaggt ataaacccac
aaggacaaag agaacagcag 360acaaacaata ccaccaaaat ataggaagct
gtaaagaaga aagacaaata acaactgact 420cacagactca ggaaagctga
ggctgcagtg gagaaaaagc agagatacaa cctgatttac 480aatacagaat
cagccatgcc cctgccccct tgcaaaggct cagaaattgt ttctggcact
540tctgctagtg gaggttaatg ttgggcaata atagacttag ctgaatgtct gtttgagaa
599155599DNAHomo sapiens 155catgcccctg cccccttgca aaggctcaga
aattgtttct ggcacttctg ctagtggagg 60ttaatgttgg gcaataatag acttagctga
atgtctgttt gagaagcaga tacatccaca 120gacaccccca ccactctaca
ctaccaagtg actaacctct accaggcagc aacagcctgg 180agacttattt
tctgaagagg gttaagaggg gatcttgctt gcagaacaac aggcacacgt
240gaatgggaat tccaagtgga aagcagggag attaagtcaa agttaatatc
agaatgcttr 300aaaccaaaat attaagaata atttctattt gttactaagg
gatgtggagg caaataaaaa 360gaacactatt ttgttgtgta gcaatgattg
ccaatggaat tcacctacat aaaaagaatt 420ttaaaataat gaactgctat
ataacatttt ctttatttct tagagctatt tcaaatattt 480atttctattt
cttttaaagt gcatggattg tttgaacatt atcttggtac atgaatgcag
540gcattttaaa gtaattgcat ttgttgtatc ctggattaga agcaggcata aatattgat
599156599DNAHomo sapiens 156atgccatgaa tgtgattgtg gttacactct
atgcccaatt gtccaaattc agtgaagtat 60gcacttaagc ttgatgaatt ttatttatgt
aaattatact ataataaaac tcacaaaaat 120gtttaacaga gagaaaacaa
acagtgggag aaaaaatcct ttcagtacca ctacatttct 180catagtaaag
ttggctaagt catatcagtc atatgtgtgt gggcaagagg agggttgtcc
240caaggcaatg ggtgttgaac agaggaaata ggggactttc tgaaatgtcc
atagaggagy 300gacaaaagga gtaacctggt tcagggagta gaggaagggt
aactaaggaa cagctgaggg 360tgtggggcca tttcgaacaa aactctttca
ttatttacat ggtccttcat gatctgggcc 420ttgcctgtgt ctccaactca
cttgcctacc ctctctctca gtctgttttt actctgactt 480cttgtttagc
tctttcttaa gtttctttgt gcactcctca tagctctatg ctgggccctg
540cttttttttt tttttttttt ttccacttac accctttgtt ctctttaggt caattatcc
599157599DNAHomo sapiens 157tgagaagtaa gtaacaaaaa aactataatc
cttaaaaaaa tcagttgaat taacaaaggc 60acttgcttca cacaagatta aattaggcca
tatgaaaagt tactttgcat aatctcttca 120tgactttgca tctagttatt
tccaagctaa tatatctagc ctctaattca aaaagaattg 180tagacatgac
tttattatct tccttatgga aaatttcttg ataaaaatta ggttgcttca
240ctattgattt gaatctaatt ttagcagtgg ttagaagttc caacacagct
ttctacaagk 300atttgagatt tgacatccat cttagtaggt gttgatttac
tttctgtttt aagcagtttc 360cacattaggg atttggggct cattctaccc
acaaacccta ataattgcct aggtataatg 420ctactctgca tatatcacat
gactggtgga aaaataaatc attcatttaa caaatattga 480tcaaagttct
gctgtgtgcc aactattatg gcaagtgtgg aagaatcaga attaactaag
540aagaaaaaac agacatggaa acatttcaag gaagaactag ctagaaggga aggatacag
599158599DNAHomo sapiens 158ctcctttaaa aaaattggaa ctgtattttc
atcagtgaaa ccctctgctt taaaatctca 60gtgtcattgc caaagactaa atacattgac
cttggactca attttgagct acacattcat 120ttctctagaa tgttggtaaa
agttgcagaa gtagagtcat ctgtatattt ctcttcaagt 180ccttaaactt
ttagtaaacc attatttatg gatctaacac acttgtaaac aatgccagca
240acatattatt tgtcctgcat gcttataaaa ttcttttttt tttttttggt
catggttagr 300tgattcccgg taactacatt ttaattctaa ttctgagaag
taagtaacaa aaaaactata 360atccttaaaa aaatcagttg aattaacaaa
ggcacttgct tcacacaaga ttaaattagg 420ccatatgaaa agttactttg
cataatctct tcatgacttt gcatctagtt atttccaagc 480taatatatct
agcctctaat tcaaaaagaa ttgtagacat gactttatta tcttccttat
540ggaaaatttc ttgataaaaa ttaggttgct tcactattga tttgaatcta attttagca
599159599DNAHomo sapiens 159ttttctggtt tcttctcatt tgctaaagga
aggcctaggg ctcaaggcta ttgtttagat 60tcttttgtcc catgggttgt tcccttgagg
tagtagtctc tcccttttcc tagggaggtg 120gcttcctgag agccaagctg
tagtgattgt tatctctctt ctggacctag ccacccagca 180agtgtacaag
gctccaggct ggtcctgggg gttgtctgca cagagtcctg tgatatgaac
240tgtctgtggg tctctcagcc gtggatacca gcacttgctt cagtgaaggt
ggcagggggr 300tgaaatggac tctgtgagaa tccttatatt tggttggtta
atgcactatt tttgtgctat 360ttggcctcct gccaggaggt ggcggtttca
agagagggtc agctatggta gtatggggag 420gaacaggtgg tgggcagggc
cctagaactc tcaagagtat atgtcctttg tcttcagtta 480ccagggtggg
taaaaggacc attaagtggg ggcaggtcta ggcatgtctg agctcagact
540ctacttggac aggtcttgct gcagctgctg tgggggatga aggtgaggtt cccaggtca
599160599DNAHomo sapiens 160gtaagttatg ccactgtcct ctgagtgaag
gaaacacagt agtgcctttc catcatgtat 60ccaagaagaa ttatgaacaa attcttgggg
taggctgagc atcttaacag tggcaacagc 120agaggtgtac agggtgtccc
cacactcact tccagaactt ggtcatctca atttaccagc 180ggttcttatt
taggttctca tagcccagaa aattctgcca gggtactaca catagtgggc
240tatttttagc actgggcctg cctcaggaaa ctggagaact tgaacactca
ttgacaaggr 300agtagaagac agcaaagact taagagagaa agatgagatg
ctttatattt tcctcctgtg 360attttatttg gcagctcatc atccagttag
gaaggtctaa gagataacga agatataaag 420tgctgagtag agagatacac
acttgggaac aggaaagata gctggcagtg ggaaggagtg 480tgaaacattt
tttacatgga gaggaggaaa agctgtggaa ttgggttact taaacataga
540gagggagtta agagcaaaga ggctctttct ggagaagttg atcaagacct gaagtgaaa
599161599DNAHomo sapiens 161catgtatcca agaagaatta tgaacaaatt
cttggggtag gctgagcatc ttaacagtgg 60caacagcaga ggtgtacagg gtgtccccac
actcacttcc agaacttggt catctcaatt 120taccagcggt tcttatttag
gttctcatag cccagaaaat tctgccaggg tactacacat 180agtgggctat
ttttagcact gggcctgcct caggaaactg gagaacttga acactcattg
240acaaggaagt agaagacagc aaagacttaa gagagaaaga tgagatgctt
tatattttcy 300tcctgtgatt ttatttggca gctcatcatc cagttaggaa
ggtctaagag ataacgaaga 360tataaagtgc tgagtagaga gatacacact
tgggaacagg aaagatagct ggcagtggga 420aggagtgtga aacatttttt
acatggagag gaggaaaagc tgtggaattg ggttacttaa 480acatagagag
ggagttaaga gcaaagaggc tctttctgga gaagttgatc aagacctgaa
540gtgaaaatct ttaaaagttc tgaaagagtg gctaaaaaat aattgtaaat tacttacga
599162599DNAHomo sapiens 162tagtgcataa ggcctccagt tgatatgtag
caagaattat taattaaact tcaaaacaag 60aacatgtaaa attaatatta gaaagataat
tgtgtgttct aagcaaaaga aaataactca 120caggaggtac tgctgcactg
tccacaattt tagactacat gacttctaaa atccttttaa 180ctctcagtaa
aaaaaagtag cattatcatt cctttgtatc aaaaaacacc atagatgtta
240tctcttttaa tgttgccttt tcttcaactt gatttttttt tcatttggtt
ttccagtgar 300aagcaattga tactggaagt cttggaatat ggcatttcat
aatttgcata acaaatatca 360gctctgctct tcaagaagac tgaagttttt
ttggttttat agtattttat aaaattttat 420aatttgtact taaaaaattg
tcagcaactt tcatttaaac atcttatttt aaattcttcc 480agttatctac
agacacacac acacacacac tccttctcaa tgcaatctag aaaggagcaa
540atgtacaaga ttttttgtct ccactatttt ttctttttcc ttgcaacaat atccccatt
599163599DNAHomo sapiens 163aatcatgaac gaaactgttt taatccacca
ataataatga atttcaatta cccatgtttt 60ggagtaaaat cgaattatct ttctattctc
tttacaggaa aaaattataa ttataaaagt 120attgtcatgt taggaggtgg
taaaacagta tgtaacccaa aacagagaaa aatggtatta 180tagaaatggg
tcaggtagtt aagaaataaa aacatcagca ctttcctgtg ttttgtggtg
240tttgcaatat ttgtgagctt tgtaacattc gacttgtgat ttttttcctt
ctcattctar 300taaatattca ggttggtgtc tagttttgta gttgcaattt
tgtcttcttt ttctttttct 360tttcttttct ttttcttttt ctttcttctt
tttttttttt ttttgagaga gagtctcgct 420ctgttaccca ggctggagtg
cagtggcgcg atctcggctc actgcaacct ccgcctcccg 480ggttcaagta
attctcctgc ctcagtctcc taagtagctg ggattacagg cgtgtgccgc
540cacgtctggc taattgtttt tgtatgttta gtagggacag ggtttcacct tgttggtca
599164599DNAHomo sapiens 164tcccttgggg ctttccccat agtgagcatg
tgatgctttc aggggaacac tgccttttaa 60tttttatccc aagattcaag cagcacagat
cctctcttgc ttcacagccc ctgtccaatc 120ctgcctttca ttaactaact
ttagtaactt tcctcgctgt gtttaattaa gattcatacg 180agcaagactt
gaaggaacac aagcatctca gtgcggctgg gccggccttt agtcttgggc
240tttttacctc ttgcccgtgg tggtgctggc tgcagaggac cccctgagct
gggagtagam 300ataactcacc ttggtttttt tcttgctgcc agacttttag
gatggctctg aaacaccaga 360ctaagtctgt gtccaaaagc ctcaagcatt
ggcctgggat tatgtaggtg gatatcattt 420gaggactatg gaggccaaat
tatttccttg attgtctaat ctccttgtta acaacatttg 480tgaaaaaatg
aagggttttt tttttttttg ttttttgttt tttttggctg caatggaagt
540ttcaagactt acaaggaaac agcttttgct gttcccctct tagggccttc cagcctgac
599165599DNAHomo sapiens 165tgggattatg taggtggata tcatttgagg
actatggagg ccaaattatt tccttgattg 60tctaatctcc ttgttaacaa catttgtgaa
aaaatgaagg gttttttttt tttttgtttt 120ttgttttttt tggctgcaat
ggaagtttca agacttacaa ggaaacagct tttgctgttc 180ccctcttagg
gccttccagc ctgacaaaag aaatcagcag cttgcccgtg ggcaatctgg
240agaggcagga aggtgggtga gggaagcatg acatcatatc aggtgggaat
aaaaaggcgy 300gtcctgcagt gtccctgttc aaacatattt tggtgcttgg
atgcccgctt tggaagctgg 360aagaccctca gcaggaactg cgaagggctc
cagagacccg gactcaagtt ttcaaacttt 420aaaaatgagt atggcaaggg
aggagtgagg ggtgaagggc agcagccccc tggtggggag 480caggggcgcc
gggagtcaga tctgacagag ggctcccggc tgtgtgctgc atgcgtggtt
540cccctttttc ttggagaaaa tggggaggca ggagtgaggc agattgctct gggacaatg
599166599DNAHomo sapiens 166gggcgcccag tggccaacac ggaggggagt
tttcagatgg aaatcggaca aaacaatgca 60atcatctgtc tcgcaatctg ttttgaaggg
gaaagaaaga gcgggcagag aggagagagt 120cgttttctac taggggaggc
ttcattcaga gagttttata ggagaagaca gatgtcatga 180atactgatgt
ggagagcctg ggtctggcag agttttttta attttctgag ttgtaaagac
240aaagtgtttt aataacacag ggaaacacat gttgatgggt gggtctttag
ctcattctgr 300tttctctaac tccctctctt tctcctcctt tctttccgtc
tttctgcctg cctgcctgcc 360tgcctgcctg cctgcctgcc ttccttcctt
ccttccttcc ttccttcctt ccttccttcc 420ttccttcctt ccttccttcc
ttcctccctc cctccctccc tccctccctc ccttccttcc 480tttttttgag
acagggtctc gctctgtggt ccaggctgga gtgcaggggt gcaatctctg
540ttcactgcaa cctctgcctc ctgggttcca gcgattctct tgccacagcc tcctgagta
599167599DNAHomo sapiens 167gctctctggg cagtggggca cgtgtgccca
taaggcaggt gctgtccctg gtcttggaac 60ttcttatgaa accagcctgc ccggcacctc
ctgccatccc tgtgaggtga tgggacaggt 120gctaagcctg cccttggaca
gataagaaaa ctgcagcccc aggcacagag gcacaagctg 180agaggtgacg
tcaggactga actgtgagcc tgggagtcca aatctaggct cacccagtct
240ttctggctcc agtgagggcc cgccactgtc atccgacgga tggcatgtgt
gatttttggy 300acacgcctgt gcaggtgact cccacaggtg ccccggaggg
aggcgctgct gtgatgttca 360tgctacatgc aggaaacaga gaggttgagt
gacttgccca cagccccaca gctcctacct 420agtgaagcct ggtttgaggc
cacacctgcc ttactagttt tattatttat ttattttttg 480agactgagtt
tcactctgct gcccaggctg gagtgcagtg gcgcagtctc ggctcactgc
540agcctccgcc tccggggttc aagagattct gctgcctcag cctccagagt agctgggac
599168599DNAHomo sapiens 168gtctgtggat ttgacttctc tgggcacctc
atgtgagcgg aattgtacgg catgtgtgtc 60ttcatgtctg gcttatctca cccagcaaat
gtcgtctagc ttcatctgtg ttgtagtgtg 120tgtctgagct tccttccttc
ttaaggctca atactattcc aatgtgtgaa gagaccacat 180ttcgtttatc
tgttcatctg tttggtgact gagctccctc catgctctcc aacaataatc
240atgctcctcc acagacaggt gtcttggctg atggtgtcag agaccccctg
gcaagccgcy 300gctatgggag gggtcttctc cctctcatgc cacccaagga
gactctgtgg ggtccctgca 360gaccccgcag catggtcagg ggctctgact
ggaggctgtt ccctccaaca ggactcagca 420gtcagggtct cccagggaac
ccctgtatgc agactctggg aagacaggtg gatcaggtgt 480ggggactgtc
tgtccctcag gagctgctgg ttgaatgaat gcgactgtct cctgctggga
540cacgcctctg cctcaggctc tgggcagtgg gggacgtgtg cccctaaaga aggtacaac
599169599DNAHomo sapiens 169cccatcgtcc tctgccgtag gaggtatcag
agagcaagta ccttccttag tcacacccat 60cacgtacata gtggatgtgc ctctttttcg
gggcaggggg taatcttaat caccaagcaa 120ttactaaatg ccgaccatgt
tctcaggctt ggcagaggtg ggtgcttgtt accccaaggg 180acaaccactt
ccctccatgc tccccacccc acccaagacc cttctccact ccactcctga
240ctgccgcctc ccacctctgc cctgggtcgc tgtctttatt gtcttcctca
acatcttccr 300tgggaaaggc caatggcttg aaacaggatt gacgagacac
ccggggcctg ctccacaccc 360gtgggctcct gggcgtgcac ccaagagcct
ccacccctga atggctggca tccaggtggg 420cttcccataa ggagccccct
tctgcgggcc tgggagggtg gggagcctgt ggcgaggtgg 480cggggaagag
aaagggcaca ggtgccccct cactccgagc ctatcggatc ccggagactt
540gcaggctata
gacctagagg tccagccagg agggctggca gggaccatga agcaggaga
599170599DNAHomo sapiens 170cccctcactc cgagcctatc ggatcccgga
gacttgcagg ctatagacct agaggtccag 60ccaggagggc tggcagggac catgaagcag
gagacgtcag ggcagagaga atgcctttta 120gagccagata aattcttact
tcccctttcc cagctgcgtg accctgggaa acttcaacac 180tccgtgtctc
agtcctctca tctgtaaaat gaatctgatg agaactgtgt aagaatagag
240gtgtgtggag agctctctgg tgccaggctc atggcaagac tgtggtgaca
ccagccatcr 300gaaggcaggg aggctcctct gtggacagct ggatgcacag
gtgcgtagca ggagctcagg 360agggtgtgcc cgcggagtcg caggtaaggg
agccactcca gattgcagag cttggcttgg 420aggtgtcgcc tcaggagggt
cttccattgc ctggagaccc cacataggcc ctcttcttcc 480ttcaaacaca
gcccccaacc tctctgcagg gaagtcctcc ctgaccttcc aaaccagggc
540agacccttgt ctgggctccg tcggcctgga catggtgcca tttcccacta gtggggcag
599171599DNAHomo sapiens 171ttgctctcca aggttcctgg actttcctcc
agacccgagt gcaagctccc tgtggcttcc 60acccaccgct cacaggagtc tctgcagcca
ccagacccag agcccagaca ccatccactg 120tcggggagag gcacgtgtcc
acagcttcct ggaatgcaag gctgcatgtg gccagggctg 180ctgcccgctg
aggggcaagt gcatgcctgg agaccacagt aaggagccag tctcatgctc
240tgggagttta gataaggctt catgcccctt ggagccaaac ctctgaattc
catggagttr 300ttgggtcaaa gagcttgcct aggtctgagt tgtggatacc
tgttgtcaat gagctctcca 360caaaggggtt accatgatag gtcccaccac
ctgtacctct cctctccaaa tttcaccact 420gttctttcac acctttgcca
atttggtaag tgcaaaatga tattttagtt gtctatgctt 480acactgattg
gaggaatgct ttaagtttga ttattggtaa gtgaaacatt ttgttacctg
540tatttactga tcccactttc cttttatgaa tgtcccagtt acatcttttg tccattttt
599172599DNAHomo sapiens 172ctggtgacat ctctgctctc atctcccttc
ctctccctgg tgtggacact gcacccacca 60ccagctctga gcacatggcc cattggctct
gcaggggccc tcctctctgt ctgcagtggc 120caccttgcca ccaggcccac
ctgaaggaac cgtgcctctc tttacggact gaccccaagg 180tttgcccatg
cttggaggtc tgtctgactt tgctttcctg atgcctggca gtggaccacc
240atgcccactt gtcggtggct gtgtagctca tactcactcc atctggcagt
ttccacccam 300cgaggaccac tcaagtttgc cccactccat gtctgctgtt
gggaggggat ggtgcatccc 360acaagcaaca ggagccacgg agctgggggc
tggggctgtc agcctggatg ggccaggagg 420ggaccttgct gtgcctagtg
gaagagtagg tggtccccta ctggctccag gccgctgggt 480gggtcacttg
cccatccctg cctgggtgtc tatagtgggt gttcccgcca aaattcatgt
540ccccctggaa cctcagaatg taaccttatt tgaaaatagg gtctttgcag atatagtta
599173599DNAHomo sapiens 173cgaggaccac tcaagtttgc cccactccat
gtctgctgtt gggaggggat ggtgcatccc 60acaagcaaca ggagccacgg agctgggggc
tggggctgtc agcctggatg ggccaggagg 120ggaccttgct gtgcctagtg
gaagagtagg tggtccccta ctggctccag gccgctgggt 180gggtcacttg
cccatccctg cctgggtgtc tatagtgggt gttcccgcca aaattcatgt
240ccccctggaa cctcagaatg taaccttatt tgaaaatagg gtctttgcag
atatagttar 300gtaaggatct tgagatgtgg tcatcctata ttgggggagg
ggacagtaaa tacaataaat 360gtccttggga aagacaaaag aaaagaccca
gccacaaaga agaaggccat gtggagacag 420aggcagggat gggggtgatg
tggctacaag gcgtggaact cagagccccc agaagctgaa 480ggaggcggga
agtttcctcc caagagctgc caggggtggg gcggggcaga ggtggcatgc
540ggaatgctct gcccacactg gatgtatgaa tctgttctca tgctgctagt aaagacata
599174599DNAHomo sapiens 174tcccctactg gctccaggcc gctgggtggg
tcacttgccc atccctgcct gggtgtctat 60agtgggtgtt cccgccaaaa ttcatgtccc
cctggaacct cagaatgtaa ccttatttga 120aaatagggtc tttgcagata
tagttaagta aggatcttga gatgtggtca tcctatattg 180ggggagggga
cagtaaatac aataaatgtc cttgggaaag acaaaagaaa agacccagcc
240acaaagaaga aggccatgtg gagacagagg cagggatggg ggtgatgtgg
ctacaaggcr 300tggaactcag agcccccaga agctgaagga ggcgggaagt
ttcctcccaa gagctgccag 360gggtggggcg gggcagaggt ggcatgcgga
atgctctgcc cacactggat gtatgaatct 420gttctcatgc tgctagtaaa
gacatacctg agactgggta atttataaag aaaaagaggt 480ttaatggact
cactgtccca cggggctgga gaggccttat aatcatggtg gaaggcaaag
540gagatgcaaa gtcgtgtctt acgtggcggc aggcaagtga gagagagcat gtgcagggg
599175599DNAHomo sapiens 175aatagaatac agatgaatcc agacttggag
caggccatgg ggtattctta aagactccat 60gtgtgtcttg gagtagccca tgtcatattc
agaatcacag ctggggctcc aaatcccact 120ggcctaccca ttaatctatc
actgtagact agtggtagaa ttggtgacca gatattctag 180tctgggatat
gatcttggga tcttaagaga actttctgca cttcaaggtc cagtttcttc
240acccagagaa ggggctgcca ggtataccac gagatgagag ttcctccaca
gggggacacr 300attgcagcag agatggccaa gggcaggaac tcctactatc
ctcatttata tatgaggcaa 360acaagacttg gagaattcaa gtgacttgct
caaggtaatg cagccagcct caaagaaagg 420gagccgagat taaaaccctg
gcccacatgc tccagagctg ggaggctttt ctgtaggccc 480atcaggagat
aagttatgtc tcctggctga aggccacctt ccacctccca gcccccaagc
540caattgcatc agacataaag atttgtttca gggtgtcttg ttggttttcc agctccaac
599176599DNAHomo sapiens 176tcatctccac cttccttact gcagcccttc
tgctgacagc tggctgcatg ggggcaaaaa 60tctgacaaca cccactcctg ctgccacagt
ctgtcctttc tgctctgggg ttctctgctg 120cagtgccttt gggagcttct
cagccatctg actcatgctg gcgaggtgtg cactctgcag 180cagcgccagc
tgtaagacac accctcagat gggcttgtcc tcttgccctg tttcatgcct
240cctggtccct gtttctgggc cttatcccca aaacgtgaca cttgagtaag
cccttttctm 300aggctcaggc agatccaaaa gcacatttaa atattttcag
gattctgccg atttagagca 360actaggattc caaagaagga aaacttactc
aatcagttta ttgtcagagg ctccacatca 420ttcatttgtt tattcatttt
ttcgcttatt cattcagtca ggccacaagt ttcttcagga 480ctgggatcat
gcttgtcccc attctgttcc taatggaggc tatccatgta gtagtcgctg
540gcaaataact cttagtgact taagttcagg aggcagaagc atggtgaagg gggcagata
599177599DNAHomo sapiens 177tgaggctctc attcctggag agagagccca
gggagggaag gtggtggggg aacctcgggg 60ttggaggcgt gggcccccaa gcatgtcccg
tcctgcagac actccctgct gcccgggctg 120accatggggg catcctgcct
ggtgccagcc agcccagcct tgtctagcct gcctctgcca 180agtggcccat
ttgactgtcc ccatctgttt gcccatggag tccggagggt gtgccctggc
240ccagagccca gctgcagcct gggaaacacc agactccatc catggctctt
tgttttatay 300tttatccaat aggcagtaag gacctcagag agcatcaggt
ccagacctct tgccctgcac 360aaatggagaa actgaggcag agagagggaa
ggggcaggtc agaggcagta tggggttgag 420tcctgcgctc tttcaagatt
ctgttggcta aatccattgt ccccagaagc ccttgtgcat 480gtagttttcc
atgccgtgat gggggctggg gagtcccttg gcatcaaatg ggtggtttgg
540attctgctga ggggtccacc tgcctggtga gcaagagacc aggagccagg agccaggag
599178599DNAHomo sapiens 178gtgaacataa gtcttcattt atttaggagt
aactgcccag gaattcaatt gttgggtcac 60atggttcttg ctatatgaaa ctgccaaact
ttttcagagt ggctgtacca ttttacagtc 120tcaccagcaa tgtaggagtg
acccagtttc ttcacatcct caccagcact tgataccatt 180attttttatt
ttagccattc tgataggtgt ctagtgatac ctcattgtag tttgaatgtg
240tagttgccta atggttaatg atgtcgaaca tctttttatg tacatatttg
catctaggtr 300tcttcttcag ggaaatgtct ctttatatct tctgctcatg
ttctaattgg gttgtttgct 360ctttcactgt tgagttttaa gggttctttc
tatagcctgg atacttctct tttgtaggat 420ttgtggattg caaatatttt
ctcccagtct ataccttgtc tttccatcct cttagcaggg 480tctttggcag
agcagaattt ttatttggat taagtccagt ttatcaagtt ttccttttat
540ggatcggctc tgagagtcaa gtctaaggac tctttgtcta cttctagatg ctgaagatt
599179599DNAHomo sapiens 179gtacataatt cattatgagt tactttttgt
aaaaggtgtg aaatttaggt tggagttcat 60tttattgcaa atggatatcc agttgcttca
gcaccatttt ctataaatgc tatttttctc 120catcgaattg attttatacc
tttgttaaaa attagtgggg tgtattcttg tgaatctatt 180tctgggttct
ctgtactgtt ccattgttct gtatgtttat ttgtctgcca ataccatgaa
240cttttgatta ttgtattatt atttgattat ataagcctat atattaagct
taaaatcaas 300tagactaaat gctctcactt tattcttatt tttcaaaatt
gttttagcta ttctaaaacc 360ttttcttttc tatatacatt ttagaataat
cttgtgtata tctacaaaaa aatcttactg 420aaactttgac aggaattgct
gtatatcaac catacctaaa cactgattta gggaggattg 480tcatctttac
tatgttgggt cttctaatct atgaacatgg tatgtctctt catttattta
540gattttcttt gatgtctttc atagtggttg tgtagttttc agcatgcaag ttctgtata
599180599DNAHomo sapiens 180tttagatttt ctttgatgtc tttcatagtg
gttgtgtagt tttcagcatg caagttctgt 60atatcaaaaa aatttacatc tagttattta
atttttgagt gatttcaata gcattgtatt 120tttaattttt atgttcacat
gtttactact aatacataga aatacaatca gttttgtata 180tttatcttgt
ctgtcacctt gctgaactaa cttattagtt tctgggaggt attgtttatg
240tagattcatt gggattttcc acagcgataa tcatgttatc tattttattt
ctcctttctm 300atatgtatgg cttttgaatt catgttaatt attctgcaaa
gaattggtac aattgtccag 360taaaatcatc caggcttgga gatttctgaa
atgatgtctt taatttcctt aatagttata 420aggctatgca aattatctat
ttcatattgg gtgagttgtg gttaagaagt tgatttatct 480aagttgtcaa
atttatgtgt gtagagtggc tcatagtatt ctattttatc tttttgatgt
540ctgcagggtc tgtaatgata ttcccggttt cattcttcat gttggcaatt tgcatcttc
599181599DNAHomo sapiens 181ccagccatta tttctgtaag cattttttca
ctatcatgct ctttctcctt tccttctgga 60actccagaaa cttaaatatt agattttttg
ttgtgtttct tgactcttgg ttccttttgt 120tgtgtccctg aggctctgtt
attttttatt tcagtctctt ttctctgtgt tgttcagatt 180cagtaatttc
tgttattctg tctcccactt cactctttcc tctgtccttt ccattcttct
240gttcaaggtg tcagtgaatt tttcatttct catactgtat ttttcagttc
taaaatttty 300catttggttc ttcttatctt ctatttcatt gcaaaggctt
tctatttttt atttgcttca 360agtgtattca taattgatcc tggaagcatt
ctgtcatggc tactttaatt attttcaggt 420aactctaaca tctctgtcat
cttggtgttg gcacctattg attgttgttt ttcatgcagc 480ttgagatctt
catgattctt ggtatgatgt gtgatttcca gttgaaactg ggatgtttct
540gtattattta gatcctgtgg ttcatctgga ttgtttttct tttgacattg ctttggcaa
599182599DNAHomo sapiens 182ctcctttcct tctggaactc cagaaactta
aatattagat tttttgttgt gtttcttgac 60tcttggttcc ttttgttgtg tccctgaggc
tctgttattt tttatttcag tctcttttct 120ctgtgttgtt cagattcagt
aatttctgtt attctgtctc ccacttcact ctttcctctg 180tcctttccat
tcttctgttc aaggtgtcag tgaatttttc atttctcata ctgtattttt
240cagttctaaa attttccatt tggttcttct tatcttctat ttcattgcaa
aggctttctr 300ttttttattt gcttcaagtg tattcataat tgatcctgga
agcattctgt catggctact 360ttaattattt tcaggtaact ctaacatctc
tgtcatcttg gtgttggcac ctattgattg 420ttgtttttca tgcagcttga
gatcttcatg attcttggta tgatgtgtga tttccagttg 480aaactgggat
gtttctgtat tatttagatc ctgtggttca tctggattgt ttttcttttg
540acattgcttt ggcaagagaa gggggtctgc tgcctcatta ttgataggtg gaggtaaaa
599183599DNAHomo sapiens 183cccagcatta tttactgaaa agatcaccct
tcctttccct tgattacagt tgtccttatg 60tcttaaatca gaagactgtg taggtgaggg
tcagctctag actcattgct tcattgctag 120tgtcaactat gggccaggat
ccagggcttg gaaccaagaa cctctttgga ttaatgccta 180ttaagataat
attgaaaatg aagtaagtgc aatggagact catcattgca ttacagagac
240agaaggggcc cccaaactaa tctggagtgg tgtacaggat cagggaagtt
gccctgaagk 300tgataagcag aatgtggaag gatgggcagg agttgtctaa
gagaagagtg tggcaataga 360agggcaccct gggccacagg gaacaaacca
tagctgaaag atgaggagtc aagaaatatt 420ctggcaccca tggggtacta
ttagcagttt aactttacag gagctgaaaa tttaagaagg 480ggaatgtcaa
gagatgaggc tgaaccttgg cagggatgga tccttggacc acatcatgta
540gttgaccctg tcacatagct tggacttcac cttgtgggtg acaggaggcc accagggct
599184599DNAHomo sapiens 184ttaatgccta ttaagataat attgaaaatg
aagtaagtgc aatggagact catcattgca 60ttacagagac agaaggggcc cccaaactaa
tctggagtgg tgtacaggat cagggaagtt 120gccctgaagt tgataagcag
aatgtggaag gatgggcagg agttgtctaa gagaagagtg 180tggcaataga
agggcaccct gggccacagg gaacaaacca tagctgaaag atgaggagtc
240aagaaatatt ctggcaccca tggggtacta ttagcagttt aactttacag
gagctgaaar 300tttaagaagg ggaatgtcaa gagatgaggc tgaaccttgg
cagggatgga tccttggacc 360acatcatgta gttgaccctg tcacatagct
tggacttcac cttgtgggtg acaggaggcc 420accagggctg acagtagagg
aagaacatgg ccatggaatc cttgggagaa gtggtgtggg 480ttcattgaaa
aggccagggc agaggctgaa agactcatca ggggaatgta gcagtgatcc
540gcaggggttg tttagggacc agtcatgact gtggcatggg gctgggaaaa tggggccat
599185599DNAHomo sapiens 185ggaaccatga tggggattat cctcttcaac
atggaataat gatgatgagg atggagacag 60taatgatatt attgtatgat cactacacaa
catgtctggt tcaggcactt tatgtgtatt 120aaactatgaa ttccttcaac
aaccttataa ggcagatatc actcttagcc ccactttaca 180gatgaggaaa
ccatggccca gagagagcca gtaacttgct ggggaacttg gtttttgagt
240ggcagagctg ggattcagac ctagaaagtc tggctccaga acccatacac
tgatagagtr 300tatttctgtt caatatttat taaactcctg catgtgtttg
acactctgct aggcaccagg 360gatttaggat ggaaaggaca gtcatttcct
tgcctgccct catggagctt ctgatttgtg 420gatggaaggc atgaacatag
gtgtggtggt catggtgcct cccacccatc atgaacttga 480accaaaacag
gaattctttt gtcagttttt tctatcggtt tttggggaag ttttattgga
540aaaaaaactt ctaaacaaaa gcttaaaaag tatgctttat tgtcttttac ccttattat
599186599DNAHomo sapiens 186aacttgctgg ggaacttggt ttttgagtgg
cagagctggg attcagacct agaaagtctg 60gctccagaac ccatacactg atagagtata
tttctgttca atatttatta aactcctgca 120tgtgtttgac actctgctag
gcaccaggga tttaggatgg aaaggacagt catttccttg 180cctgccctca
tggagcttct gatttgtgga tggaaggcat gaacataggt gtggtggtca
240tggtgcctcc cacccatcat gaacttgaac caaaacagga attcttttgt
cagtttttts 300tatcggtttt tggggaagtt ttattggaaa aaaaacttct
aaacaaaagc ttaaaaagta 360tgctttattg tcttttaccc ttattatcga
accagtggaa aatcagaaaa atacaagtgc 420ttacaccagc aataaaaaaa
tatggttctc atcaacacca ccctttgccc cgagccctag 480agtgtctttc
tccaagttgt ctaaatttcc cttcagttcc tgggaccagc tgagaggaca
540gggagcccac acttggcccc acatgagacc tggttccatt tctctccttg gggcactct
599187599DNAHomo sapiens 187taaacaaaag cttaaaaagt atgctttatt
gtcttttacc cttattatcg aaccagtgga 60aaatcagaaa aatacaagtg cttacaccag
caataaaaaa atatggttct catcaacacc 120accctttgcc ccgagcccta
gagtgtcttt ctccaagttg tctaaatttc ccttcagttc 180ctgggaccag
ctgagaggac agggagccca cacttggccc cacatgagac ctggttccat
240ttctctcctt ggggcactct acaacttccc actctgcccg ggtcatgtgt
ggagctgacy 300agatacttaa aaacaacaac aacaacaaca acaacaacaa
caacaaacaa tgttattttg 360taagagcagt tttaagttca cagcaaaaat
gagtggaaag tagagcattc ccacaggtcc 420tctctcccca cgtgcgcagc
cccggttatc aacacgccca ccagactggt gcatttgtta 480caactgacgc
agctacactg acacgtcatt tccagtgaag tccagagtct gcattagggt
540tccctattgg ggctgcgcca tttttctcac cagcagtgaa tgagagttct gctgctcca
599188599DNAHomo sapiens 188ctgcccgggt catgtgtgga gctgactaga
tacttaaaaa caacaacaac aacaacaaca 60acaacaacaa caaacaatgt tattttgtaa
gagcagtttt aagttcacag caaaaatgag 120tggaaagtag agcattccca
caggtcctct ctccccacgt gcgcagcccc ggttatcaac 180acgcccacca
gactggtgca tttgttacaa ctgacgcagc tacactgaca cgtcatttcc
240agtgaagtcc agagtctgca ttagggttcc ctattggggc tgcgccattt
ttctcaccar 300cagtgaatga gagttctgct gctccacatg ctcagcagcc
tttggtgcca tcagtgttct 360ggattggacc attccctaac gacatacgat
gtggggcacc ttttcaaatg cttacttgca 420tctgtacatc ttctctggcg
aagtgtctgt tcaggtcttt tgcccattgt ttaactgagt 480tgtgctgacc
aggtactttg aggaactcca gacttgtggc tatggcatca tcctggggcc
540ccataggcca gttcaggagg gtggctggtg agcgatcctg cttgctggcc tgtgcaaaa
599189599DNAHomo sapiens 189agccaggatg gacacctgac cccacctgtg
ttggttgggt tatttctgag ctggtttctt 60gaccacgaga attgaaatgg ccacttccca
actgccaagt gctccaagaa gcagagaaca 120caggagtaaa aagaagcaca
gaagggacag aggttccagt tcttcttgag gcctgctgtc 180ccatccttgg
gttttgagag acacctctgt gtccttgcag agaattcacc actttgttca
240aaccagtctg agaaagcttc tttattgtgg tccccaagtg cagctgctgc
aatgaccacy 300gttaacttcc ccgccttggc aaaataactg atactccaaa
ctgctaagag tcccaggact 360gcaccagtta gctattactg tgtaacaaat
tgtcccccga tacagcagct tcaaacagcc 420ataaatattt attacctccc
aggttctgag ggccaggcat ctgggagtgg cttggagggg 480tgtttctggc
tcagggtctc atgaggctgc agtcatactg tccctgaggc tgcatcgtct
540gaaggcttgg ctggggctga aggatccact tccaagctcc catgcatgct tgtggacac
599190599DNAHomo sapiens 190gtgcttcccc cagagtcaga gatgagagag
ggagggaggg agtggggtta gagagagaga 60cggggtgtgg ggcaggagat tgaagctgca
atctttcata acctaagctt ggaagtgcta 120ttccatcact tctgccacgg
gctgctggtc acttggacca tccctgggga aaggaaacta 180cacagggtgt
gaaaaccagg aggcggggct cactgggggt ctctgagaat ctggctacca
240gcaagatctt gcaggaagtg atggacagcc ccaggtggac gcgtggcata
ggggtctgcy 300gcctcctcct cgtattatct tatcttctga gagctgctcc
tgggtgaaca ggtgctcact 360gcctcttttt ctgggttcac atggacctgg
gttagaaagc tgcctctaac atttactagc 420aagtgacttc tctatgcctc
tattttctta tctgcaaaat cgggagaaaa atattgtcct 480catcgagttt
ttctgaacct taaatgcaga gatcttatca gaaagttctt ggccgttgtc
540tcagaaactc agagtctctc ctgctttagg ggcaacgaaa gttcattcac ctacctgta
599191599DNAHomo sapiens 191cagcccaccc atcgccctgg acctctggcc
tctaggtatc tgggattctc ctttgtgaga 60ggcaaaaaaa aaaaaaaaaa cccaaccaaa
aaaaaccccc aaaaaaaccc caacttgaag 120tggattcagc cacaatgtat
tggatggtga acacgaaggg caggaggaag gggggggggt 180gggggtggta
gggaggggcc tggttcaggc cccacaggcc ctaggacgct ggtgccctct
240ccccctctgg ccacaccctc cagggctctg ctgacccctc cccagcttcc
cccctgcaty 300cgtaccatgg cgggagcagt gcaagcctca cgtctagtag
gaagcagcag gagtctttcc 360cagcattccc caacaagagt ctcattggct
gtggttgggg cacatgacag tccctgacca 420atcactgagg cctgggtctg
attggctagg cttgggtcac atggcccact tttggcccag 480tgggtgaagc
cactcttgaa atggatcctg gccaggagga gtcctcctta taggaaagtt
540gggttacggt tcccagaaga ggtgggaagg gatgctgggt agccagaact gacactggc
599192599DNAHomo sapiens 192taaccaaggg cattgcgttt gtcccacatt
ccgaaattca cagtggcagg tggtggctca 60gaggctggaa cctggccctg agagacccat
tgcctttctc tgttctgtaa cctcttccca 120tagagatttt tatcctgtaa
ccctgtggtc atcaccatgc ctcccattta tgtgcagttc 180ctatgggctc
ctgatgcttt cctggatttc tcccaggaga ggctgttggg tgttggggtg
240ttggggaaga gaattagtgt tctgcagtct ggagttcact ggtctgcaga
ctgctaaaar 300tctgggggct gcgtctgcca gggatagtgg ctctggctgg
tatggggacc aagggcaaaa 360ggatcagtga tttcagcaga tgcctttgag
ccccgagtct ctggctgtgg actagtccag 420tagaaagagt gtcttggagt
gtggcagagt cccagtcccc tgtctttctt actgtcaaaa 480ccaaggtttg
ggcaatcgat gatctagcta aaaaaacgat gtttttcagc ctgtcctttc
540tgggctcctc ctgtcccaaa cacagatgtg aagcaatgtg cgagaattcc tattctaca
599193599DNAHomo sapiens 193gtatcctttg accatggttt taaaatttgt
agacattttt aatatattct aatacaaatc 60ctttgtcaat tataagtatt gcatatatct
tcttctttgt gcctgttctc ttcatttttc 120ccacagtatc tttggtcata
ctaaagtttt ttttgttgtg tgtttttttt tttttacatt 180tgatacagtt
aaattaaatc ttgttttgat tgtacttttt gtgttagttt aatacataat
240ttcttatctt ggtgtcagaa aggcattcta tcagaattta ttttcaaatt
gtatagatty 300tccgtgtaca gtttggtctt tggctcaact gaaatttatt
tctttttgta ggtgtaagga 360aaggatatat ttttatcttg ttttcctttg
taaagccatt tgtccccaat ccatgtattg 420aattcttttt cttttttttc
tacagatata ttcttatata ttgtttccat aaaattcctc 480tctattttgt
cccatcaatc tatttattca tgcactaata ccacacaatt ttaattatga
540tagttttact gttaatcttt atctttggta tgactctttc tcactcgttc cttccttcc
599194599DNAHomo sapiens 194gaatttattt tcaaattgta tagattttcc
gtgtacagtt tggtctttgg ctcaactgaa 60atttatttct ttttgtaggt gtaaggaaag
gatatatttt tatcttgttt tcctttgtaa 120agccatttgt ccccaatcca
tgtattgaat tctttttctt ttttttctac agatatattc 180ttatatattg
tttccataaa attcctctct attttgtccc atcaatctat ttattcatgc
240actaatacca cacaatttta attatgatag ttttactgtt aatctttatc
tttggtatgw 300ctctttctca ctcgttcctt ccttccctac cttcttttcc
tcgtcttcct ttttcaagac 360cttcttcctg tttttagcac cttaatcatt
cacataaatt ttaggattac cttgttaagt 420tttatgaaat aatctgttgg
aattttggtt agacttgcct taattcatac attaactgga 480gtagaattgt
catctttacc atactgagtt ctactcagga gcatgacata tctcttaatt
540tatttaatgc ttcctttgtg tctttccatg aagatttaga attttctcca taggtcttg
599195599DNAHomo sapiens 195tgtacagttt ggtctttggc tcaactgaaa
tttatttctt tttgtaggtg taaggaaagg 60atatattttt atcttgtttt cctttgtaaa
gccatttgtc cccaatccat gtattgaatt 120ctttttcttt tttttctaca
gatatattct tatatattgt ttccataaaa ttcctctcta 180ttttgtccca
tcaatctatt tattcatgca ctaataccac acaattttaa ttatgatagt
240tttactgtta atctttatct ttggtatgac tctttctcac tcgttccttc
cttccctacy 300ttcttttcct cgtcttcctt tttcaagacc ttcttcctgt
ttttagcacc ttaatcattc 360acataaattt taggattacc ttgttaagtt
ttatgaaata atctgttgga attttggtta 420gacttgcctt aattcataca
ttaactggag tagaattgtc atctttacca tactgagttc 480tactcaggag
catgacatat ctcttaattt atttaatgct tcctttgtgt ctttccatga
540agatttagaa ttttctccat aggtcttgca tgtcttttgt tagacttctt cctaggtgc
599196599DNAHomo sapiens 196atagattgaa agtaaatagg tggaaaatga
tataccatac aaacgataag cataagaagg 60ttggttgaag gggttatatt aaatcagata
aaataaactt ctaggcaagg tgcaataact 120ggtataaaga ggaacatttc
ataaaaaaca taataacaca tgtaataaat tacttaatag 180caaagggaca
ttcataagga agatacaata ggctatatat atatatctgt taatggatct
240tcaacatgaa tgaagcaaaa tttgacaaaa ttgcagggtg aaaaaatatc
cacaaatatr 300attggaaatt ttagtaccta tctgtcagca attgatagaa
caactagaca gaaactgaga 360gaagacatgg aaaagctaag cataagtatc
ctattaactg cctttgttga attgatactt 420ataaaaatca acatccccaa
ggagagaata cacacttttt tcatattcat tatgatggac 480tatatgctgc
accatacatg aaaattgtta ctgttcttgt ctttttccct ctgtgtataa
540tgtgtctttt tctctggctg ctttcaagat tttctcttta tcacttgttt gattacaat
599197599DNAHomo sapiens 197ccagttcttc caaatgtccc cattttacag
cagaggaaac tgagggtcag gatctctttg 60ggcacggttg caaagaaagg cctcctagag
aaaggggcct gtgtgcaagc ccagggggat 120ggggggtgag gcttagagca
tttcccgtgg gtggaaacag tgaacaggcc tctggaatca 180agctagccca
taacctgccc ggggcacagc aagtggtatg gcgagaacag accaagtttt
240gggtgccgaa taaggatgag gtaaaccagg ggcagagttt tggaatctca
gcccaaaggr 300gtggcctgag tccaaggctg ggggagcatg cacctgctgg
ttgctgacac aggtgatcct 360ggctgtgttt ttgttaagac tggctttgtc
gtagctccat ggatctgggc acaatccaga 420gatgttgtct tcttgcacac
tcattttaca gatgaagaaa tcaaggcttg gggtagtaga 480gaactttcca
gaagtacagg gcaagtttgt gtctaagcaa agctgagccc tctgccccct
540tgtggtgatc tcctcagccc cgttctcatc cttccagggc aatagtcttt ccttgggag
599198599DNAHomo sapiens 198ggcatggcca caaccctcac ctggatgcct
gtcctctgtt caccctctgt tctctttcca 60gcagaacatt cagcccagcc ttgggtgtca
ggcatgtgcc tgcctctctg acctcatctg 120gtggccaggc tgtgggaagg
gaaaactgga ggagtctttg ggggctgagc ctctgggcat 180ttgtaggagg
caccaccagg gtgtcaatga agataatgac gctgaagctc caggcccttc
240atttgcatgg gcccatccca cagttcagcg tgggcttccc tgcccctacg
ctgaaggatk 300ctccttgact gtgagtggga ctgtgggctg tggcaacctg
gtaggtggac ctcatggatc 360actgactctc tctcttggct ccaaggagga
agatgaagca gtcgctgctg cgcttcctgc 420tcagggccat ggtgcccagg
ctttatggcc atctcttccc tccaggacca gagggaatga 480gggcctggct
cagttggctt ggttgcccaa ctgtggtcat caggagggtg aatgatgtca
540aagaactggt gtctcttaca gataccctgc ccaggcaaga aattgtagag gacatttca
599199599DNAHomo sapiens 199ggggcatgtg agcatccttg tggtgtgtcc
ccatgtgcac acatgcatgt gtgcccacat 60gtgagaagga ggtgggggca ttgctgccag
gagatggatc atggggagag aaagaaactc 120tttttaccaa ctcttggaat
caggcctgtt catacatgat ggcattgctg gatctgggga 180tgtgtctgta
gatgaatttc aaggtctctc ttggcttaaa atttctaaga atcccaagca
240attaccttgc aggagaaata tgggaaaagc ccttttttag tctgtccatt
catgcatctk 300tttattcaat cacctatccg ttcactgact taggcatcca
tctacccact cacacattca 360cccattcact catccatcca accattcatc
tactcatcca accattcatc tacccatcca 420ttcagtcatc cattcacttg
cccattgacc cacccatcca tccatccacc catccatcca 480accatccatc
cacccaccca tccatccatc catccaccca tccatccatc catccatcca
540tccacccacc cacccatcca tccatccatc catccaccca tccatccatc catcccccc
599200599DNAHomo sapiens 200ggagttcccc agttccggct ttgaagccct
gcctggtttg gaagttaagg ctatcctgaa 60gacttgagcc ccaggacatt ggaaagagct
tttgttctca tgcaaatcac agggggccag 120ttctcctggg gtttgcatgc
taatagctgt cttttttgtt ttgttttgtt tctaattcac 180agcagataaa
cagtgaatgc caggaacaga caagtgtgca gggtcagcag atacaagccc
240cttgtgggaa gggggttttt ctctaagtat cagattcgtc aattactggg
taaatttctm 300atctcttagg acttcccctt tcaataaata ctttcccaga
aagtctcacg aaatcaaccc 360tgggtctaaa aataaggctc tactcccatc
ccctgggcat gagtggtccc catgagccca 420ggtgcatggc ttgaggaagg
cactgggcgg tcacaggagt gctttgtgga caaggtgcca 480atggtgtggg
cagagatctg gcagacagta gtccctactc tcttcctgtc ttgatgagga
540ggatccgagc tggcccagag aaggggcaag ccttccaggt agagggaata acatgggca
59920173344DNAHomo sapiens 201aatcatgaac gaaactgttt taatccacca
ataataatga atttcaatta cccatgtttt 60ggagtaaaat cgaattatct ttctattctc
tttacaggaa aaaattataa ttataaaagt 120attgtcatgt taggaggtgg
taaaacagta tgtaacccaa aacagagaaa aatggtatta 180tagaaatggg
tcaggtagtt aagaaataaa aacatcagca ctttcctgtg ttttgtggtg
240tttgcaatat ttgtgagctt tgtaacattc gacttgtgat ttttttcctt
ctcattctag 300taaatattca ggttggtgtc tagttttgta gttgcaattt
tgtcttcttt ttctttttct 360tttcttttct ttttcttttt ctttcttctt
tttttttttt ttttgagaga gagtctcgct 420ctgttaccca ggctggagtg
cagtggcgcg atctcggctc actgcaacct ccgcctcccg 480ggttcaagta
attctcctgc ctcagtctcc taagtagctg ggattacagg cgtgtgccgc
540cacgtctggc taattgtttt tgtatgttta gtagggacag ggtttcacct
tgttggtcag 600gctagtctcg aactcctgac ctcatgatcc acctgcatca
gcctcccaaa gtgctgggat 660tacaggcatg agccactaca cccggcctta
tttttcttaa agagcccctg tccagttgtg 720taagctccag gctccttggc
gcctggcttc accccaccct ctcagcatcc cctgcccagg 780gaatccactt
tactggagtt gggggtagat tccaaccagg acgctttgcc tccctcccat
840agggtggggt ggaccctgtc ctcctaacct tcgtgaccat gcagaacagc
tgcccccatc 900cttcaaggac tggcacccac ttttcacatg cctcccctca
tttaatcccc ttaatttcac 960atcgcttctg tatattttca gaattattgg
ttaagccaaa attggattat tgatcattcc 1020aatatttcag aataatgaac
accacccagg ttgccataga gagatttgag gcaggagagg 1080tgaacacacc
ccagcttccc agccagtaag tggtcgtgct gggatgtgaa cccagggcta
1140tggctcccct gctggcagcc ctagtgccat tgtattctcc actcttggtc
accagcgatc 1200acagcagcct tgtcaatagg aacagaaacc ttttatgtgc
accctcccct gtgccctgtg 1260ccttgcgttg gaccacattt cagtctcaca
gcagtgtttg aagatggcta cactgattat 1320cctgtgttac agataagcaa
attgaggcta agagtggcta agcaatacat tcacgatggc 1380acagctgata
tgtagtgaga gttcagtttt gaactcaggt ctgagagccc cattttcatg
1440accctggcat ccccagggaa gtcatccctg ccacccctgg attggtgcta
tcagccttcc 1500tgcgcagaat gttccagaat gtcatcccct gcccgggaaa
actggccctt tgagtggctg 1560accagccccc actcccaacc actctccttg
gctctatttg taaagtgaat tactgcatta 1620tgggaggaac aagaaggttc
tttatctcca cttgggcaaa tccattagga ttagaggccc 1680ctctgaagcc
cctctgaggg ggtgacgtaa gcctgtcttt ggtgatttgc agagtgacag
1740catgataagg agtccgggcc cgttttagtg gtgacaggac atcctccccc
tgcagcaccc 1800aagaattagc gggcctatct ctccatttat caaagccctt
tgggggatga ggcaatcggg 1860cggaggagta ttgcagcctc tctgtctcgg
agtctgtgga gctgtcgctt cccgccagct 1920tgcccaggtc atacagctgc
ccaggatctg cggggtcttc gtgacttccc acagtgagaa 1980ccaacagaag
ggtctccaac tgccaggctt cgtggcccag gtccctccag tgtctgacct
2040gcatggcctg ccaccctcta gacaatgccc agacttttgc cctgaaatac
catgaggatg 2100gggatgccat tatctagcaa ggggaccgcc atgtctgggg
aaaaattcaa gggttctgcc 2160tggctcaggc tcagtctgag gtgctaggga
agatggcagg tcccaaagat gatgccccct 2220gtatatctcc cattccacct
gctcttctta caaagtaagg tcgacactct ccctttgaga 2280ggaagagtga
ccctgtccct gagcttgtgc agacctgtac gctgacagag tatatggcag
2340gagtgacgcc ctgtggctcc tgagttgagg gctgaaaagg caatatggct
ttcatttgac 2400tctctctttc ttggaattca tcctccatgt tgtgaggaag
cccaagccac atggagaggc 2460catgtgtggt tctggccagc agcccttgcc
aggcccgcag ctgacatcag cctcaactgg 2520cagacatgaa ggtgaatgag
ccttcaggtg gttctgtctc tagcctctga gccaccccag 2580ctgaggcccc
agatgtcact gggtggagag aaaccatccc cgctgtgcct gcttgaccgg
2640cagaagccat gagagataac aaatgatgat tgttgttttg agtgactcca
tcttggggca 2700gtgttattca aacagaataa ccagaacaca tgctgctaat
aaagacgtat ctgagactga 2760gtgatttatg aaggaaagag gtttaattgg
ctcacagtcc cacatggctg gggaggcctc 2820acaatcatgg ctgaaggtga
acaaggagca aaatcacgtc ttacatggca gtaggcaaga 2880cagcatgtgt
aggggaactc ccctttataa aaccatcaga tctcaggaga cttattcaca
2940gtcacgagaa cagcatggga aagacccacc cgtatgattc aattacctcc
caccagatcc 3000ctcccatgat aagtgggaat tatggaagct acaggaatta
tgggaattac aattcaagat 3060gagatttggg tggacataca gtcaaaccat
atcaccgttt gtgtgtggaa ggcagaatag 3120tggcccccaa aaatgtcttc
atcctaatcc ctgaaatttg tgaacatgtt aggttacagg 3180acaaagggga
attaaagtca cagatggaat taaggctaat aatcagcagg cctcaagata
3240gggagaccat cctgaatcat ccagcttggc ccagtgtcat cacagggtcc
ttaaaagtgg 3300aagagaggga gtaagaggag aatcagaggg agttgtgatg
gtggaggcaa ggcacagaaa 3360gatgcagtgt tgctggcttg gaacatggag
aaggggcacg agccaggaaa tgctggtggc 3420ctccagaagc tggaaaaggc
aaggaaatga tttgcacccg caggctccag aaggaacctg 3480gattcaagcc
ctgtgagacc tgtcctgacc tctgggactg tagagtgata agtgtctgtt
3540actttacgct accaagtttg tggtgttttg ttgtagcagc aataacaact
gacacagcct 3600ctatgtgctc ttgggaatga gagaaggaga taatatcaaa
gaaaaagagg gcctagctgc 3660aggagaaagg tcttgcatag gtgagaggga
atgggggcca ggaccccagt catagccatt 3720taatagtaat gccatcagca
tcattgttat cagcatcatc accaccattg tcatcatcat 3780tgtcaccatc
attaccacca tcatcatcat caccatcatc atcataatca ccatcatcat
3840cattgtcgtc ataatcacca ttatcatcat tgtcatcatc accattatca
tcgtcatcat 3900catcatcacc accaccacca ccaccaccat caccaccatc
atcatcattg tcatcataat 3960caccattatc attatcatca ttaccaccac
caccactacc atcatcatca ttatcatcat 4020catcaccacc accatcatcg
tcatcactgt cattattatc attgtcattg tcaccattgt 4080tgtcatcttc
attgtcatca tcattatgaa gactgttcag caaagacccc aggaggtagg
4140gccccatcag gagacagcat tttccctgca gggataggtg gcctctagca
cttagttcaa 4200ctctttcctt ttctggggat gggggtgcag gagggaaaac
ctaggatccc atccaaaccc 4260tccacatttt atctcttgct tcatttgcct
ctttctctcc tgccttattt gagagctgat 4320gtccctccga cctcttttgg
aacactgttg acagacagca cagggctgta ggaacccact 4380ggccctggag
ccgactgcct gtgcttgaat cctgtctcta gcaccaatat ttgggtaacc
4440ttgggttatt taacctctct gtccctcagt gttcccacct ctagaaggag
atgaatgctt 4500ctgcctcata ggggagttgt gacttatacc tggaatgaac
tttggcctat aatgggtgtg 4560tgacaagtct cctcagcatt ggacagcttc
actgctctgc gcccaagact gccctcgtca 4620gtgctggatg aatgaggcca
ggaggcgggg gaaagaatgg aggcaggtgc ccaagcttgg 4680gtttggggca
acatcgagct aaagagccag aaggcagggc tgcatgatcc caaactctac
4740cagaggcttc ctctccctga ctccaaagtc ctttagccct gggcaggtag
aaagaaggcg 4800ggggccggag atggagattc ccggtggaca gtaatggtgc
ctggccgcta ccatggctga 4860agtttgcccc tctggccttg cctggggact
ggcagtctca agacagtgga gagaggctaa 4920actccatcct gcccctggta
gaacctgaca ctggacatca gaggcatctt ggaaggtggt 4980gtcttcccgg
cctgttccag ggcaggcatg tgagacaact ttgcccaaga atgcaagcac
5040cttcctgggt ccctaccatg agggctcatg ttgtttacca tagtagtttg
cagacataaa 5100caaaataata ataaaattga tgtattaaag aaacttttca
ttgaatggag tttttaatag 5160aaaacttagt ttgaaaaaaa cagacaggct
gagtgtggtg gctcacacct gtaatcccag 5220caatttggga ggctgagatg
ggaggattgc ttgaggccag gagttcaaga cctgcctgga 5280caacatagca
agacttcatc tctacaaaaa aattaaaaat taacctggta tggtggcata
5340cgcctgtggt cccagctact cgagaggctg aggtgggagg attgcttgag
cctggcagtt 5400cgaggctgca gtgagctatg atcgcactgc tgccctccag
cctgggagac tgagtgagac 5460cctgtctcta aataaataag taaataaata
aatggtcctc ccagtggaca cagccctggc 5520tggaaggtgg gttcttggct
gagtttcaac cccgttcaac cacgtgatgt tgggaagatg 5580gtgagatctt
tctgaatctc agtgtctcca tctgcagaga cagaggcgca aaatggcacc
5640actacacagc actgctccct gggccgtcag gggcagggtt cctgggtggc
gccagccatg 5700tgggctcatg tcccctggca atcttgtgac gtcgtctccc
atttccacct ggacattgcc 5760catcggtccc tccatgggtg gaagcttccc
tgtgatgctg ggggtgcaga gcgctcctcc 5820atggttctgc ctgtgcctgt
gggtgatgcc cttgctcggc tgggctggaa gtggccactt 5880ggccgtacaa
agcactctcc atctgtgata ggatgacttc acagccgcag ctgggtctcc
5940tgggcctctc ggacccttcc tcagaaggct ctcagggctc tgcagctggg
cagagcctgc 6000atgattcgtg gcactgtccc tttctccctt gatttctctg
cacctcagtc ttcccatctg 6060taaagtgggg atgctgacag cccatgcggt
agggtgttag gaaaagcagg cagagaatgc 6120ccggggaaga cctggctggc
ggttgacctg cagtgagtag tggtgagggg cagtgttgcc 6180acttgaggaa
tagcgctgag agagaccagg cagaggtgag gttttgagac cagggagatg
6240ttcagggtga ctggggtggt gggtagtgag aaggggagac tacagcgttg
ttaggggctt 6300ggaagtctga gctaaagagc ttagacttca tgttgtagca
tggaagagct ggttgtaggg 6360ctgaagagac agaaacagag aaggcaagca
acgtagccaa tgtcacatgg cccatttttt 6420ttttttttga gatggagttt
agctcttgtt gccgagactg gagtgcaatg gcatgatctc 6480ggctagctgc
aacctccgcg tcctgggttc aagcaattct cctgtctcag cctcccgagt
6540agctgggatt acaggcatgc gctatcacgg ctggctaatt ttgtatttct
agtagagacg 6600gggtttctcc atgttggtca ggctggtctc aaactcctga
tctcaagtga tcctcccacc 6660tcggcctccc aaagtgctgg gattacaggc
atgagccacc atgcccagcc cacactgcac 6720tttagtggca aactgggatg
aggatgggca tcctgtttct ctacctctca acagtgtctg 6780agccttgggt
gcagccttgc aggtgaaacc ctgggctgag agtagaggct gtagcgccct
6840tgaccttgag tgcaggtgac atttccaagc tgtctttaat ttgccttgaa
atcaggcaca 6900aatcctttgc aaaacaggaa actctctctt tgggactgac
atgaaatagt attgctattg 6960aattaaagag ttagagctgt ctcaaaggag
tggcatattg aaatagccgg tggggtcagc 7020ccagcctggc taagcctttg
atagcacagc tgataataga ccccggccta taaataccgg 7080gaatcaatca
cgggctggag ctgctgacag cctgcatgtt cacatatcat ggcagatggg
7140cgggaggcag gggcggcgat ttgtcttgcc tttcagatgg atttcctgtt
ttctagggag 7200tgggaaagga cccatctggt aatcagatcg tggccaagat
cacctcctct gggtcactgg 7260cccctgctcc atgtgtcccc tcggccacgt
ggccccagca ttgcggcggt caggcggccg 7320ggcctctgaa aatgagagcc
acaccaggag gcctctcgcc ccgtggaagc ttccggaggc 7380tggggaggcg
gggactcctg cctttcatct tcctttctgc ttcttttctt ggcacctggc
7440tttgctcata ggcatttcgt tattattttt ttcttcaaag gctcgtctca
acttgcacat 7500gtatgtgcaa acttccacaa acacatgcac atgtgtgtgt
gcacacatgg ggtccacagc 7560ctcctttgca ggccctcctg ggcttccctg
tcaacccaca gctcctccta gatgcgtcct 7620gatgccttag ccaggtagag
ttctctgtaa tattatttgt tctgatcatt gcattttcac 7680tgctcctgac
tctcagttta caacatagcc caaggccagc tacggctctg agccaccttt
7740ttgtcttggg caaggtgtcc cagagctgaa gggtccacac tctccttggc
tccgccagga 7800gtctctgtcc ctcctcccct cttacttccc ccaatcccca
ggcattcaca gagtgggtcc 7860tttgtgtgag accttgggct ggtggacaca
tggggctctt tcttcctgag gagctggtcg 7920ggggatgcgt ctatcctgat
catatctcag gtgtcttctc tcccctggct catgaaatct 7980cctgtctccc
aaattatgtc cagacagggg tggtagcagg catctctctc ttccagccca
8040gaggcccacc caccagccaa atggggcatt taattggaaa gggaggctgg
caggctgcct 8100ggaaatcctg cagaaaggat cggagtggcc tgctttgaaa
actttgccac ataccttccc 8160cgcagatttc tgtttcaaat atttgaaggg
gttcttggga ccatttgaga attacacccg 8220gagccatgca atgacagatc
cctccaaacc ctggtggggc ctgtgtggtg gtgccgccca 8280atcacttggt
ataaatggga aacggaggca gatcagaggt ggagaaagaa ttgaattcaa
8340tttggttcag cactccaaat gttggttgaa ggctctttct gtgagagaca
cacaaaatac 8400ttacctgaaa gcccctcccc gccaaatcct gaagtcacag
cttccttagg gacttcagcc 8460agaactctcc ccaatatttc agtcctgctg
gatgattcct gagcctgcag attcctgttg 8520gtgtgagtca gcagggtgga
gggatgggtg aaggaaggag tgagggtcgg tgagggagat 8580tcatcctaga
ggcctcatgg gtttatctgc caagcagata aagcccctcc tttcagagcc
8640aaaatcaggg ttcatcaggg ctggagtgag gccatggaag gcaggatcag
ctgtgtgtgc 8700aagacagact gagagcaaga gaagaactgg ggtgtggagg
ggtggctggg ggcagctgtc 8760agaaggtcca ggccctgaag ccccgggtgg
tcagctgctc ctcttcacag agaccacggt 8820gctggcatct catcatcagg
gggcatgtgg ccagtggaag ccatgcaact tggtaaccat 8880gggtgagtag
ctggacctcc tctagcctgg tttcttcctt ggcagagcag gaatgaccag
8940agttgctttg ccaggtacct tgagatgaaa tgaggtgtga gggcagaggg
ccgccctgtg 9000ctgctcagag ctggtccatc agtccacagg ctgtttccag
ggccatattc cagctctggc 9060ctttttgagt catggtgctc taggaaagtt
tctaagccta gagccccatg ggatactaat 9120gggatagtaa cagtcctacc
tcacagggct ggggcatgaa attggttaat ccatatagat 9180aacctggaat
agtccctgac tggtacacaa agggggttaa attgaactgg tgctgtgatg
9240gtggtggtgg tagtgataat gatgatgatg gtatgaggag aatggtggtg
ttgatggtga 9300tagtgttgat ggtggtgata atgatggtgg taaacgtggt
gatgatgatg atgatggtca 9360tgatgatgat gatgatggtg atggtgatgg
tgatgatggt agtggtggca gtggtgatga 9420tgatggtgat actggtgatg
gtgatggtgg tgatggtgat gatgatggtg gtggccagtg 9480gtgatgatga
tggtgatact ggtgatggtg atggtggtga tggtgatgat gattatggta
9540ggcggcagtg gtggtgatga cagtgatact ggtgatggtg atgatggtga
tgatgatggt 9600gatactggtg atggtgatgg tgatggtgat gatgatgatg
atgatggtgg tggcagtggt 9660ggtgatgatg gcgatactgc tcatgatgat
gatggtgatg atgatccgtg atggtgatga 9720tgatgctatc ggcagtcgtg
atgatgatgg tgatggtgat ggtggtgatg gtgatgatgg 9780tgatgatgat
gatggtgatg gtggtgatgg tgatgatggt ggtggcagtg gtgatgatga
9840tggtgatgat gatgatgatg gggtagtggt ggtggtagtg attgtgatga
cgatggtgat 9900gatgatgata tggcaatagt ggtgatggtg atggtggtga
taatgatgaa taaatcgtca 9960tcatttagca cttgttatat gcttagatct
gtcccagcca tggggatacc acaatgaaca 10020agacaagtat ggttcctgct
ctcctgagaa tcagtactac tgatggcaat agccagtggg 10080taagttaacc
gacccatgag caaagtaaca tttcagaggg aggagctgga gagttgtgtg
10140aagtgtgggg cagcccagta ggctccttgg aggaggtgac atgtggatga
agagacgggg 10200ggagccacca tcatgagggg cagagaattt atattggctc
agataactag gacatctggg 10260gttgcatcta gcattgggaa caggcgttaa
agatgccctc tcgctccccc tctctcctct 10320ctgcctctcc tgactacctt
ttgacttcca tggtaccccg aatcaatgcc actcttacgg 10380cttccaagat
ccgttgtccc gggctagttg tgtcccctcc ctggaactca gtggtcccat
10440ctggaaagtg tgatggggaa cgctagccag acacccctgt ggtcccttcc
atctctgggg 10500tcccgagtgc
ctggccctgt gctggcgccc ttgttgggcc atggagtaac tgacagtaag
10560cagtgggcat gaggagcact tcctgcttca gggcctgcgg gagggtgaac
agttcacttc 10620acagtaggtc tctgtggctt acctgggatg gagctggctc
caggagcaat ttcccctgga 10680tgaaacaatc tttggaatcc accgtatatc
actcgccatg acgtcttctg tttaaacagc 10740ggcagccggc agagggtgag
cgaggaggcc gtgctgggag gagggcccat gtcccagccc 10800ccaaccccgg
ccccggtgga aggccccgct atgggggaaa gcaggcatat ggaacccatt
10860tgggaaattc tttctgcata aaccactttt tccaggtaag acacatgccc
atattgactg 10920ggaaagatgc aatacctctt acactttgcc ggctacattt
ttatggacct taattaaacc 10980cacggtctgc cgggttggga aattggacac
tctttgtgcg gcgccttctt aagaagtact 11040gttggcccag gggaggccaa
ttataacctc gcgtcctccc cacctcccag gacctcacag 11100accctccaag
cgcttggaaa atgtgcgctc gacagagggc ctttgattct gcttgcctgg
11160acagcgttag gcctgtttcc aggcctgagg caagtggtgg tcagggtccc
aggcggccgg 11220cggaggggcc acagagaccg gagttttcaa acttcattga
gcaccagcgc tttcctttca 11280tgcccaatcg catggagacc tcggatagaa
accagatgag cctgctgggg ctgaaggggg 11340aggttggtgg ggggtgcacg
tggccccttg ctcaccccca gctcctgttc gccatgaggt 11400gacagcgagg
acagccgcct gggtgttcag tgagttgtta acgcctggat ggttgtgctc
11460gttatcctgt ttaacaggca caggccaagt gaggtaggtg ctgttaccat
tgccatttca 11520cacctgaggg aacctaggcg cagagcagca gagggacggg
cccagggtgg cccggccgga 11580gcaggaggag tggtggggtt tgggtcctgg
aagcccgtgt gcgtggccgc ctctccagaa 11640ggctgctggg gagctactga
ttgggcccaa gcctctcttt tgacggtgct ccgggctcag 11700tgctgtgcct
tccactcccg gtggcccctg cctgtgcgtg atctccacag cacagccccc
11760ttcttgtgtc gggtagtggc ctaggcccct cctatgcttg ggttcatgga
tccagcaggc 11820cgggggggtc ctctcaccgc tggaggggct actctgccag
cctctctggt tgggtggaac 11880ctgcccttga ctagcataca tggtccgggg
caccccagga cttttcaagg atgcctttgg 11940ttggaggaga aggtgtcttt
gctttggtcc tttttgtgct ctgggcttcc acgaatattt 12000catttttagg
gaagagattc gttaatcaag aaaagtgtcc cctggatgag cttttcctgg
12060gattggctct tcctgggatg ctcaggtcat ggccccagaa accccaacct
agccaaggga 12120gcatgttagg aagccaggcc aatggaggga taatttacat
gcggtaacat ccatcctttc 12180aaggtgtatg ctttggtgaa ttttgacaaa
tgcaagtagt cacagacacc ctcgtaatca 12240agatacggaa gatttctatc
acctccaaag ctccctcgtg cgtcctccca ccccagcccc 12300ccagtggtgg
atccgttttt ggtcctcata gctctgcctt ttctagaatc gcatcaatag
12360acccatgcag ttggcagtct cttcagtgtg gcttctttca ctttgtatta
tgcctttaac 12420atccagccat agttacaggg acatcgctgg cacctcgcag
gctgggtggc ctcagggaag 12480atggagctgg gctcaccccg ggtaccctgg
agcagtcgag ctctctggca ggtagagcag 12540ggtgggtcca gaagcttctg
ctagtctttg tttcctcatt aactcaggaa tgttaatcag 12600tgctgacttc
ttggggttga tgggaaatga tgggccattt ggatacttgc tcagggactg
12660tgcacagtgg ctcatgcctg tgatcccaag gttttgggag gctgaggtga
gagaagcact 12720tgaggccaag aatttgagac cagcctgggc aacatagtga
gaccccatca ctagatatgt 12780gctcctgacc tcatagcaca gaaacccaac
cagaaaggat tcaataagtc tggatgagga 12840tggctccagg gcagcttcat
ccaagcactc atgacatcag tgatctgggt gactcctcag 12900ctgcaagatg
gtggcagctt cttctagcat cacgtcccta cgggacaaca tccaagtggg
12960aaggggcact tccctgtggt gttcccctct gttagcaaga aacccttttc
cgggagcagc 13020ccccagtttc agcagtcttc cctgtgcctc actggtcagg
gtgtgtccca tgcgtcatgt 13080ctacaccaat ctccagcaac agacgggagc
tgccaggaga gggtgaagcc tgagcagcct 13140ttgctctggg ctggagaggg
gctggtgaag cacagagcag ataatgcctg gataagacgg 13200gggctctccg
ggcaagggaa ggaggacgtg cccagaggtg gggaactggc cgtctgctag
13260atgctgtgtg tgagtctgat tgcaaggagg ttctctgtct acaaaagacc
agaacaggag 13320ggagccatta gggaagaagg ccaccaacat ggccggctga
ctgtggttgg ccttcctcag 13380ggctgaggct tagatagggt gagcctatct
tgtagatgtt cctcaaagga gaggacacaa 13440atgagcaatt tgtgaccttt
gtgtgcttgc tgtccatacc ttcatccttc catctctcca 13500tctatccatc
cgtctctcca tcccttccta atccattcat cccttcatcc atccccttca
13560tccatccatc atccatcaat ctctctatcc ctccattcat ccatcaatct
cttcatcctt 13620ccatccacct attatccatc cacttctcca tccatccatt
catctatcct ttattcattt 13680atccatttat ccatccatcc atctctctat
ctcttcatcc atccatccac tcatctatcc 13740atctctccac ccctccatac
atccattcat cagttgtcct tccattaatt cgtccatgtt 13800tccatccctc
cagcagtctc tccatccctc catctctcca ttcatgtatc atccctccac
13860ccatcatcca tccatatctc catccatcca ctcattgatc ctccatttat
tcatccatcc 13920acccacccat ccatccatcc atccatccat ccatccatcc
atctcctatc tctccatgca 13980tccgtctctc atttctccat ccctccatct
caccattgct ctatcactgc atccttctat 14040ccctccatgt ctccatccct
tcttccaagt aacaaccaag cacttgctct gggtgggccc 14100tgtgctgggt
cctggagaga aggggagaaa ctgggctctg tcgttcagga ctttggcaag
14160ggcccctcac ggttggggtg tggaggcgtg gtttcccttg gggctttccc
catagtgagc 14220atgtgatgct ttcaggggaa cactgccttt taatttttat
cccaagattc aagcagcaca 14280gatcctctct tgcttcacag cccctgtcca
atcctgcctt tcattaacta actttagtaa 14340ctttcctcgc tgtgtttaat
taagattcat acgagcaaga cttgaaggaa cacaagcatc 14400tcagtgcggc
tgggccggcc tttagtcttg ggctttttac ctcttgcccg tggtggtgct
14460ggctgcagag gaccccctga gctgggagta gaaataactc accttggttt
ttttcttgct 14520gccagacttt taggatggct ctgaaacacc agactaagtc
tgtgtccaaa agcctcaagc 14580attggcctgg gattatgtag gtggatatca
tttgaggact atggaggcca aattatttcc 14640ttgattgtct aatctccttg
ttaacaacat ttgtgaaaaa atgaagggtt tttttttttt 14700ttgttttttg
ttttttttgg ctgcaatgga agtttcaaga cttacaagga aacagctttt
14760gctgttcccc tcttagggcc ttccagcctg acaaaagaaa tcagcagctt
gcccgtgggc 14820aatctggaga ggcaggaagg tgggtgaggg aagcatgaca
tcatatcagg tgggaataaa 14880aaggcgtgtc ctgcagtgtc cctgttcaaa
catattttgg tgcttggatg cccgctttgg 14940aagctggaag accctcagca
ggaactgcga agggctccag agacccggac tcaagttttc 15000aaactttaaa
aatgagtatg gcaagggagg agtgaggggt gaagggcagc agccccctgg
15060tggggagcag gggcgccggg agtcagatct gacagagggc tcccggctgt
gtgctgcatg 15120cgtggttccc ctttttcttg gagaaaatgg ggaggcagga
gtgaggcaga ttgctctggg 15180acaatgggcc cctctcccgt cgggtgggag
cggctctggg cccaaacaat aggcctgggc 15240cggcccctct cctgctgccc
accgtctgag acagatgccg gggagccgcc gggagtgccc 15300cagaggtgac
cttcgggggc tgccctgtca ctttgtggag gagtcctgga gagggaggga
15360ggcaaacaat ggtggcctca tgccaggcgc ccggcctccg gcacgggcca
gggctcccca 15420gggagagcac ggcctggcag gtgctgctat tgtctcaggg
cgcaggggcc ttccgcggag 15480gtctcccggc agggaggcag ggcaccggtc
agcacgcggc aggagaggct tgggctggag 15540gccctcttgt tgttctccag
ggaggacgca aggagctgat tctgctggct ccattcaggc 15600ctgacagccc
cagcccagtt ctgccctcag cccctaaaag cgtcattcag aaaagcaatt
15660aacgtctctg gcctccaatg gcaccgggac tctgagtgtc agattttaca
gccggacctg 15720ccctaggaaa tgcccaaatc tgagctgaca tcctcgcttg
agctgggggc acaggcggag 15780ttttctggag gaagggcatc agctcaggag
gacaaggggt gagccctgga tttgtctttt 15840ctctgcaaag agacttgccc
tgggagaacc cccacaccat aagctgaaag cagtggatga 15900gcgcagcaag
ggctctctca tcctggggag gagcagtagc taatgggtgt gcgtgtgtcc
15960gtgtgtgtgt gtgtgcatat gtgtgtgtgc atatgtgcat gtgtgttttt
gtaggcatgt 16020atatgtgcac atgtgtgtgg ctatacatgc gtgcacacac
acatacactg caaatgtgtt 16080catgttgtgt gtgcgtttgt gtgcacacac
gtgtgtctgg gcaggtgtac atacctgcat 16140gtgtacacaa gtgtatttgt
gtgtgcatgc ccatgtctgt cccatgtctg tgcacatgtg 16200tgcatacgtg
tttggcgggg tgcatacttg tgccaggcac tttgctgggg atttttgcaa
16260acgtcattca tgtgacttat gatctgctgg gaacaggcat tgctatcttg
accacagatg 16320aggacacaga cccctgaaag gcacatgact tgactatacc
tcctcaaact cctcagaccc 16380caaggtgggt ctgcaagacc tcacaacttg
ggccttttct actgtccact catctgcagg 16440ctgtgtcctt cctcagcctg
ctggctctgg gatctgggaa tgtgccttgg tcggctgggt 16500ctttgagact
gttctaggcc ctaggggaga agcagacaca gtctctgccc ttgtcctgca
16560aaggggaagg gaacatggag ggcagaagtg gctcctctag gtggcaggga
aggtggtagg 16620ggagtccaga ggaggcccat gtcctgctct caggggccag
ggaatgcttc ccgggagaat 16680gatgtccaaa gccaggctgc aggttgagcc
agcgtgaggc aggtgagaga ggcctggaga 16740agtccctagc tgtagagaag
gtgcccgcag ccctgaggga gccaggggtt acctgggggg 16800aggtctgagg
ctcaccaagg ttgggtgctt gctgtcacct gcttcattgc ggagccatac
16860atggagctgc ggagttcaag gttggcttct cagacaccta aggcagcctc
acagctgagc 16920cagtctgggg aggaggacca cctaggggcc tggcaggtgg
tccaagtggc tcctcaactg 16980gaactatgcc ctgccttgcc ctggttccct
gtgctggggt gactctgtgc tcaagcctat 17040gataatcgtc tctctgcctg
cctctggtgt ccctggtcct ccttgtactg caggagcttg 17100tgcagggcag
ggtgagtggc ggggacttga ctctcacagt ccctagctct actggctctg
17160agatttcagc caacctcccc tccatgagct gcgctgtcct catctgtaaa
gtggggggat 17220tggcagaaag ccacggacag tttcccacag tgccctgccc
atcaagcagg ccatattcag 17280acagtgctgt catttcaccg aatggaggac
tccctctcac cccctctggc tggcatttca 17340ccaaaccgag ggttccctct
caccccctct ggctggcatt tcactgagca gggggccccc 17400tctcaccctc
aggcagacct gtcattgcac ccagcctttc tctctcctga tgtgcaacac
17460caggctgggc cggcgctgac caccctggac atggcagtgt ggacggtaac
agagccggtg 17520acccgccctc cgtcggggcg ccttccctgg cggctcttgc
tcctgccgtc ttgagttcaa 17580cctcccaaga ggggctctgg tgggtccagg
tagttcttct ccccgctgtg tgtggctttt 17640gctcctgatg gtttcaggct
gtcggtgccc cgggggttgg tgttttcccc ccagctcctg 17700gtctctaagc
tgaactaggt ccaggctctg tgaacactgc ccagtccctg tggcagctcc
17760atcaggggcc tctgagcgtg gcaggcaccc atgcactgtg ggcgttttct
ttgagatgct 17820gcctgcccgt tgcgagctgc tggcctaagc tcctcactga
gactgcctgg cattcggagg 17880acgaccacag gggtgtgagc tgccccgggg
tgcattcgcg tcaaagaggt tgaggtggaa 17940ccagctgcga ccctcagcag
cagcaagtgg ccactttggg gaccctgtgg gttttgagtc 18000agaggaaaac
agagtttaag ccttttccca tttgtcctga gagtactcac caggggcttg
18060cgactgcagt gtttaccccg agataactcc gccacgaaat agctcgattt
tattattatt 18120tttgcatcgc tctagtatat tgactttgga aacaaaagac
gtcatatcct actcatagca 18180ttctgtttct agtagcggca tttccattta
caaaatagag tcattctcga tcgctgaaaa 18240tgtcacatcc tagaaaacac
agaattccta cgcgtggttg ttctcggatg tttgttggcc 18300aaagattgat
ttgacgaatc cgttttttcc aaaatagacg attctgatga ttcacgcgag
18360tctgatgtta gttctgttta gaaatgactc caagaacagt ttttatgttt
tattttctca 18420ttgaaaagca gtcagatttg cttcagcctc aagaagtgtg
tttatgtaaa attaaatgag 18480tgctggcttc gagccgcact tttttttccc
cctaaacaag aaaagggtta aaactggaag 18540aaccttagaa atgacccctc
aatgcacaga tgctgacaca gaggcccaga aagaagggtg 18600tttttggggt
ccctgggaag ctggggctct gctgccctca ggacatggag cgggaatact
18660cagcccaggg caccctggcc ttttctctct gggctcccgg gtgagtgttc
aggacagcag 18720ccaggtcatg actgatgatt ttctagggac ctctactttg
ctcatttaga atcactgtga 18780ccctatgggg tggggggcac cggagatgtt
tgttccgttt tacagtcagt aaaactgagg 18840cccagaagga gccaggatgt
gctcgaggtt gcacctgagg ccagggcaca gcagtgtcca 18900gggttctttt
agaaacgttg cccttggtct gagtcctagg cgcgtgggtc caaagggatc
18960tcaggtggga ggatggtgct ggggggtggg gcccacccag cacctctcag
ggaggcccgg 19020actcatggct gcccggggct gggtggagga gctctgttcc
tctgggtctg tgcaggcagg 19080agcagaggtc atctcctccc tgagtgaaca
ggccttgacg gttgtgtcat ggggccccgt 19140tggggggaca ctgtttaatc
tgactggcat gagtagattt caacgggtcc aagtctgact 19200gctgtggggt
gcctgggagc ggggctgggt gtgcacggcg gaggccccag ataccatcct
19260gcctggagat gcaaggtggg aaggtgtggc agagtcctca tggccttggc
gggctcgggt 19320ggcagggggg acctccatct ccaccctgct ctgtttgacc
tgggctgctt actggagggt 19380ggagggagag cagcagggcc ttggagggac
ttagtgaatg accagcagaa ggagtggctt 19440ccgatggcac aggcgtccag
ggcagatggt tccggcccgc ttacggtggg tgagacacgc 19500agaggaaata
ccctcagagc taaaccctgg ctcctgggtc agccacggag tttcttcaag
19560ccccagcttc tgtatctgga aagggggtga ggagatgacc tttcttgagt
aagtcagtgc 19620tggagaagct gttcgtgttc gctgagggtc agcttttgtc
ggcgcaagaa tcagacctgg 19680ccatgttgcg gggcactcac tcagccagtc
tggttgggaa acctgccttg accttggctg 19740gagcgaaccc ctctcccaga
cagtgattca tcgggggatg tggtgttgag gaaggggtgg 19800tgaacacgtg
ctattgaagg gacgctgttt ttctcccccc gcccccgggg tttcgtcact
19860ggcctgggaa aaggctgaat ttggagccct gtgggccgtg cacttggtga
ggactggtgg 19920gtggggtgtg tcccggctgc caagggagga aggcacaccg
tcctcttttc ctcttttcct 19980gaggcctcgt ggtggtcatg acagtagcag
ggccgatgac agctcacacg gccagcagtg 20040tgggctcctc actcaaagct
caaacatgag gcacaggcga gcttggtcac ctggcaactt 20100gctcagggtc
acatgtctgc tcagccatgg ccgggactcc aatctgcctc gcgtcctctc
20160ctgctccttc tgggccacgc tgcgcaggga gaaggacccc ggctgggtgg
aagcccttgg 20220actccctgcc tcagtttacc catcatgtct tttgacctaa
ccatagcgac ctttggcgct 20280tatgtataaa gctcgctctc ttggctgcgt
caccaggcct gggttccaga gagccctccc 20340tccccatggg cccaaggaag
ggcctggagt gaggtggcca gccgcagctt ggctgggatg 20400gtatggtggt
ccataaggcc tcgtgggctg tccagctcca gccagccagc ctcggtgaag
20460ccagccgact tggcggcagt ctccagcact ttgagacgtt tgtccccctc
ctgcccccgt 20520ccagctatga caagtgggct ttcagtagat atgacagcct
ctggtggggg gtccctggcc 20580cctgtccatg tctctacact tgacttgctc
ggagttcact ggcccgaaat aatgttccca 20640atgcaagtcg gcggacggaa
cattcggagt ggacggtttg cttccccccc actttttaat 20700acattaaaca
tgcgttactg gagttctacc cgattcctct gacagctgtg aaaaaataaa
20760gaaaattcag tttgaactta aaaagctcgg gcttaattta tgtcccgcac
ctttgtctgc 20820tgggtccttt ttcctcttcc gatggaaagg ccccagggag
cgggcgacag aggctcggcc 20880accccacgtg gcccctcagt gcccgggcct
taataggggc gcccagtggc caacacggag 20940gggagttttc agatggaaat
cggacaaaac aatgcaatca tctgtctcgc aatctgtttt 21000gaaggggaaa
gaaagagcgg gcagagagga gagagtcgtt ttctactagg ggaggcttca
21060ttcagagagt tttataggag aagacagatg tcatgaatac tgatgtggag
agcctgggtc 21120tggcagagtt tttttaattt tctgagttgt aaagacaaag
tgttttaata acacagggaa 21180acacatgttg atgggtgggt ctttagctca
ttctgatttc tctaactccc tctctttctc 21240ctcctttctt tccgtctttc
tgcctgcctg cctgcctgcc tgcctgcctg cctgccttcc 21300ttccttcctt
ccttccttcc ttccttcctt ccttccttcc ttccttcctt ccttccttcc
21360tccctccctc cctccctccc tccctccctt ccttcctttt tttgagacag
ggtctcgctc 21420tgtggtccag gctggagtgc aggggtgcaa tctctgttca
ctgcaacctc tgcctcctgg 21480gttccagcga ttctcttgcc acagcctcct
gagtagctgg gaccacaggc gcccatcgtc 21540acgcccagct aatttttttg
tagttttagt agagatggag ttttgccatt ttgcccaggc 21600cggtaacaaa
ctcctggcct caagtgatcc acacacctcg gcctcccaaa gtgttgagat
21660tacaggtgtg agtcaccatg cccggcctct ccttttttct tcttctttct
ttcctttctc 21720ctccttttcc ttttatcacc ctgtctccct ctgtctgtct
ctttctccct gtttcttctc 21780ttggcctgtt atggggttcg ggagccacac
aaaacatttc cttctgtgcc ctttcacggc 21840ccaccttcct ggttgagaga
aggaatctgc tcttctgaag cactgtgctt ccatctgaat 21900ggcacagcat
ttccgagttt ggggacagaa tgtattgagc taaaagaggt gtttgctcat
21960gcactcactc tacaatgggg gcgggaaaaa caggtgaatc aagtgtgggg
cctgcctgtc 22020cgtcaggagc tgctggtcag acaaatatga acgtggacac
aacctgctgg gaggcgtctc 22080tgcttttggc tctctgggca gtggggcacg
tgtgcccata aggcaggtgc tgtccctggt 22140cttggaactt cttatgaaac
cagcctgccc ggcacctcct gccatccctg tgaggtgatg 22200ggacaggtgc
taagcctgcc cttggacaga taagaaaact gcagccccag gcacagaggc
22260acaagctgag aggtgacgtc aggactgaac tgtgagcctg ggagtccaaa
tctaggctca 22320cccagtcttt ctggctccag tgagggcccg ccactgtcat
ccgacggatg gcatgtgtga 22380tttttggcac acgcctgtgc aggtgactcc
cacaggtgcc ccggagggag gcgctgctgt 22440gatgttcatg ctacatgcag
gaaacagaga ggttgagtga cttgcccaca gccccacagc 22500tcctacctag
tgaagcctgg tttgaggcca cacctgcctt actagtttta ttatttattt
22560attttttgag actgagtttc actctgctgc ccaggctgga gtgcagtggc
gcagtctcgg 22620ctcactgcag cctccgcctc cggggttcaa gagattctgc
tgcctcagcc tccagagtag 22680ctgggactac aggcgccagc caccacaccc
agctaatttt ttgtgttttt aatagagacg 22740gggtttcacc atgttgacca
ggctggtctt gaactcctga cctctggtga tctgcctgcc 22800ttggcctccc
aaagtgctaa gattacctgt gtgggccatc atgaccagcc actattattt
22860tttaaattgt ggtaaaatat aacataatat ttatcattct agccagttgt
gagtgtacaa 22920ctctgtggca tttcatccat tcatgatgag gtatagccac
tgctgctccc tatacccaaa 22980catttccaga gtcctcagca aaacctgggt
acccattaaa cagcaactcc tcccagcccc 23040tggtaacctc tgttcttctt
tctgtgtctg tggatttgac ttctctgggc acctcatgtg 23100agcggaattg
tacggcatgt gtgtcttcat gtctggctta tctcacccag caaatgtcgt
23160ctagcttcat ctgtgttgta gtgtgtgtct gagcttcctt ccttcttaag
gctcaatact 23220attccaatgt gtgaagagac cacatttcgt ttatctgttc
atctgtttgg tgactgagct 23280ccctccatgc tctccaacaa taatcatgct
cctccacaga caggtgtctt ggctgatggt 23340gtcagagacc ccctggcaag
ccgctgctat gggaggggtc ttctccctct catgccaccc 23400aaggagactc
tgtggggtcc ctgcagaccc cgcagcatgg tcaggggctc tgactggagg
23460ctgttccctc caacaggact cagcagtcag ggtctcccag ggaacccctg
tatgcagact 23520ctgggaagac aggtggatca ggtgtgggga ctgtctgtcc
ctcaggagct gctggttgaa 23580tgaatgcgac tgtctcctgc tgggacacgc
ctctgcctca ggctctgggc agtgggggac 23640gtgtgcccct aaagaaggta
caacccccgg tcttggtgcc tggagtcata agatccatag 23700acacagggca
agaggggctt cctgggcacc cgccgtgtgc aggctctgcg tgaggcacag
23760ggttcgggac tcagtggtga ataaactgcc atccccttgt ggggaagaag
ggcaggtgca 23820cctagcttac gcgttcactt gacaagcaag tattgagtgc
cttctgtata caggtctgca 23880gctggtgctg ggggccggcc tttggatctg
gtgtccaccc cctgacctgg gcccaggccc 23940tccccatcgt cctctgccgt
aggaggtatc agagagcaag taccttcctt agtcacaccc 24000atcacgtaca
tagtggatgt gcctcttttt cggggcaggg ggtaatctta atcaccaagc
24060aattactaaa tgccgaccat gttctcaggc ttggcagagg tgggtgcttg
ttaccccaag 24120ggacaaccac ttccctccat gctccccacc ccacccaaga
cccttctcca ctccactcct 24180gactgccgcc tcccacctct gccctgggtc
gctgtcttta ttgtcttcct caacatcttc 24240catgggaaag gccaatggct
tgaaacagga ttgacgagac acccggggcc tgctccacac 24300ccgtgggctc
ctgggcgtgc acccaagagc ctccacccct gaatggctgg catccaggtg
24360ggcttcccat aaggagcccc cttctgcggg cctgggaggg tggggagcct
gtggcgaggt 24420ggcggggaag agaaagggca caggtgcccc ctcactccga
gcctatcgga tcccggagac 24480ttgcaggcta tagacctaga ggtccagcca
ggagggctgg cagggaccat gaagcaggag 24540acgtcagggc agagagaatg
ccttttagag ccagataaat tcttacttcc cctttcccag 24600ctgcgtgacc
ctgggaaact tcaacactcc gtgtctcagt cctctcatct gtaaaatgaa
24660tctgatgaga actgtgtaag aatagaggtg tgtggagagc tctctggtgc
caggctcatg 24720gcaagactgt ggtgacacca gccatcggaa ggcagggagg
ctcctctgtg gacagctgga 24780tgcacaggtg cgtagcagga gctcaggagg
gtgtgcccgc ggagtcgcag gtaagggagc 24840cactccagat tgcagagctt
ggcttggagg tgtcgcctca ggagggtctt ccattgcctg 24900gagaccccac
ataggccctc ttcttccttc aaacacagcc cccaacctct ctgcagggaa
24960gtcctccctg accttccaaa ccagggcaga cccttgtctg ggctccgtcg
gcctggacat 25020ggtgccattt cccactagtg gggcagaagc ctgtctactt
cagtctccct tgtgtcccca 25080agcaatgggg acttgagcat aaacgttcat
gagtgacaca tttatattga taggcagggc 25140cacactgtgg gaggagctgg
tggcctgaga acccctgtga acagcagggt gacacgtggc 25200ctctggtgat
cccttttggg aaacgtctga gagtctgagg ctgtcaggcc cctgacgctg
25260actcatggct gggacaacct tgagagagtc actgctctat ttccccatct
gtcagccagg 25320ggcttggcat gggtgttctc tgtgggtcct tccagcactg
aggttctgag gtcattgttg 25380caggggtaga cgactctggg gtggcaggtg
gggctgccgt aatcttgggg gaatgagctt 25440tgctttaggt gaggctgtgc
agaggcatct gtgtcgaagg agaccaaggc ctgctctgct 25500tgcctccctg
cagctggctg ggctccttgc tctccaaggt tcctggactt tcctccagac
25560ccgagtgcaa
gctccctgtg gcttccaccc accgctcaca ggagtctctg cagccaccag
25620acccagagcc cagacaccat ccactgtcgg ggagaggcac gtgtccacag
cttcctggaa 25680tgcaaggctg catgtggcca gggctgctgc ccgctgaggg
gcaagtgcat gcctggagac 25740cacagtaagg agccagtctc atgctctggg
agtttagata aggcttcatg ccccttggag 25800ccaaacctct gaattccatg
gagttgttgg gtcaaagagc ttgcctaggt ctgagttgtg 25860gatacctgtt
gtcaatgagc tctccacaaa ggggttacca tgataggtcc caccacctgt
25920acctctcctc tccaaatttc accactgttc tttcacacct ttgccaattt
ggtaagtgca 25980aaatgatatt ttagttgtct atgcttacac tgattggagg
aatgctttaa gtttgattat 26040tggtaagtga aacattttgt tacctgtatt
tactgatccc actttccttt tatgaatgtc 26100ccagttacat cttttgtcca
tttttctatt attgtgtttc ttgttcttac tgatttgtaa 26160gagctctttg
tatattcagg ttatgaagag ggtcaaggtt tattcatgaa tgacatttct
26220cttttctgaa gggggcaaat ggagcattta ctcctttctc aaagtgagct
gatatttgaa 26280tttattattg tctatttttc catactctgt tttacacttt
tctttgcact ttgtagctgt 26340ctgggcacag atgccaccga gagagctaga
aaaagtcaca aggagatctt ggtctcagag 26400caaagggccc gcatgtaacg
gctttgtagg tcccagtgtg caggagagga tgtctgagtt 26460catgctctgg
gtgctttccc tggccggcag atgacaggga aggagcaagc cccagtccct
26520ccccaacaca cacagcccct gcccccgacc aaacacgaag tcacttcttt
ggggacaagc 26580agatttttca aacaaagttt gccaaatatg cacatttttt
ttttttctcc agggcagatg 26640caaacggtct tttcaaatca gtttggagga
aaataaatga gcccacgctg aggcttcaat 26700aaatctttgc gtagccacaa
gggtgagttt tgggcccgat gaagggccca gtgtgtggct 26760tatgaatgat
gcccagtgac ggctctgctg cccccgcctt cccctcttcc cctcctccgt
26820cccccaaccc aatttaaact tggacattaa tgttttaaga caaagggacc
tttgggcatt 26880tctccccctt gtggaggaag tctctccggt gaattatttg
tcgtggctgt gctcggcgtg 26940tgatgggggc tcgtgtctcc gagccagggc
ctgtctccag gagatgatcc atgtgccgcc 27000ctcctgccct gggggctcca
ggacccccag ccccagatgc agacaggact gtggtccccc 27060gaggggatta
ttcctccctg cctgccatcc ctgctggatc ctggatcgtg ctggcagcaa
27120cccagtgtgg ctcacataga catcgcctct tgatgggtct ccctgcctta
gtccccatcc 27180attctccaaa gtgggggtgg ccgaaggatg gcgtgagagg
ctctgagcct gcctttcccc 27240tgaatatccc tggatcaagc ccaaagcctt
agcttagcat cctggtgaca tctctgctct 27300catctccctt cctctccctg
gtgtggacac tgcacccacc accagctctg agcacatggc 27360ccattggctc
tgcaggggcc ctcctctctg tctgcagtgg ccaccttgcc accaggccca
27420cctgaaggaa ccgtgcctct ctttacggac tgaccccaag gtttgcccat
gcttggaggt 27480ctgtctgact ttgctttcct gatgcctggc agtggaccac
catgcccact tgtcggtggc 27540tgtgtagctc atactcactc catctggcag
tttccaccca ccgaggacca ctcaagtttg 27600ccccactcca tgtctgctgt
tgggagggga tggtgcatcc cacaagcaac aggagccacg 27660gagctggggg
ctggggctgt cagcctggat gggccaggag gggaccttgc tgtgcctagt
27720ggaagagtag gtggtcccct actggctcca ggccgctggg tgggtcactt
gcccatccct 27780gcctgggtgt ctatagtggg tgttcccgcc aaaattcatg
tccccctgga acctcagaat 27840gtaaccttat ttgaaaatag ggtctttgca
gatatagtta agtaaggatc ttgagatgtg 27900gtcatcctat attgggggag
gggacagtaa atacaataaa tgtccttggg aaagacaaaa 27960gaaaagaccc
agccacaaag aagaaggcca tgtggagaca gaggcaggga tgggggtgat
28020gtggctacaa ggcgtggaac tcagagcccc cagaagctga aggaggcggg
aagtttcctc 28080ccaagagctg ccaggggtgg ggcggggcag aggtggcatg
cggaatgctc tgcccacact 28140ggatgtatga atctgttctc atgctgctag
taaagacata cctgagactg ggtaatttat 28200aaagaaaaag aggtttaatg
gactcactgt cccacggggc tggagaggcc ttataatcat 28260ggtggaaggc
aaaggagatg caaagtcgtg tcttacgtgg cggcaggcaa gtgagagaga
28320gcatgtgcag gggaattccc ctgtataaaa ccatcaggtc tcgtgaaact
tactcaccaa 28380cacaagagca caggaaagac ccatcctcat gattcagtta
cctcccacta ggtctctccc 28440aggacatgtg gggattatgg gagctacaat
tcaagatttg ggtggggata cagccaaact 28500gtatcacttg atttcaggat
cctggcctcc aggagtgtga gagggcaaat ttctgttgtt 28560ttaagccacc
tggtttgtgg caatctcttc cagcagcccc aggaaatgaa cacagggtcc
28620attgccaaca gtcctaaaat catttttgaa ggaagcattt ctcaatttcc
aggtttcctt 28680caagtagagc aggtcctttc cactgctgcc acccagagca
ctcgtctgtg agcccagaga 28740gcttcaggca ccatctcctc tgcccttaca
gctgccctgg aagagagagg cccatgttgc 28800cccctcttca tggaccaaaa
aattgagccc cagagagata ggcacatgat caaggcttca 28860gagcttgacc
acttgggctg actccctgtg acttgggcca ggccacaggg ggaagcagca
28920gacaggctgt ctatattcac agaatctggt tttgtggctc cacacactgc
ttgtacctgg 28980gtgggagctg gtagacttca ctgctaccag aatgttcacc
caggaggcag tcagaatgca 29040ttgaatgaat gactgcctga ctatgaagga
atgaattgat gatgcagcca gtctggcaaa 29100ctccagggat gacgatcact
tttaccattt ggaccaacca accaatcggt taaattacca 29160ttcagccaac
caaccaacca accaactaac caaccaacca accaatcaat cggttaaata
29220accaaccaac caaccaacca accaaccaac caaccaacca accaaccaac
caatcaacca 29280accaaccaac caatcaacta accaatcagc caaccaattc
aataagcaac taactaaaca 29340acctaacaac caactaacta attaaccaat
taaataacca actaaccaac caaccaatta 29400aataaccaac taaccaattc
aatagccaat caattgatca attaacaaac tcatctctcc 29460ctccctacct
ttctgcctta atgggagtgg ctcttgttcc ccttgcaggg ctcccagtcc
29520ataagtgcct ttggcatact ccatttggga agtggacagc tcatctcatt
ttctaagaac 29580acctctggat tatgcccctt ggtgatgtag ccaccttcca
ctcagtgatg gtcaacatct 29640ggaggtgtaa atagaataca gatgaatcca
gacttggagc aggccatggg gtattcttaa 29700agactccatg tgtgtcttgg
agtagcccat gtcatattca gaatcacagc tggggctcca 29760aatcccactg
gcctacccat taatctatca ctgtagacta gtggtagaat tggtgaccag
29820atattctagt ctgggatatg atcttgggat cttaagagaa ctttctgcac
ttcaaggtcc 29880agtttcttca cccagagaag gggctgccag gtataccacg
agatgagagt tcctccacag 29940ggggacacaa ttgcagcaga gatggccaag
ggcaggaact cctactatcc tcatttatat 30000atgaggcaaa caagacttgg
agaattcaag tgacttgctc aaggtaatgc agccagcctc 30060aaagaaaggg
agccgagatt aaaaccctgg cccacatgct ccagagctgg gaggcttttc
30120tgtaggccca tcaggagata agttatgtct cctggctgaa ggccaccttc
cacctcccag 30180cccccaagcc aattgcatca gacataaaga tttgtttcag
ggtgtcttgt tggttttcca 30240gctccaacct ggctcaggat ctccttttgt
tttttggact cattcccagt gcagaggtgc 30300ctgggctatt aatagcagag
gaatctgggc tccatcacca gcctttccat ccatccatcc 30360atccatccat
ccatccatcc atccatccat ccatcagtcc atctcatatc tatttgtctc
30420caacatctgg tttagtataa acatcgatag aatgaacaaa tgcaccagtg
ggccttgtgt 30480tggacacttt ctgtgtcctg cctcaaatca tctccacctt
ccttactgca gcccttctgc 30540tgacagctgg ctgcatgggg gcaaaaatct
gacaacaccc actcctgctg ccacagtctg 30600tcctttctgc tctggggttc
tctgctgcag tgcctttggg agcttctcag ccatctgact 30660catgctggcg
aggtgtgcac tctgcagcag cgccagctgt aagacacacc ctcagatggg
30720cttgtcctct tgccctgttt catgcctcct ggtccctgtt tctgggcctt
atccccaaaa 30780cgtgacactt gagtaagccc ttttctaagg ctcaggcaga
tccaaaagca catttaaata 30840ttttcaggat tctgccgatt tagagcaact
aggattccaa agaaggaaaa cttactcaat 30900cagtttattg tcagaggctc
cacatcattc atttgtttat tcattttttc gcttattcat 30960tcagtcaggc
cacaagtttc ttcaggactg ggatcatgct tgtccccatt ctgttcctaa
31020tggaggctat ccatgtagta gtcgctggca aataactctt agtgacttaa
gttcaggagg 31080cagaagcatg gtgaaggggg cagatactgg gccagaaaga
catgcattcc aatcccagct 31140ctaccacttt gtagaagtgg ggtcttgggc
atgtcatttc acctctctga gcttcagttt 31200tcccatatgc aaaatgggca
taaagatagc aatttgaggg gttcctgtgg ggctgcaatg 31260agacctcatg
catcaggccc ttcacacaga gcctggcgag ggctcatggt gagggatggg
31320ctgtcactaa tgtgactggg agcaagcagc cttgggcagt tgggctggat
gtctggggcc 31380tggcacccga actcttttgg cctgcctcag tacccgaggc
tgcccgacac atttcttggc 31440cttagaaaca gccaagaaaa tcagcagccc
ctggctcatc ggtagaaacc caaagaaaca 31500aacaccttgg tggccaggag
gggatgggca ccttgccctc ccagcgggac agctgacagc 31560aggcctgatg
cagtgatcac aggcatctgt gggggtgact agccttgccc tggctgtgtg
31620agacatttcc ttgggaaaag tcttgctcct ttatgtgcat gtcagctggc
tgtgaaatga 31680gaacttctga gaggcttaaa gaaacccacc caatctttgg
agatctctgc cgccctcttc 31740aagtctcaat agcatttttc tgccgacggc
tcgtgactca cagaggctac atttgtgact 31800ttcgtaccct cagaattgga
tttaaagata ataaaaattt ccaataggaa aaaaaaatgt 31860ctgggttctg
acattatgct aagtctccac cttttggggc tgagtgccca gtggggcaaa
31920tgcgggtcac tttcttgaca ggcccaagga agggtctcct tccagcagga
accttggatt 31980ctcgaatcag tatctttcct gatgcccagt gtgaggtgca
attcttgaaa gaacagacca 32040gatcagtttt ttttctgttc ttttcttatc
atcagtttgt tttagctgtc tttcagcaaa 32100agtttcatgc atttcatttc
cttatgtagt cctgacatca tctcttaaga gcaagacact 32160gggatcatgc
ccatttcaca gatggagaaa gtgaggctca ggaagaggaa atagcttgtt
32220caaaatagtg cagctggaaa gcagagtgtc tgggacctga acccagggca
gccaccctgc 32280accagccatg tgtcagagcc tttctcagct cccacctggg
caggtcatcc cacaaccctt 32340cgtttcctgg ccccagccag tggcatctga
gctgaagacg gagggctgag gatgaggctg 32400atggcttgtg gctggttgga
gtctccacag acctgtaccc cactgcgagc ttccatgagc 32460tgctggcgcc
tcacagccct gggcctgagc ctaggtgggg tcactcaggg acatgggcct
32520gcctgctgct gaggctctca ttcctggaga gagagcccag ggagggaagg
tggtggggga 32580acctcggggt tggaggcgtg ggcccccaag catgtcccgt
cctgcagaca ctccctgctg 32640cccgggctga ccatgggggc atcctgcctg
gtgccagcca gcccagcctt gtctagcctg 32700cctctgccaa gtggcccatt
tgactgtccc catctgtttg cccatggagt ccggagggtg 32760tgccctggcc
cagagcccag ctgcagcctg ggaaacacca gactccatcc atggctcttt
32820gttttatact ttatccaata ggcagtaagg acctcagaga gcatcaggtc
cagacctctt 32880gccctgcaca aatggagaaa ctgaggcaga gagagggaag
gggcaggtca gaggcagtat 32940ggggttgagt cctgcgctct ttcaagattc
tgttggctaa atccattgtc cccagaagcc 33000cttgtgcatg tagttttcca
tgccgtgatg ggggctgggg agtcccttgg catcaaatgg 33060gtggtttgga
ttctgctgag gggtccacct gcctggtgag caagagacca ggagccagga
33120gccaggagaa tggggaggct cagggccagc cgcccacctc ccttgggcac
cttaatatac 33180gcagcttgtg tatatacata cacttgtgca aggagcttta
cgtcctgcct ttgtccattc 33240aggctgctgt aacaaaacac catagatggg
tgggcggctc gtaaataaca gatgtttatt 33300ctggaggctg gaagtccaag
atcaaggcgt cagcagattc agggtctggt gagggcaggc 33360tggttcgtaa
accacacttt ctcacagggt ggaaggggtg aggtgtctct ctatggggtc
33420tcttttataa gggcactcat ccctttcatg agagctctgt ccccctaagc
taatcacctc 33480cgaaaggccc catttcctaa caccatcacc ttgggggttt
gcattttggg ggaacataaa 33540caatcagacc atagcagtcc tccactcaat
acccatgcct ggctagtggg tacccgtgtc 33600tggctagtgg gtacctgtgt
ctggctggtg atacctgtgt ttggctagtg gatacctgtg 33660cctggctagt
ggatacccct gtctgactag tgggtacccg catctggcta gtggatatcc
33720ctgtctggct agtgggtacc aatgtctggc tagtgatacc tcgtgtctgg
ctagtgatac 33780ctgtgtctag ccagtgatac ctgtgcctgg ctagtggata
tccatgtctg gctagtgagt 33840acccgcatct ggctagtgat accggtgtct
ggctagtggg tacccatgtc tggctagtga 33900tacctgtgcc tggctagtgg
atacccgtgt ctggccagtg ggtacttgtg tctggctagt 33960gataccccgt
gtctggctag tgatacctgt gtctggccag tgatacctgt gcctggctag
34020tggatacccg catctggcta gtgataccta tgtctggctg gtgggtaccc
atgtctagct 34080agtggccaat acccagaggc acccaattca cattttgtct
cctttggcag aagatgacct 34140gtttgctgaa atgaaacctc ttttctgggg
acaccctctg accaccagaa atcgggctgc 34200tcttatgcag ggggtgagtt
ttgatgagat gggaacaatt tcaggattga gcttctcctg 34260gaggaaacaa
agtgcctcac gtagggagaa gcaaggggct taaaagttgg gagagagaga
34320gagtgtcaaa gacaaaactc aggggcaggg tgtcggacag aaatccaagg
tgaacctcaa 34380aggcatgatg tcacgttttc ttgtagtcac attaaaaaaa
aaaagaacaa ataggcaaaa 34440tgtattttaa taatatattt catttaattc
aatcgatcca aaatgcaatt gtctcagcac 34500ataactacta taaagcattc
ttttttgata tttttattga tatagttgta tgcatttggg 34560agtcgtgaca
ttttgatcaa tgtacacaat gtggaataat taagttaggg taattgggat
34620atgcaccact gcaaatattt atcttttctt tttcctttct ttcttttttt
tttttttttg 34680agacggagtc tcgctccgtc acccaggctg gagtgcagtg
gcgcgatttc agctcactgc 34740aagctccgcc tcccgggttt ataccattct
cctgccacgg cctcccgaca tttatctttt 34800ctttgtgtgg gaacattaca
cgttttctct tctagttaac ataaagcatt attaatgaga 34860tattttacac
cttttttttt tttttttttt ttttttggaa aaagccttca gaattcgaca
34920cctctctatt tggaccagcc acatgtgaag tgcctggagg ctgtgacggg
gcagtggctg 34980tcatggtgaa ctgctatgta gtgattctag agtcagatag
agatgggttt gagacctgcg 35040tgtgccacta actgcctgtg tgacttacgg
gtgccaagta ctattctaag agctttacac 35100atatgaattc acccagtctt
aggaagtagg gtgctgttat catccctcct tttttttaag 35160ttgaagacat
gagggcacag agaggttaag tgatttgccc acagctacac agctattgag
35220aggtagggcc gagatctgaa ccccgagttt gatttgtcag aagtgctttg
taaactgttt 35280cacaaagcct gatcattaat caatcagcga ggcaactcat
agagtagctc cctgggaatg 35340gagccattga gtgtcgccat gccctgggaa
ttcaccgcag ctcagcagac atttattaga 35400tgcttgctcc ttgccagcta
taggggagcc tggggcagac ctgagttttt ctgccaggga 35460ctgttttttc
ccggccttcc cacggagccc ctcctgcttg ctgggtgtcc acccagagcc
35520ctcgtgggct gggctccccc accctggcct ccaccctgcc tcagcctcgc
ccgagagctc 35580acatgttcag gccgagacct gcgccagcct gggcattcct
gcaagtgggg gaaagctggg 35640cccacatcca cggacagtct tgtggcccag
cccgccctgt ggccgggcag gatttttgcc 35700caggaatctg cagggtgctc
ccttgtctct ggggcctcct gggtccctgg aaacaggtgc 35760tggttttaat
agccgagtca gtttctggtc tgggtttgat tctcctgacc cacggagctc
35820agcccctccc tccttctctt cccctgtgtc tcatttatcc acctaaaagc
cattgaacac 35880tattttctac agttgagttt taacgtatat aagtagcatg
cacacatttt aggtggacag 35940ccaggggata ttaacttacg tttacaccca
tgcaactacc gcctggctca aggtagtaag 36000gatttccagc ccagcaaggt
tgccctgtgc ccattcccag ccaatagccc ccactgcagg 36060tcaccactca
tctgagtttt gtctctgtag atgagttctg cctgcccttg aacttcataa
36120cagtggaatc ctccagtatg tggtcttttc tatttgtttc ttttgagcaa
catgaacttt 36180ttgagattca ttcattttgt tgtgtgtatc catgattttt
tattttattt ttaaaaattc 36240ctgagtagtc tctctttgta ggaatttacc
atgggtttgt tcattgtttt tggcattggg 36300ctgttttcat tttgttttgt
tttgtttttg tttttagaca ggatcttgct ctgtcaccca 36360ggctggaggg
cagtgacgtg atcttggctc actgcagcct ggacctccaa gggctcaaac
36420gatcctccca cctcagcttc ccaggtagct gggaccacag gcacgcgcca
ccacacccag 36480ctaatttttg tattttttgt agagatgggg ttttgccata
ttgcccaggc tggccttgaa 36540ctcctgggct caagccatct gcccgcctca
gtctcccaaa gtgctgggat tacaagtgtg 36600agccacaacg tgcctggccc
ttgggctgtc attactaaaa cgtgtatagc attccagtac 36660gcatcctggg
tggacacata catgcactgt tctctaggac tgaaaatgct ggcctgagca
36720ctgtagttgt ttaactttag tagatcccac cactcagttt gccaaaatgg
cctatttcct 36780ttcctgcttc caatgacaag gcaggaaggt tctggttgtt
ccacatcctc gcctacattt 36840ggtatggtcg tttttttttt ttaattttag
ccattctgtt gggtgtgcta taattatggt 36900tttaactgca tttccctgat
gactaacgat attgagcacc ttctcatatt cccagtggct 36960atctaaacat
cttttgtgaa ctgcctgttc aagcctttcc ctcactttaa aaacatttgg
37020ggctgggtgc ggtggctcat gcctgtaatc ccagcacttt gggaggccaa
ggcaggtgga 37080tcacctgagg tcgggagttt gagaccagcc tgaccaacat
ggagaaaacc cgtttctact 37140aaaaatacaa aaattagcca ggcgtagtgg
cacatgcctg taatcccagc tacttgggag 37200gctgaggcag aagaaccact
tgaaccaggg aggcggaggt tgcagtgagc cgagatggcg 37260ccattgcact
ccagcctgga cgacaagagt gaaactccat ctcaaacaac aacaacaaca
37320acaacaaaac agcaacaaca cattcggttt tgtctgtctt tttctaactc
atctttagca 37380actgtttgta tactctgatg acaagtcttt ggttggatct
atgtatcatg aatatcttct 37440ttcactctgt gacttgcttt ttcactctgt
ctttagacgg agtgtctttt gacagctttt 37500ctctttttga tttcttaaac
tttttggctt tttaaaaaaa ttaagctttt tattttgaga 37560taattgtcaa
ttcacatgca gttgtgagaa ataatacaaa gatatcccgt gtactctttc
37620atcagtctcc ccccaatggt aacgtctttc aaaactatag tacaacctcg
caaccaggct 37680actgacattg atccagtgaa ctaactgaac gtttccatca
cctcgaggat tcctcatgtt 37740gcatttttat acacacacct actctcctcg
tgtcccccac cctccttaac ctttggcaac 37800cactaatctg ttctccatct
ccataaattt gtcattccaa caatgttata taagtggatt 37860aataaatttg
ttttttccct cagcataatt ctttggagat tcatccaggt tgttgtgtct
37920gtcaataggt tcttcctttt attgccaagt aatcttagtt tgtttaataa
ctcacttgtt 37980aagaacattt ggattgctct ccagtttctt gctattacaa
taaggcagct ataaacattt 38040atgtccaagt ttttgtgtga acataagtct
tcatttattt aggagtaact gcccaggaat 38100tcaattgttg ggtcacatgg
ttcttgctat atgaaactgc caaacttttt cagagtggct 38160gtaccatttt
acagtctcac cagcaatgta ggagtgaccc agtttcttca catcctcacc
38220agcacttgat accattattt tttattttag ccattctgat aggtgtctag
tgatacctca 38280ttgtagtttg aatgtgtagt tgcctaatgg ttaatgatgt
cgaacatctt tttatgtaca 38340tatttgcatc taggtatctt cttcagggaa
atgtctcttt atatcttctg ctcatgttct 38400aattgggttg tttgctcttt
cactgttgag ttttaagggt tctttctata gcctggatac 38460ttctcttttg
taggatttgt ggattgcaaa tattttctcc cagtctatac cttgtctttc
38520catcctctta gcagggtctt tggcagagca gaatttttat ttggattaag
tccagtttat 38580caagttttcc ttttatggat cggctctgag agtcaagtct
aaggactctt tgtctacttc 38640tagatgctga agattttttc ctctgttttt
ttctaaaagt attatagttt cacatgtaca 38700taattcatta tgagttactt
tttgtaaaag gtgtgaaatt taggttggag ttcattttat 38760tgcaaatgga
tatccagttg cttcagcacc attttctata aatgctattt ttctccatcg
38820aattgatttt atacctttgt taaaaattag tggggtgtat tcttgtgaat
ctatttctgg 38880gttctctgta ctgttccatt gttctgtatg tttatttgtc
tgccaatacc atgaactttt 38940gattattgta ttattatttg attatataag
cctatatatt aagcttaaaa tcaagtagac 39000taaatgctct cactttattc
ttatttttca aaattgtttt agctattcta aaaccttttc 39060ttttctatat
acattttaga ataatcttgt gtatatctac aaaaaaatct tactgaaact
39120ttgacaggaa ttgctgtata tcaaccatac ctaaacactg atttagggag
gattgtcatc 39180tttactatgt tgggtcttct aatctatgaa catggtatgt
ctcttcattt atttagattt 39240tctttgatgt ctttcatagt ggttgtgtag
ttttcagcat gcaagttctg tatatcaaaa 39300aaatttacat ctagttattt
aatttttgag tgatttcaat agcattgtat ttttaatttt 39360tatgttcaca
tgtttactac taatacatag aaatacaatc agttttgtat atttatcttg
39420tctgtcacct tgctgaacta acttattagt ttctgggagg tattgtttat
gtagattcat 39480tgggattttc cacagcgata atcatgttat ctattttatt
tctcctttct catatgtatg 39540gcttttgaat tcatgttaat tattctgcaa
agaattggta caattgtcca gtaaaatcat 39600ccaggcttgg agatttctga
aatgatgtct ttaatttcct taatagttat aaggctatgc 39660aaattatcta
tttcatattg ggtgagttgt ggttaagaag ttgatttatc taagttgtca
39720aatttatgtg tgtagagtgg ctcatagtat tctattttat ctttttgatg
tctgcagggt 39780ctgtaatgat attcccggtt tcattcttca tgttggcaat
ttgcatcttc tcctcctttt 39840tttcgttatc agtcttgcta gaagtgtgtc
cattttattg ttctcttcaa agagacagct 39900cttttttcat tgattttatt
ttttttcaat tttattcatg tctgctgttc tctattattt 39960ctttcttctg
ctttctttgg gttgattttt ctcttctttc tctagtttct tgaggtggga
40020acttagacta tggttttgag gcttttcctt ctttttgatc ataggtattt
tgtagtataa 40080tttttcctct cagcattgtt ttagctgtgt cacacaaaca
ctagtgtgtt gtattttcat 40140tttcattaag ttcaatgtat ttttctgtct
tccttgaaac ttcctctttg atccaaagat 40200aatttagaag tgtgttgttt
agtttccaag tgttcagaga ttttcctgtt atctttctgt 40260tactgatttc
tagtttgatt tcattgtgtt tggagaacat accctgtatg atttatattt
40320tttaaagttt tttagattgc tttatggccc aggatatggt ctatctattt
tacatgagca 40380cttgaaaaga atgcatattt ttctgttatt gaggggaatg
tgttgtaaat attgattaga 40440tcctgggagt tgacagtgtt gagtgtttta
gtattcttgt tgattttctg tctagttcta 40500tcaattgtag agagaaaagt
gttgaaattt ctaactctaa ttctgtactt gtctattttt 40560cctttcagtt
ttctcagttt ttctttggtg ctttgaagac ttttttctgt ctttagtttt
40620cagaagttta
attagtatgt gtcttggtgt ggatttcttt ggtttatcct atttacggtt
40680tgttcagctt cttgaatctg taagtttgtg tctcttcaca aatttaggaa
gtttccagcc 40740attatttctg taagcatttt ttcactatca tgctctttct
cctttccttc tggaactcca 40800gaaacttaaa tattagattt tttgttgtgt
ttcttgactc ttggttcctt ttgttgtgtc 40860cctgaggctc tgttattttt
tatttcagtc tcttttctct gtgttgttca gattcagtaa 40920tttctgttat
tctgtctccc acttcactct ttcctctgtc ctttccattc ttctgttcaa
40980ggtgtcagtg aatttttcat ttctcatact gtatttttca gttctaaaat
tttccatttg 41040gttcttctta tcttctattt cattgcaaag gctttctatt
ttttatttgc ttcaagtgta 41100ttcataattg atcctggaag cattctgtca
tggctacttt aattattttc aggtaactct 41160aacatctctg tcatcttggt
gttggcacct attgattgtt gtttttcatg cagcttgaga 41220tcttcatgat
tcttggtatg atgtgtgatt tccagttgaa actgggatgt ttctgtatta
41280tttagatcct gtggttcatc tggattgttt ttcttttgac attgctttgg
caagagaagg 41340gggtctgctg cctcattatt gataggtgga ggtaaaatta
attttggtgc atggtataaa 41400ttagaggtag gagttcattt tcccccattg
gctctctggt ctccccagca ttatttactg 41460aaaagatcac ccttcctttc
ccttgattac agttgtcctt atgtcttaaa tcagaagact 41520gtgtaggtga
gggtcagctc tagactcatt gcttcattgc tagtgtcaac tatgggccag
41580gatccagggc ttggaaccaa gaacctcttt ggattaatgc ctattaagat
aatattgaaa 41640atgaagtaag tgcaatggag actcatcatt gcattacaga
gacagaaggg gcccccaaac 41700taatctggag tggtgtacag gatcagggaa
gttgccctga agttgataag cagaatgtgg 41760aaggatgggc aggagttgtc
taagagaaga gtgtggcaat agaagggcac cctgggccac 41820agggaacaaa
ccatagctga aagatgagga gtcaagaaat attctggcac ccatggggta
41880ctattagcag tttaacttta caggagctga aaatttaaga aggggaatgt
caagagatga 41940ggctgaacct tggcagggat ggatccttgg accacatcat
gtagttgacc ctgtcacata 42000gcttggactt caccttgtgg gtgacaggag
gccaccaggg ctgacagtag aggaagaaca 42060tggccatgga atccttggga
gaagtggtgt gggttcattg aaaaggccag ggcagaggct 42120gaaagactca
tcaggggaat gtagcagtga tccgcagggg ttgtttaggg accagtcatg
42180actgtggcat ggggctggga aaatggggcc atgatggcac ctgttttcac
ttgtggtatg 42240attggacttt aatgtggttc ctatggtcat cctggttgca
gagctggagt agacaccaga 42300tcatctcact gcagtcctct caacacacag
agacagagga tgaccatggg ggtcaggggc 42360aaagtgagga aagttctcta
accccctggg agaatagcag caccatcaat gggcagatct 42420gtattagggc
tctccagaga aacagaacca ataagatgtg tacatataca gaaatatata
42480tatatgtatg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtatagt
atactagatg 42540aggctgacct acattaggga gggcaatctg ctttactcag
tctatggatt ttaatgttca 42600tctcatccag caacaccctc acagacatac
ccagaatgta tgaccaaata tctgggcacc 42660ctgtggccca gttaagttga
caaataaaat taattattat gagtccactc tttcccatcc 42720ctgtcagagg
cagcagggtg cactagggac cacagactct gttcttctca gcattgacat
42780attccatatt tatttatttg ttctgtgtct cctcccagat gggacgtcag
ctctctgagg 42840gcagggattt tggctgagat aaccgtgcag agactctggg
ttctgaatgg gttcagaggg 42900gaagggaacc atgatgggga ttatcctctt
caacatggaa taatgatgat gaggatggag 42960acagtaatga tattattgta
tgatcactac acaacatgtc tggttcaggc actttatgtg 43020tattaaacta
tgaattcctt caacaacctt ataaggcaga tatcactctt agccccactt
43080tacagatgag gaaaccatgg cccagagaga gccagtaact tgctggggaa
cttggttttt 43140gagtggcaga gctgggattc agacctagaa agtctggctc
cagaacccat acactgatag 43200agtatatttc tgttcaatat ttattaaact
cctgcatgtg tttgacactc tgctaggcac 43260cagggattta ggatggaaag
gacagtcatt tccttgcctg ccctcatgga gcttctgatt 43320tgtggatgga
aggcatgaac ataggtgtgg tggtcatggt gcctcccacc catcatgaac
43380ttgaaccaaa acaggaattc ttttgtcagt tttttctatc ggtttttggg
gaagttttat 43440tggaaaaaaa acttctaaac aaaagcttaa aaagtatgct
ttattgtctt ttacccttat 43500tatcgaacca gtggaaaatc agaaaaatac
aagtgcttac accagcaata aaaaaatatg 43560gttctcatca acaccaccct
ttgccccgag ccctagagtg tctttctcca agttgtctaa 43620atttcccttc
agttcctggg accagctgag aggacaggga gcccacactt ggccccacat
43680gagacctggt tccatttctc tccttggggc actctacaac ttcccactct
gcccgggtca 43740tgtgtggagc tgactagata cttaaaaaca acaacaacaa
caacaacaac aacaacaaca 43800aacaatgtta ttttgtaaga gcagttttaa
gttcacagca aaaatgagtg gaaagtagag 43860cattcccaca ggtcctctct
ccccacgtgc gcagccccgg ttatcaacac gcccaccaga 43920ctggtgcatt
tgttacaact gacgcagcta cactgacacg tcatttccag tgaagtccag
43980agtctgcatt agggttccct attggggctg cgccattttt ctcaccagca
gtgaatgaga 44040gttctgctgc tccacatgct cagcagcctt tggtgccatc
agtgttctgg attggaccat 44100tccctaacga catacgatgt ggggcacctt
ttcaaatgct tacttgcatc tgtacatctt 44160ctctggcgaa gtgtctgttc
aggtcttttg cccattgttt aactgagttg tgctgaccag 44220gtactttgag
gaactccaga cttgtggcta tggcatcatc ctggggcccc ataggccagt
44280tcaggagggt ggctggtgag cgatcctgct tgctggcctg tgcaaaattt
gttaatgtag 44340catgcgactg gctgctggga cagtgctgac aggctgattt
tgggtgaccc cactcgtgtt 44400gggtgtgggg tgagctcagg gctctgagct
tcccatgctc ctctgcccac actcgagttt 44460gaacacatgt ggcctgttgt
gggcccccac ctgtctgtgc tgttactgtg aggcctcctc 44520tggctcccag
ccccctctct gctgctgggc tgggctcagg tctgaagtca gggcagcact
44580acaggtggcc tctgactcca gcttcatgca tctctgcagc attaccaact
ggatacacta 44640ggcaaaaggc ctacctgaca tggggagatg gctggagcct
aaagcttttg catctcccag 44700gcctttcaat tctcaagcaa aggagacaga
acccacatca ggtcaagtgt gagcctgcat 44760gaatggtcag atgagcacgg
ctggtgatgg tggatggtgg atttgtgagc agagttcccc 44820acagtgctcg
gggtgggaga aaacagttta ttcagtttct gactttcaaa tatggaccct
44880gaaccttgct ttggctacac acttgccacc tgaaaggagg atgtgccaca
tgtggtattg 44940acttcaatgg gtatctttct agtacccttc tcttagaact
ggcctctcct ggaatctcat 45000tcgggtgccc taccaatggt cctggatgtt
tctcttcatc accatctccc gccatgacaa 45060atggagccag gatggacacc
tgaccccacc tgtgttggtt gggttatttc tgagctggtt 45120tcttgaccac
gagaattgaa atggccactt cccaactgcc aagtgctcca agaagcagag
45180aacacaggag taaaaagaag cacagaaggg acagaggttc cagttcttct
tgaggcctgc 45240tgtcccatcc ttgggttttg agagacacct ctgtgtcctt
gcagagaatt caccactttg 45300ttcaaaccag tctgagaaag cttctttatt
gtggtcccca agtgcagctg ctgcaatgac 45360cactgttaac ttccccgcct
tggcaaaata actgatactc caaactgcta agagtcccag 45420gactgcacca
gttagctatt actgtgtaac aaattgtccc ccgatacagc agcttcaaac
45480agccataaat atttattacc tcccaggttc tgagggccag gcatctggga
gtggcttgga 45540ggggtgtttc tggctcaggg tctcatgagg ctgcagtcat
actgtccctg aggctgcatc 45600gtctgaaggc ttggctgggg ctgaaggatc
cacttccaag ctcccatgca tgcttgtgga 45660cacgtctcag gttcccactg
ctgttggcca gaggcttcag tggcttacac agggcatctc 45720cacggggctg
cagtgtgctt cccccagagt cagagatgag agagggaggg agggagtggg
45780gttagagaga gagacggggt gtggggcagg agattgaagc tgcaatcttt
cataacctaa 45840gcttggaagt gctattccat cacttctgcc acgggctgct
ggtcacttgg accatccctg 45900gggaaaggaa actacacagg gtgtgaaaac
caggaggcgg ggctcactgg gggtctctga 45960gaatctggct accagcaaga
tcttgcagga agtgatggac agccccaggt ggacgcgtgg 46020cataggggtc
tgctgcctcc tcctcgtatt atcttatctt ctgagagctg ctcctgggtg
46080aacaggtgct cactgcctct ttttctgggt tcacatggac ctgggttaga
aagctgcctc 46140taacatttac tagcaagtga cttctctatg cctctatttt
cttatctgca aaatcgggag 46200aaaaatattg tcctcatcga gtttttctga
accttaaatg cagagatctt atcagaaagt 46260tcttggccgt tgtctcagaa
actcagagtc tctcctgctt taggggcaac gaaagttcat 46320tcacctacct
gtacatctgt ccgtccatct gtacgggagg ctgtccatct cacacaggtc
46380tactgagcac ccccaatgtg tcaggcatgg tgtcaaacac aagccagcac
tggagagaaa 46440atgggctgtg tgctcagagt gtgaccagga ggcccaggct
ctgggctgcc cgagcccacg 46500tggccaggct gggaggggct atgaagggag
gagcatcagg gaggcttcag gagctgagct 46560ttaaggccag taggatgggg
agaggccagg tgacaggagg aggatgggag agaagtcagg 46620gaatggaggc
aaagcacaga gatgagggaa gacctgccat attctgcagt gttgcccagg
46680tcctaatgat gagagatgca gctgtcaagg aaggtgggaa gctcacgcag
ggccagtatc 46740ttgctaaggg actagagggt ggggacttct ggggggtgct
ggaaactcaa aaggtttaag 46800caggtgaaca acaatttcag ataactccca
ggtgagtgtg tagacattgg aactggaaac 46860cctgcaaggt gggggcaggg
agatactttt attgttccct gtttgcagaa gtagaagttg 46920aggcttgaga
ggtgaagaag cttgtgggag gtgtcacagg cctaggtgtg gagtgcggct
46980ttaagccttg gctgttgggc ccctagcaca ggcccccacc caactgccct
gagcacctgc 47040tgtaggttaa atcgtgtctt tcaaaaagat atgttcatat
cctaacccct ggtacctttg 47100actgtgacct tatctggaaa tagcgtctgt
gcagatgtaa tcttgagatg agatcattct 47160gggtttaggg tgggctctaa
atccaatgac tgatgtcctt acaagagaaa tgaagggaga 47220cttcaggcag
acacagagga gaaggccatg tgaagatgga ggcagacatg ggtgatgcgc
47280ctacaagcct gagaatacca gcaccagaag ctggagagag gcctggggtg
attctctcag 47340agcctccaga aggaaccacc ctgctttaca ccttcatttc
agacttctgg catctggaac 47400tgcaagagaa tgaattattg ttgttctaag
ccacctggtt tttgatcatt tttgttagaa 47460cagccctagg atatgaatct
agcctccaaa gccccctcct ggggataagc cggcctcctg 47520gcctgccaca
actcccggag tttccagcca ctcaacaaga aagcagggaa gattctgagc
47580cccagaccca ggtgggagga tggaggggct cctcctcttg cctgctctca
ccaggaaaat 47640tccgcgatgt cacctgcttc tccagggcat gatctgagct
cctacaaaca gagagataga 47700gagaggcaga cagatagtca ccaggcagag
caggaggggc accctgtctg gggacagtgg 47760ctctgaaacc ttagtgtcta
gaagagtcat ctggagcgct tgaaatacat ccttgagccc 47820ccacccccag
cggttctgat tcagtcagtg tgaggtgggg cctgggaata tgtatgtctc
47880cccagttccc agcaaccttg acactgctgg tttggggacc acactttgag
tagcactgtt 47940ccaggcagag ggggctactt ggatagaggc tgggagaaaa
gagcagaggc gcagtctggg 48000cagacagcag ctatcacgga gcttggtaat
gacgttacaa gtgggacagg tcatgcggag 48060gagggcaggt gctcgccaag
gccaggatgg tagcaccagg gtctgcctga gggaagggga 48120gccatgcatg
ggccagcgca tacggaacat agaacttggg caaccaagtg gcagatgggg
48180gccttcagtc aagggccttg agtgaacatg aaggtcagcg gctgccgaca
tgggggttta 48240gagagggaac cccatcctca ggccggcggg cggggggttg
tcagctcacg aacatcagtt 48300ccctcaacag tggccccatt atccaaactg
ggtgccaaaa ctttcttaga aactccagcc 48360tgcaacctgc agtgcccagg
ctcacaggtg gactttgctg agagaggccc agatgctgat 48420acactgaaac
cgatcaagaa gcttggaggg caagcaggcc ccattccccc tttgagttct
48480tctcaaaaga gaagactcct tccatctgca atgccaggcc ccagctttgc
caatgccgcc 48540caccccccat ggagcctggc tgggcccaga gtgcttaatg
cagtacgcag ggccctccac 48600agacctttcc cagctggtaa gagctgtttt
cttttcccct ctaagaggtt tgttcctggt 48660cataaattct gcaggcccgg
tcggccagac taggatgtac acgttggtaa acactgtagt 48720tcaaaacacg
cttcacgctt cacggctgaa aaaggcagcc ccgacaatgg agccttgtcc
48780ccggcagcaa ctctaacggc caccttcttt cattccttaa ccttgctgtg
ggcttgtatg 48840aaattggtcc cattctctgg ggtccatcaa acgtgcattt
aaacgacttc attagcatct 48900tcctctgatc cataaccact gggcaaatcc
aaaagtcatt tcggtgaggg cagccgcggt 48960tttctatctg gtgaacatct
aaaactcctt gacaaagttc cttttaaaat ttacttcttt 49020tgttccgtct
tcgtcttctg ttgagatctt tagtggccaa tgtactccga gatgacttgg
49080ggacaaaaat cccgtctggc ccagacagta aatctagcct ccattcagac
ggcttaaatg 49140catgctttat gcctattgtc cccggctctc caaaagctcc
tgcgccttca agggtttcct 49200acaataaatt aagcccatcc aagacggtgg
agggaaagag ggcctgcctg gatgctgtcg 49260gaaggccagg ctgggccggg
ccccgacaca gcccacccat cgccctggac ctctggcctc 49320taggtatctg
ggattctcct ttgtgagagg caaaaaaaaa aaaaaaaacc caaccaaaaa
49380aaacccccaa aaaaacccca acttgaagtg gattcagcca caatgtattg
gatggtgaac 49440acgaagggca ggaggaaggg gggggggtgg gggtggtagg
gaggggcctg gttcaggccc 49500cacaggccct aggacgctgg tgccctctcc
ccctctggcc acaccctcca gggctctgct 49560gacccctccc cagcttcccc
cctgcattcg taccatggcg ggagcagtgc aagcctcacg 49620tctagtagga
agcagcagga gtctttccca gcattcccca acaagagtct cattggctgt
49680ggttggggca catgacagtc cctgaccaat cactgaggcc tgggtctgat
tggctaggct 49740tgggtcacat ggcccacttt tggcccagtg ggtgaagcca
ctcttgaaat ggatcctggc 49800caggaggagt cctccttata ggaaagttgg
gttacggttc ccagaagagg tgggaaggga 49860tgctgggtag ccagaactga
cactggctgt gatctctaac caagggcatt gcgtttgtcc 49920cacattccga
aattcacagt ggcaggtggt ggctcagagg ctggaacctg gccctgagag
49980acccattgcc tttctctgtt ctgtaacctc ttcccataga gatttttatc
ctgtaaccct 50040gtggtcatca ccatgcctcc catttatgtg cagttcctat
gggctcctga tgctttcctg 50100gatttctccc aggagaggct gttgggtgtt
ggggtgttgg ggaagagaat tagtgttctg 50160cagtctggag ttcactggtc
tgcagactgc taaaagtctg ggggctgcgt ctgccaggga 50220tagtggctct
ggctggtatg gggaccaagg gcaaaaggat cagtgatttc agcagatgcc
50280tttgagcccc gagtctctgg ctgtggacta gtccagtaga aagagtgtct
tggagtgtgg 50340cagagtccca gtcccctgtc tttcttactg tcaaaaccaa
ggtttgggca atcgatgatc 50400tagctaaaaa aacgatgttt ttcagcctgt
cctttctggg ctcctcctgt cccaaacaca 50460gatgtgaagc aatgtgcgag
aattcctatt ctacaatcgc tgtgtatatt taacactatg 50520aagcttctct
tttttgccag tctgacggat atgatggggc atcgcttact gctttcattc
50580ccatttcctt catcatcatt gaggttggtt gtagtgtcta ttctggtttc
tttcgctata 50640ttttgactcg ttgtatcctt tgaccatggt tttaaaattt
gtagacattt ttaatatatt 50700ctaatacaaa tcctttgtca attataagta
ttgcatatat cttcttcttt gtgcctgttc 50760tcttcatttt tcccacagta
tctttggtca tactaaagtt ttttttgttg tgtgtttttt 50820tttttttaca
tttgatacag ttaaattaaa tcttgttttg attgtacttt ttgtgttagt
50880ttaatacata atttcttatc ttggtgtcag aaaggcattc tatcagaatt
tattttcaaa 50940ttgtatagat tttccgtgta cagtttggtc tttggctcaa
ctgaaattta tttctttttg 51000taggtgtaag gaaaggatat atttttatct
tgttttcctt tgtaaagcca tttgtcccca 51060atccatgtat tgaattcttt
ttcttttttt tctacagata tattcttata tattgtttcc 51120ataaaattcc
tctctatttt gtcccatcaa tctatttatt catgcactaa taccacacaa
51180ttttaattat gatagtttta ctgttaatct ttatctttgg tatgactctt
tctcactcgt 51240tccttccttc cctaccttct tttcctcgtc ttcctttttc
aagaccttct tcctgttttt 51300agcaccttaa tcattcacat aaattttagg
attaccttgt taagttttat gaaataatct 51360gttggaattt tggttagact
tgccttaatt catacattaa ctggagtaga attgtcatct 51420ttaccatact
gagttctact caggagcatg acatatctct taatttattt aatgcttcct
51480ttgtgtcttt ccatgaagat ttagaatttt ctccataggt cttgcatgtc
ttttgttaga 51540cttcttccta ggtgccgctc tttatttaat gctattttaa
gtgttatctt tttaaagtta 51600ctttttatga ttgttgatga attagaatgt
aattgaatct acttagattt tcttacaaga 51660aaataattca ctggtaaata
atggcaaata gacatagtta attaagtcaa cagagaaata 51720gaatttcaaa
aaatattcta ttaaggacca aatggaacaa aaaaaaggaa aggataaaca
51780taggggaata taaaagagaa gacaaatgga cctaaattca actatatata
aaattatgct 51840aaaaaattta acattctgag agagagagag agaggaagaa
gactcaacct gctgtcaaca 51900agagacacat tttaagtata aagacacaga
tagattgaaa gtaaataggt ggaaaatgat 51960ataccataca aacgataagc
ataagaaggt tggttgaagg ggttatatta aatcagataa 52020aataaacttc
taggcaaggt gcaataactg gtataaagag gaacatttca taaaaaacat
52080aataacacat gtaataaatt acttaatagc aaagggacat tcataaggaa
gatacaatag 52140gctatatata tatatctgtt aatggatctt caacatgaat
gaagcaaaat ttgacaaaat 52200tgcagggtga aaaaatatcc acaaatatga
ttggaaattt tagtacctat ctgtcagcaa 52260ttgatagaac aactagacag
aaactgagag aagacatgga aaagctaagc ataagtatcc 52320tattaactgc
ctttgttgaa ttgatactta taaaaatcaa catccccaag gagagaatac
52380acactttttt catattcatt atgatggact atatgctgca ccatacatga
aaattgttac 52440tgttcttgtc tttttccctc tgtgtataat gtgtcttttt
ctctggctgc tttcaagatt 52500ttctctttat cacttgtttg attacaatat
gccttggtgt agttgtcttt accttttatc 52560ctgcgtggga ttccttaggc
ttcttgggtc tgtgggttta gagtttacat tatatttgga 52620aaattttcaa
ccattgtttc ttcagatatt tttcctgtcc cctttgtatt gatcatctta
52680tgctacataa atatttaccc caaaacttag tggcttgaaa caataagcat
attatctcac 52740gcagtgttct gtgggtcaga aatttggtag aagctgagct
gggcacccct ggatcaaggt 52800ctctcataat aagtttacaa tcaaagtgtt
gggctgcaga catctaaaag taatagttct 52860ttcccagatg ggcctgttta
gagggctgct tgagtgctct catgacatga tggaggcttc 52920cccaagaatg
aatgattcaa gagagaataa gacagaagcc acaatgtctt ttatcggctt
52980gctttccttt ctaggagttt gctttggtca agttggttga ttgtgttaag
ttgtctgtgt 53040tcctcttaat tttctgtgga gttgttctgc cagttagtga
gagagaagtg ttaaaatctt 53100tgcctaaaat tgtggatttt tacatttctt
ttttcagttt tgtctgtttt tgcttagtgt 53160gttttgaaac actcttattc
attgcgtaca catttagaat ggttatatct tggttaagtg 53220actttagcat
tatgaaacat ccctctttat atctttttcc gtccttttac tttaacctat
53280gtgtatatgt gtatttaaag tggatttctt gtatacagca catagctggg
tgttgatctt 53340ttattcagcc tgacaacatc catgcagaat tttgatggtg
acttaaactt tcctctaagt 53400caaaattgcc acaatatgtt ctgtgtcaca
ttttttcagg acttcagagg atatgtctct 53460ctagaggatg tgtcatcatt
gcaaatccgt cctctgcagt cagcagggat gcttccattt 53520tatagatgag
ggtattgagc ttccacgagg ggaggtgaag tacttgagtc cactcccacg
53580gccaccagag gttgaagcac gactctctgg ctcctggcca gccttccttt
tcccatcaca 53640gctgcagctg tggggaagga ggatgattct gaactgaccc
tgtgggttga gatggagacc 53700tccagcttcc tgggaagagt tcttccttct
ttgcaaaaat aaatgaattg atataggcca 53760ttttgtattc aaattagatt
ggtcaggggc tatttaagca accacatcag aaggctcatt 53820ttcccttttg
acattaaagt gtcttttcca gaaactgtag gaggtggggt ttccctagaa
53880tgagttgaca gcttgtacct attgttaaaa aaagcaaaaa aaagaaaagc
cttgtacacc 53940tcttcccaca tcttcaatgg taacagaatg agcataatcg
aaagaggttt gtgatgatta 54000tttttttttt aagagaaaac actcacagcc
ttctgcctgg tgtaaggctg aaatagggca 54060aaaggggaaa ctgagcatga
gcagggcata gaatatcaaa ggcagtaagt ccttttggcc 54120acatctggac
tcttctccca tcccacagaa aacctcccca gccagtctgg aggtgggtgg
54180atggcgaggg tcccctttca taggtcactt gatccgctcc ttgcccaccc
ctcctgccca 54240ccctctgccg gcttaggtta cccctggaaa ccacccacat
ttttcatctg tccagagaaa 54300tcaggagggg acgaacacct ctgttgggtt
ttccaatcaa acactggggg aacggagcat 54360tttaatcctc aagaatctcc
ccaccagcga agtgaacccc tgagaggcac tgtggatgtg 54420caaaggcaag
ccctgtcccc gatggcccag cactaagtgg tagagatgac atggtcatga
54480caacaccgag gctcaggcat gagaggtgtg tcagccccat cctgggacac
tgcgacagtg 54540gggacaagga agactgctgg tcagaaacag ggttcagagg
caggcccgac tgacattgac 54600aaagctcctt tcatgtgctg ctataggagg
caggtgggct ctgggatcat ttggcagctt 54660gtacctattg ttaaaagagg
aaaacaggcc aggcgcagtg gcttacgcct gtaatcccag 54720cactttggga
ggcccgaggc aggcggatca cgaggtcagg agatcgagac catcctggcc
54780aacatggtaa aaccctgtct ctactaaaaa tacaaaaatt agctgggcgt
ggtgacgtgt 54840gtctgtaatc ccagctactc gggaggctga ggcaggagaa
tcggttgagc ccgggaggtg 54900gaggttgcag tgagccgaga tcgcgccact
gcactccagc ctggtgacag agtaggactc 54960cttctcaaaa aaaaaaaaaa
gaaaaaaaaa aaaaggaaaa caaaatatgg taaatatctt 55020gtcacctctt
cgatgtagga tggcatgaga tgacataagc ccagttcttc caaatgtccc
55080cattttacag cagaggaaac tgagggtcag gatctctttg ggcacggttg
caaagaaagg 55140cctcctagag aaaggggcct gtgtgcaagc ccagggggat
ggggggtgag gcttagagca 55200tttcccgtgg gtggaaacag tgaacaggcc
tctggaatca agctagccca taacctgccc 55260ggggcacagc aagtggtatg
gcgagaacag accaagtttt gggtgccgaa taaggatgag 55320gtaaaccagg
ggcagagttt tggaatctca gcccaaagga gtggcctgag tccaaggctg
55380ggggagcatg cacctgctgg ttgctgacac aggtgatcct ggctgtgttt
ttgttaagac 55440tggctttgtc gtagctccat ggatctgggc acaatccaga
gatgttgtct tcttgcacac 55500tcattttaca gatgaagaaa tcaaggcttg
gggtagtaga gaactttcca gaagtacagg 55560gcaagtttgt gtctaagcaa
agctgagccc tctgccccct tgtggtgatc tcctcagccc 55620cgttctcatc
cttccagggc aatagtcttt ccttgggagt aaagttcaac ctcagtttgg
55680cccagacatt
tggcttttcc cagtggtggc agaatttgtg ggatcagtgt gtgtgtgtgg
55740tgggggcagg gcagggggct gagttaggga gcttagggat gggcagcttc
tcccacatcc 55800ataaaattgg ggcgtttacc aattcccaca gctggtataa
ataccctccc tggtgcttag 55860caaaggctgc tgggagtggg gttgcccctg
cccgactcag attctcttaa agacccagga 55920gaaacacttg cattgcaatg
aggtctctat gtcctcaacc attggactga gcacctccgc 55980atgggaatgt
ctggaattgc aggttttgaa ggcctaaatt agggctgtga atgattttct
56040tcaaaattca ggggcctgtg ggcatggcca caaccctcac ctggatgcct
gtcctctgtt 56100caccctctgt tctctttcca gcagaacatt cagcccagcc
ttgggtgtca ggcatgtgcc 56160tgcctctctg acctcatctg gtggccaggc
tgtgggaagg gaaaactgga ggagtctttg 56220ggggctgagc ctctgggcat
ttgtaggagg caccaccagg gtgtcaatga agataatgac 56280gctgaagctc
caggcccttc atttgcatgg gcccatccca cagttcagcg tgggcttccc
56340tgcccctacg ctgaaggatg ctccttgact gtgagtggga ctgtgggctg
tggcaacctg 56400gtaggtggac ctcatggatc actgactctc tctcttggct
ccaaggagga agatgaagca 56460gtcgctgctg cgcttcctgc tcagggccat
ggtgcccagg ctttatggcc atctcttccc 56520tccaggacca gagggaatga
gggcctggct cagttggctt ggttgcccaa ctgtggtcat 56580caggagggtg
aatgatgtca aagaactggt gtctcttaca gataccctgc ccaggcaaga
56640aattgtagag gacatttcag atacggcctt gccaataaca acacatgtaa
ttgaaagaaa 56700tttccctaag acatcaaaag taaacaaact gcttttaaac
aaaacaaaca aacaaaaaac 56760atgtgctgga ggacagactg aagcattttt
tattcgctct gtggaaaatc atattacgaa 56820atcattgtca tacaaataag
caatcaaaga atatgcagcc aaaaaaaatg taggaaaagg 56880gtattataga
ggtggccgag gcagttactt acttgtggaa tcatatgcta tttttctgat
56940ttgatactta tggtttgttc agctttttac aaatttgtca tttctttctc
attctaaatg 57000attttttttt ttttgcactt tgtagctgtt aatttggtgt
tatttttctt aaataagccc 57060tccagattgc ataacgttta ggcccccaaa
gtccagacca ctccagttcc cagcctcacc 57120atttgttcag aaatgagctg
cttgcttcct gctttcactc aagaccttgg gtgaaagcag 57180gaagcaaggc
cgaggctgtg tattattgca cttcccgtaa gggggtctgc ttgaaagaat
57240atttcccatc ctcctaaaag gaacaaaagc tgttgcaagt attgaattcc
ctagtcacag 57300ggtttgtggg gatctggggt ccacacagag gcctctgggg
agaggaacag agggaggcag 57360aggggtgggg gaagggctct gtgagagctg
ggtcagacca gatggcagag caggtggtca 57420ggtgagaagg gccagggata
tcctcccctc ccacttccct ggggatctcc aggccttgcc 57480ctttcccagc
tcaggacaag atgccagggg aagctggcct tgtgtggcac tactagcccc
57540agtgaggcta acatgggggt atgcaggctg ctttatgaca gcagtgtcct
gatgtctggg 57600gcatgtgagc atccttgtgg tgtgtcccca tgtgcacaca
tgcatgtgtg cccacatgtg 57660agaaggaggt gggggcattg ctgccaggag
atggatcatg gggagagaaa gaaactcttt 57720ttaccaactc ttggaatcag
gcctgttcat acatgatggc attgctggat ctggggatgt 57780gtctgtagat
gaatttcaag gtctctcttg gcttaaaatt tctaagaatc ccaagcaatt
57840accttgcagg agaaatatgg gaaaagccct tttttagtct gtccattcat
gcatcttttt 57900attcaatcac ctatccgttc actgacttag gcatccatct
acccactcac acattcaccc 57960attcactcat ccatccaacc attcatctac
tcatccaacc attcatctac ccatccattc 58020agtcatccat tcacttgccc
attgacccac ccatccatcc atccacccat ccatccaacc 58080atccatccac
ccacccatcc atccatccat ccacccatcc atccatccat ccatccatcc
58140acccacccac ccatccatcc atccatccat ccacccatcc atccatccat
ccccccactc 58200aactgatgct cattgaacca cacattgtgc tgaaacatgc
tctggctgct gagtgttggg 58260gacataggtg agtcagacat ggtctttact
ctgagtctta gtgccattct gaagaaagat 58320caggggagaa acaattgcaa
caggacaggg tccatggttt ggttgaggcc agtgaaatgg 58380gaaccccagg
gagctcctaa ctcatcctga gatagaccca ggaggaattc acagagcagc
58440aggccaaggg agacagctct gctcagcctc tagggacaga tgaagtatgt
ggcagtcagc 58500tccaagtcca tgttggtcac ctgttggcat tcacaccctt
gtgtggtgtc cttccacctt 58560gagcccaggt tggtctgtat gatggagtca
gtgcagcaga ggtgacagca tgtgtctagg 58620ccataaaagg cattaagctt
ctgctttggc ctcatgaatc cctctctctg agggaaacca 58680gctgctatga
catcaggaca ctcaagaggc acattggcgg ggaactgagg attcctacca
58740gcagccagca ctcactagcc atgagggagc tgctttggaa gcagatcctc
tggcctggtc 58800aaacctccag aggactaccc ctccagctga catctgcttg
tatcttcatg agagaccctc 58860agccagcact gcctagccca gccctgtgat
ccacagaaac tgtgagagta gcaaatgtct 58920attgtttaac cctccatgat
gggggaattt gttacacagc aatgaataac tgatacatgg 58980ggcatggagg
gaaacctggc gatgccctgg tgcagtcccc atgggggtga ggtggaaggg
59040atgtagcttg ggagggcctt ccctgctgag ttggggacct cacccctcag
cctctgggcc 59100ctgtggagcc atggcaagct gatgcatgat aagcttttgt
ttaatgaagg tcactctgta 59160cagggggtcg ttcactccag gaagctatcc
ttgaccacct ccctgtatca ggccgggctg 59220cctgccttta taggatcccc
aagccctgaa cttgccctgc actgcacctg ttattagtca 59280atattgtgat
ggtccagctg actatatgtc cccactactg gactatgtgc ttggggtgaa
59340gtgttagtgt agacagggca gtaaatatgt ctgtcttgct cacggtgtaa
ccccagtacc 59400atgtatagga cctgctatgc agtacggact ttgatatgat
ttggctctgt gtccccaccc 59460aactttcatc tggaattata atccccatgt
gtcgagggag ggaccaggtg ggaggtgatt 59520ggatcgtgaa ggcagtttcc
cccatgccgt tcttgtgata gtgagtgcgt tctcatgagc 59580tctgatggtt
ttataaggca gtcttccctg ctcttgctag ctctctcttt cctgctgcca
59640tgtgaagaag gtctttgcct ccccttcacc ttctgccatg attgtaagtt
tcctgaggcc 59700tccccaacca tgcagaacta tgagtcaatt aagctttttt
cttcataaat tacccagtct 59760cgggaagttc tttatagtaa tgtgaaaaca
gactaataca gactttttac atgttactga 59820gcagacacag gatgagttac
aatctgatgg gccctctggg ctgtagggca agagtctctg 59880gcatcctcat
tttacagctg tgacccagga gggaggatct cctacactgg gcaactgcag
59940cttccagccc tgcaggctgt gactcctctt ggatctcatc cccaatccct
ggactttcct 60000cctctgcacc acccaccttg acacccatct ggctgccacg
agtagtttcc atcagagcca 60060gagtttgggt gaaaggagtt tccagaaggt
gtcccctact cattcagtag atattcactc 60120agggcccact gtcctggaga
aacaaagaag tgagtgctag gaagagagat taactaggat 60180gaggggctgg
gggtgtctgg gggtgggtgt gggggctgtc tgagtcatgg tgtcagggcg
60240tgctgtactg acaaggggca tttgaataga tccctgagaa atgtctgaga
gtgagccctg 60300ttggtacctg gggaggagtg ctcctggcta cggcagccac
agtgtgtgca aaggccctga 60360ggcaggagtt tgcttggtgt gttggaggag
cagcaagggg atcagtgtgg ctgcagcaga 60420gtgagtgcaa ccgagagctg
atgaggtcag gaggtggggg ccaggcaggc cagggagggc 60480ctcgtgatgt
ggctggagaa ggtgaagtgc ttgttcctgg cctgggagct tatctcaacg
60540gttcctatgc tcccagctct ctgacattgg cccacggcag ccccagaatg
gatgctttgc 60600aacatctaac agtttggggg ctaaaattag gtgccaagct
gggttagggc cagcagaatg 60660ccactacata tgcttggcat ctgcatggca
aggggaaaat gttgctgctg cctcttgtcc 60720atgttgctgt acctcagcga
cttccagagt aaaattcaac gtctgcggcc tggagttgga 60780ggctcttctg
tgtctagtcc cagcttgtgt ttccagcctg agcccacctt gcaggctgaa
60840cttcccctcc cctccaagct gtgagctgag gtccaggcta ctgcctccct
cttcctaaaa 60900tgctctttct ggctaccttg cctgttctcc cccttggagt
ctgagctcaa gggcacctgc 60960tccgtgacgc ttccctacac cccagcccaa
caggtggcgg gtcttttttc tgccgcgcag 61020ctcccgccgc acactggttt
cttctggctt gtattgtttc tgatgagatg tcttcatcat 61080tcttatcttt
gtctccctgt aagtaatgtg tagttttttg ctactttatt gaggtataat
61140ttatatcctg tcaagttaat gcttttgagt gtatacttct gtgagttctg
acaaacacac 61200acagttgttt aattacctgc acagtcaaga tacagaatgt
ttccatcacc cctgagggtg 61260cctcattccc accctcaact cctagaaacc
acttaatatt agtctgttgg ggctgctaca 61320aagaagacca tagaccaggg
gctttaaaca acagacattt atttttgctc gttctggagg 61380ctaaaagtcc
aagatcaatg tgtgattagg gttggtttct attttctctc tctctctttt
61440tttttttttt gagacagtct tgctctgtca cccaggctgg agtgccgtgg
tgagatcttg 61500actcactgca acctctgcct cctgggttca agtgattgtc
ctgcctcagc ctcctaggta 61560gctgggatta caggtgcctg ccaccatgcc
tggctaattt tgtgtgtgtg tgtgtatttt 61620tagtagagat ggggttttgc
tatgttggcc aggctggtct cgaactcctg acatctgagc 61680ctggccaggg
ttgggttctt gtgagtcctc tcttcctggc ttggagatgg gtgtctttct
61740gctgtgtctt cacatggtgg gaagagagaa agagagaaag agagaaagag
agagaaagag 61800atatggtatg tcttcttctt cttcttcttt ttttttcccg
agacggagtc tagctctgct 61860gccaggctgg agtgcagtgg tgcaatcttg
actcactgca acctcctcct cctgggttca 61920agggattctc ctgcctcagc
ctcccgagta gctgggatta caggcatgcg ccaccacgcc 61980tggctaattt
ttgtattttt agtagagaag gggtttcacc atgttggcca ggctggtctc
62040aaactcctga cctcaggtga tcctctggcc tctcaagtgt tgggattaca
ggcgtgagcc 62100accatgcccg gccaagattg tgtcttaatt caacactgtg
tacctttcat gttgtgcagt 62160gccaggcatg ttgctgtgtt tgtttattac
ttgtaattta ctagattctt ctatttcttg 62220accttctgga attgaacaca
atcaattgct attagttatt tatttatttg cttttttatt 62280gttttcttaa
gcttgtgagg tctttaggtg agagtgggaa gggagtggct tccaacacac
62340gaaacatcca aggaagaagt cagagttcca tgtataaaac ctaaagaaat
ggcttctttt 62400tctattttaa gcaaggtagt ggagatgttc tgttctgaag
gttgcagtca acactatcac 62460aaggtacagg gacaggctgg agaattcctt
tctatcaaag tcttagacca gtagagttag 62520cactaagagg aatgcaaccc
attcatttta ctgatgagga gacagaaggt caaggtggac 62580catggtgggg
tttcactcaa cattctggat tccccatcct gatagttcct tctgtatcac
62640agatcctagc ttacaataca aagtccaatt tttcaaaaag gcatgtaatt
aaaaaaaagt 62700cccaacactc aggtgtctga cccctgattc ctcatttctt
cctgtgtgcc gagatgcctt 62760tggcagacct agggggagct tctccccact
ctatggggaa aggagcacca gctccttcct 62820cctctgggtc ccctcaagga
ggccaaaatg cccatcatga ccctgatatt tttctcccca 62880ctcctctgga
acctcacttc ctcatcccag gtggtacctg ggtttctaat gccccaaaca
62940ttcataaatt taacacatat ttattgagaa cgtactgtat actagcccct
tgttaggtac 63000tgtgactaca gcagccagca agacagtctg ggacccaggc
ctgctcatac attcactctt 63060tcctcttcac tagggtctgg gagagagctt
tgggatcgag actcagccca aggtaagtcc 63120tggacggtac tcagccctga
tgtggacctt gtggatattt tttaaaaaat tatttaaata 63180ttttttattt
acagagtgat tgaacagatc gtacatagag ttccatatac ctcccaccct
63240ctctgtttcc cctattacta acatcctgca ttggtgtggt atgcttgtta
caatcgatga 63300gccagtattg atacattact gagtcctaat ttttttacta
ggataatcac taaaatccat 63360atttaggtta gagttcactc tttgtgttgt
acaatccgtg ggttttgaaa aatgcataat 63420gacatccatc caccatgata
gtatcaaaca gaagacctcc actgccctag agacccttga 63480tgctcctcct
gttcctccct cccttctaac ccctggcaac cattgctgtc tttactgtct
63540ccacggtttg gccctttcta gaacatcaca gagtggaaac catgcggtgg
ggagcctttt 63600cagattggct tctttctcgg ctcacaggaa gaaatgatga
attggggatc agacacctga 63660gagttgggat ttttttttta attacatgcc
tttttgaaaa actggacttt gtatttataa 63720gctaggatct gtgatacaga
aggaaccatc gggatgggga atccagaatg ttgagtcaaa 63780ccccaccgtg
gtccaccttg accttctgtc tcctcatcag taaaatgaat gggttgcatt
63840cctcttagtg ctaactctac ctaagacttt gatggagagg aattctccaa
cctgtccctg 63900tacctcgtga tagtgttgat ttcacttcac actcctccat
gtcttgttgc agcttgccgg 63960ctcatttctt cttattcctg aataacgtgg
gagtcttctc tacagatcct cccaggtggt 64020tccacggggg agctgagtgg
agcttctgtg atctagtgac ctagtcccca gcatggagtg 64080ctcggaagtg
ccctccttga acatgtaaac atcccaccaa gttgcctccc ttctcttgct
64140attttgatgt agctttcttt tcaatggtct tatttctggg tctagccccc
agacacactt 64200tccaccccat gtcctaacct acactctgca gcacatcgca
cctgtgcagg gtgatcggtg 64260attgcaggcc tgggtccacg tctctgctct
gcttcttgct ggccacgagg ctgcgtgctc 64320cttactggcc cctgcgtgct
catctgtaca gtgtgcagga gcaggagcat ctgccggcag 64380acttcttgtg
agattctagt tctgaggcct ccagacggcg tgggtgcacc gcctgagtcc
64440tgctgcattc tgtctgctgc agacccaagc ctggttcctg cgtggggtcc
ctcacgggtg 64500gtgtgtgttt cacagggcag cagggagcca aggggctggg
gctgcccgtg gggagtgtgt 64560gaatcaaagg agcagaccgc agctggagcc
acctcgcctg gattcctgaa cgcagactct 64620tgacagaccg attgtgtaac
ggcattcctc ccaaggaaac acgcctgccc cctccaagaa 64680ggtgcgagag
cttcccagac acagaaaggg ccctgctggg taaatcagtt cttcattatt
64740ccgttcccga ggctctccta ttggccaagt gcccggcacc agcagacgtc
tgcccgcacg 64800gggtcggtcc gcatggggtc ggtccgcacg cagctgacgc
tgaggctcag gtagtctctt 64860tggtcccact aagcggagga tgcattcaaa
aggatgcaaa tttccatcca tttcctgtcc 64920cccctgcctg ggataagggg
cctgttgtgg ctgtgcaagc tggctttctg gtatctaaat 64980acttctctgg
tgaggacaca cctgttcaca tctgcctgca caccacaggc aagctggctt
65040tctggtatct aaatactcct ctggtgagga cacacctgtt catatcctgc
ctgcacacca 65100caggcaagct ggctttctgg tatctaaata cttctctggt
gaggacacac ctgttcacgt 65160cctgcctgca caccacaggt ggggtttatt
gtgtggggct gggatttggc cagccgactt 65220ctggaactca ttgtttatct
ctccatcact gcaacaaata acccccagac ccggaaatgc 65280caccttcgac
taaggcctca gtgtggggtc atcaaaaatg gcaagctggc cagccccgag
65340gtgggtgagg accagtgcag gccttgtcct cttggagtca ggtagggctg
ctactggcag 65400gtggcatgag gtctctaccg cctccgaatg accccgcacc
ccttctcctt tcctttctgc 65460ccctcccttt ttcattcagg atggaggcag
aagaggtgct gagtctggaa cccatggctg 65520ctgcggacga ggagctgggt
gatgcttgcc tgggcaccgt atcgctctca tcctgttttc 65580tcgcctgtga
aatgggaatg gcgctcatgc ttctctgtgg gatgctggga aaggaacatg
65640agggcgtcca tggaagtgtt tgaggcatgc ctgctccagg gggaagctcc
agaaatgaca 65700cctatgatct cccagctgtg ttccctttaa gttaacaaac
actcgtctgg tctggggctg 65760gggtacagcg atgaggatga cctggtccga
gccccaggaa tgtgggccgt aggaagggca 65820tgggcatgaa agacgtgctc
aggggacccc ttccaggtgt caccaaagag ccctgggttg 65880tggtgtcggc
gggagcaggg caggtgggag gcggtggggg tgggcaaggt ctcggacgcc
65940agatgcctgg gttcacagcc caggcctgcc tgttaccagc tgtgtgattt
cacctttctg 66000aacctcagct tccccaaatg tgaaatggag tcgatgctga
tagcagcttc tcctggggtt 66060gttgtgaggc tgaaacgagt atttgcacaa
tacacaaata cttgatgcct ggcaaaaggt 66120atctaagtgt gttaaatatg
tagctgtgtc tacacatcag ggggccaacc tcactgtgct 66180gagaggcaaa
aatggagaaa aaagggaggt tgccaagatt ttgctcctgg tggccccagg
66240ctttggagtt tcagagacgg gtgagagagg gagtcggggc agtcaggacc
ctggtgtgag 66300tagcatgctt cgtaaaagtg actgggagaa accttgggac
gtccttgtct aaactagact 66360cctggcctgc ggagagccac gccccacctc
cctcagtccc taccattcgc tatctttctg 66420ggctgcctgt acatcctgct
gcagccttcc gagggccacc cggcagggaa accggagctg 66480caggcaggag
gcacaggccg tttcatccac ccggggatgg gagcgagtta caggtgtggc
66540cattgttcct gagcacaggt ggggataatg catgctgaca gcccaaggat
gggcccctgg 66600cagcctccat cggcctggcc cgagccccag ggcagccctc
atgggcaccc aaattacaaa 66660acgtcctgtg aactctcccc acggtcccgg
cctcttcatg tgcttccaac gccggcggct 66720tggacacacc tgggagcagc
cacggcccat tcacgaagca ctttggtgaa ggtcaccaac 66780tgcagggaca
gagcgggtat tgtcaaggac gccagcctag cctttgtgcc ccgccgtctg
66840ccccgaccac aggaattcct cacactcacc ctcattcaca ccaggagggt
gcccactgcc 66900actgggggcg gcctccctcc ctccctcccc atgctatttt
caggcaggag gctggagcct 66960cggccaaagg aacctcaccc acgattttcc
aaaacctgat tgccgtggct gtgtctgtga 67020tgggcacaga cccaggggcc
gggcctgcca agactctccc cgtgtgaata cctgcacagg 67080gcacctcctg
tgggaaccgg gagtcacaca gagcctggca tttgtcccca gcctgtcttg
67140tgacattagg tagatcaaag ccccattgta aaaagtcatg ttgcctctgt
tcatctgctt 67200ggagcctgtg tcctaggacg gcccttccct cggctctggc
tcggggaggg agctgaccgc 67260caacacatct gctcccattt gggtcctagt
gttcctcctg gaaggagccc caccgaaagt 67320gaaattgcct ttcatgggtc
tgaggctggg gcacaccctg agaaagaatg agaaagcatg 67380gggcagcgca
gctcctctcc aaagtcttca gaggaacaag ttcctacttg gctctactac
67440ggaacagcaa gaaggcagag aaaaatgtca ctgatgccaa aatcctggag
gcttcctgaa 67500tcggcgatga ggggtgggga gttggcagag gctggggtgg
gggcagcctc tgtccagcag 67560ccccttgggg catggcaggg aaggaggtga
tggaaggagg tgagaagaca cgaggctttg 67620acaatcctga attgtgagtg
gtggggcgag gtcagatcct tccagaggga cagcttcccc 67680ttgactccca
agcctgaccg ttgtgtgtca aatgaggggc agtcaaattg ctcaaccacc
67740tgagtggtag gtaacttgtg agctggaggg atctttaccc accttacagt
ccttaggtag 67800tccattggta tgggctgcct ggagcatgtc tgagatggga
ggaaaatgtg ccaagatgga 67860ttagtaatgt ctggatggct gccagtctct
tagtgatggt gtgtgtgtca tgtgtttgcc 67920atctctggta tgttagtcag
gataagctag gttttgctgc cataacaaat aaatctccaa 67980acctcaattg
cttattgctg tgagaactta ttttctctca ctcaaatccc aaagtgaagg
68040gggtgacttg ttaggacagc tgtgctctac atagtgattc agggatccag
cctgtttgca 68100tctcatgtgc taatggaggg tcacatggtg cttctcatgg
cctcagcctg gaagtgacac 68160acacgtctct ttttactttt catcatccag
aactgcttct gtgcaatctg atccctgact 68220ccctcagaag gcagcagggg
tccaggaggg aagaaagtgg gatgggtctg tggggcaaag 68280aacattatct
ctaccacact cagacccatc ctctttgtta tagaggattg ggtttctata
68340actcaatagg gatgtgggat gtggtttcta gacaagaaag tgacttgaac
aaagtcaaca 68400aggggtgttg gcaccgttgg gaccagccta actaccatgt
aggcattttt tttgatgtac 68460catagtgcca aattgtctaa gtcatttttt
caatctatct ctcatctttc ttgtgaattt 68520tgtcatcccc agaggtgatt
tctcttactg gaaagtctag tggagggacc atgtcccttg 68580gcggactctg
ccaatgggtg cccttcttag aagcaccgtg tcctctttgc tggggtaaag
68640ccattcagta ctggatgact tgatgaaggt aaaccatagc tgcccagggt
cctggacaca 68700tgaggcctgc tcttgattaa tctatatccc ttattcccca
aagagaatgg caaaatcctg 68760gagctatgct catgtttgag ttctgtattg
gacaggacca ttttgggtgc aattggcttg 68820tgcatttgtg tacttgaaaa
gctcagggat ttcagcttca ggaatggctg gattcagaag 68880ctcaaatgat
atcagaactc gatctcactt tctccatttc ccgtttctgt cttcctctga
68940gaaggcttta atccctggat ccactttgat tggtgagact ggggtcgtat
gcccaaccct 69000aaaccagcta ccatggccag gggaataaga aacactgatt
gaccaacctg gatcttgcaa 69060acctcctttg cccctcttga tcctcctggt
ctgaaaaagg cttgcactgg aatggggccc 69120tgatgcacaa gacacggtgc
cccactttgc tctcacctgt tgctagtgat acacgttcca 69180gggcttctgt
gctggagagg tagaagatca tactgcagaa gtccagtggg aggaggtgct
69240cactctgccc aggaaatgga tcatcaggga aggcttcctg gaggagatat
gtttaccaga 69300cagccaaagg ggaatgagga gggcatagca gcagtggaaa
cagcaggggc aaaggcagga 69360gggcaaaaag accaccctaa ccagaggact
ctggttgctc agtgtgatgg tgacttgttg 69420gggtggaggg gagggtagca
gggggaggga catacaggac ccagggctgg tgaggctgtc 69480tggggcctgt
tctgaccatg ccttgagatt gggtgagctg ggtgggaacc ctgaggagca
69540aaagcaaact taaattccaa ggggagaaga atgggatgtg ggctagtgta
gacctcagat 69600ggctgagcag agagtaggtg atgggcattt cttaattgtg
accctggggc agagatggat 69660ctggtgccca aagaggctgg tcaggccagg
aagctccttg aaagtcggcc agaggagcta 69720gggtgtatcc tccccaaatg
aagacccact gaagggtttc aagcatgtgg gactgttttc 69780tgtgtggaca
tatcattgag gctgctgtgg tgtatggtat gggttggagg aggcaaggcc
69840agccggagag aggtaagggg ctagtgctaa tggccgactt catgttcact
aagtgcatat 69900taggctcaga actaggagct gggtttggta gatctgggag
ctggggcaca gcgagggatg 69960aagggagggt ggagggttag aagagtcact
aacccccagc tttgagaatt tcagccactc 70020cgtccgcaga caagatgcat
gaaggaagca gacaaggcat gaggtttcac aaatgctctg 70080cactaatatg
cccgccttac agtcatagcc tggttactct ttctttatat aaaattataa
70140cggatattct aaacttcttt tcctactcta tagtaaatta ggagctcata
cattggaaat 70200ggtgtgtgtg tgtgtgtgtg tgtgtatgag agagagagag
attcaggggg tgcgagagaa 70260gggagcaata aaggcagcag ctgagatgga
gataaagttc tcctaaagac atcccatgaa 70320ctcataaagc tcggcatttt
gggccactgg tgtaaaggtg atagttttct ataactcagt 70380cctacagaag
aacatcccat tagaagatgg gaacattagc aagtgttggt agttgctcca
70440tctggccact tcaaggcaag caagtcttct tggctttgcc cagagtatcc
acgatgctgg 70500cacatcctgg tgattgccaa gtgggtgaat gggtgaatgg
atgcacgttc caatgacacc 70560tgcgttcttt gagcaattga tcctgtgggg
gaaactgaca tcccagaaga tctgtcgggc 70620tgctgcctgc ccccaacccc
aatgcagtgc cctcgataag gaaagtgagc tccatggctt 70680ctgtttagga
agatggggaa gctgcaatgc aatgaggaaa aaaaaatccc accccaaacg
70740ggtttgcatt
ttaggaagtg ttttgttgtc cctgccaagt gacagtgtgg actcagggtg
70800ggggaggact ctagacttgg caaaccaggt gtattagtct gttctcacac
tgctataaag 70860atactacctg agactggata atttatgaag aaaagaggtt
taattgactc acagttcccc 70920atggctgggg aggcctcagg aaacttacaa
tcatggcaga aggtgaaggg gaggcaaggc 70980acatcttcac aaggcggcag
gagagagagc gcgaggaagg aagtgccaca tttttaaatc 71040atcagatctc
atgagaactt actcaatatc atgagaacaa catgggggaa attgccccca
71100taatccaatc acctcctacc aggttccttc ctaacacatg ggaattataa
ttcaagatga 71160gatttgggtg gggacacagc caaaccatat caccagggga
caaggagtgg ttcagagcaa 71220agctgtcatc gcagcttggg tggccgtagg
agatggaaat accccactct gcttaagcct 71280ctctgatgcc aggcaccctg
tgactgcagc caacccactt cttaatccct gggaactgtg 71340aatacatgac
cttacatggc aaaagggact ttgcagttgt gataaagtga aggatcttga
71400cacgggagag gaccctgggt tgggagggtg gccctccctt atgagaggga
ggaaggggga 71460gttggagcca gaggagatgt gcagatggga gcagggcttg
gagagctgta ctttgaagaa 71520cgagggagag ggccaccagt gcagagggag
ggaggggcca ccagcgcaga gggagggaga 71580ggccaccagc acagggattt
gggtgacctc taaaagcaga aaagacaaga caagaattct 71640ccttgagggc
ctccagaagg aacatgactc cattgaggac ttctgacctc caggattctg
71700ggatcaataa atgtgtgctg tttagaagct gctaagtatg tggtcattta
ttacagcagc 71760aattggaaac aagtatacaa gtcccagcta acacacctgc
cacattccca agtgagaggc 71820agagcctggt aatggaaggg cccagtggtt
tgggtcctgg gtctgccccg gctcaagtgc 71880cctgggtgct gctcacccct
ggacatcatg ctcctttcat ccaccgggag ctctgcttct 71940ctcttccttg
gatacctgcc attcactcac tcacgacttt ttcattcccc tattaaggcc
72000accgagtgca gggatgcagg aatggaggaa aagaagagga ccaaaacctg
ctggtcccag 72060gtcccctgcc tcttccttct ggtgggaggg cctgggggtg
caaacccaat gctgggcctc 72120cagctcccca gcacacagct gcatatgaga
ggctcctgca gacaggtgcc gtcatgggct 72180gaattgtgtt ccccaaaatt
tatgtgttgc agctctaacc ctcaaaacct ctgcatatga 72240ctgcatttgg
agatagggct ttaaagaggc aattaagttt aaatgaggtc gttagggtgg
72300actcgtgtct ttataagaaa aggagattag gacacacaca gagggattga
gagcagactg 72360gcccctgtga ggactctgag ggacagagcc ctgttcctgg
agcctctgca tgccctggga 72420agtgtgggga gtaggcaggg cccccagcca
aggctgaggc tgtccctcct aggcttcctg 72480ccttgcaaag ccagagtcac
cctgcgggtc cttgactcac tctgtagagc cccttcctac 72540cttggccaag
ctttgtctgg gctagcatca gtgagaagat acttgggaag agtttttacc
72600cactaagggc agcttaggag gaaggaaagg cagaggtaga gtgagcactg
ggggtttgag 72660tcacaggcag gcacaggagg aggccaccag agttccatct
ttgtgacgca gcaccatgga 72720gttcctgtgt tggtctctga gtctttgccc
atgttattcc ctctacctgg aaggcttgcc 72780ccttctctgg gccagctcgg
atcctcctca tcaagacagg aagagagtag ggactactgt 72840ctgccagatc
tctgcccaca ccattggcac cttgtccaca aagcactcct gtgaccgccc
72900agtgccttcc tcaagccatg cacctgggct catggggacc actcatgccc
aggggatggg 72960agtagagcct tatttttaga cccagggttg atttcgtgag
actttctggg aaagtattta 73020ttgaaagggg aagtcctaag agattagaaa
tttacccagt aattgacgaa tctgatactt 73080agagaaaaac ccccttccca
caaggggctt gtatctgctg accctgcaca cttgtctgtt 73140cctggcattc
actgtttatc tgctgtgaat tagaaacaaa acaaaacaaa aaagacagct
73200attagcatgc aaaccccagg agaactggcc ccctgtgatt tgcatgagaa
caaaagctct 73260ttccaatgtc ctggggctca agtcttcagg atagccttaa
cttccaaacc aggcagggct 73320tcaaagccgg aactggggaa ctcc 73344
* * * * *
References