U.S. patent application number 16/164598 was filed with the patent office on 2019-10-24 for fibrosis susceptibility il22ra2 gene and uses thereof.
The applicant listed for this patent is INSERM, UNIVERSITE D'AIX MARSEILLE. Invention is credited to Laurent Argiro, Alain Dessein, Mathieu Sertorio.
Application Number | 20190323060 16/164598 |
Document ID | / |
Family ID | 47667907 |
Filed Date | 2019-10-24 |
United States Patent
Application |
20190323060 |
Kind Code |
A1 |
Dessein; Alain ; et
al. |
October 24, 2019 |
FIBROSIS SUSCEPTIBILITY IL22RA2 GENE AND USES THEREOF
Abstract
The present invention discloses the identification of a fibrosis
susceptibility gene locus, the IL22RA2 gene locus, which can be
used for detecting predisposition to, diagnosis and prognosis of
fibrosis as well as for the screening of therapeutically active
drugs. The invention further provides a method for determining the
likelyhood of a patient affected with a viral infection to respond
to a treatment with an antiviral agent and/or an interferon, which
method comprises determining alteration in IL22RA2 gene locus or in
TL22RA2 expression or IL22RA2 protein activity in a biological
sample of the patient.
Inventors: |
Dessein; Alain; (Marseille,
FR) ; Sertorio; Mathieu; (Saint Ismier, FR) ;
Argiro; Laurent; (Marseille, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITE D'AIX MARSEILLE
INSERM |
Marseille
Paris |
|
FR
FR |
|
|
Family ID: |
47667907 |
Appl. No.: |
16/164598 |
Filed: |
October 18, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14236869 |
Jun 13, 2014 |
10150989 |
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PCT/EP2012/065222 |
Aug 3, 2012 |
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16164598 |
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61515438 |
Aug 5, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/14 20180101;
C12Q 2600/106 20130101; C12Q 2539/10 20130101; A61P 1/16 20180101;
C12Q 1/683 20130101; A61P 31/20 20180101; C12Q 2600/156 20130101;
C12Q 1/6883 20130101; C12Q 1/6827 20130101 |
International
Class: |
C12Q 1/683 20060101
C12Q001/683; C12Q 1/6883 20060101 C12Q001/6883; C12Q 1/6827
20060101 C12Q001/6827 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 5, 2011 |
EP |
11306018.0 |
Claims
1-30. (canceled)
31. A non-invasive method of preventing or reducing the progression
of fibrosis, comprising: a) obtaining a biological sample from a
human subject, wherein the human subject has been infected with a
hepatic virus or a parasite; b) detecting in the biological sample
obtained from the subject with an assay a single nucleotide
polymorphism at a IL22RA2 gene locus, wherein the single nucleotide
polymorphism comprises rs6570136 having a genotype of GG or AG; and
c) treating the human subject with an anti-fibrotic therapy.
32. The method of claim 30, wherein the human subject
self-identifies as being Chinese, Brazilian, or Sudanese.
33. The method of claim 30, wherein the hepatic virus is hepatic C
virus.
34. The method of claim 30, wherein the biological sample comprises
saliva or blood.
35. The method of claim 30, wherein the assay comprises selective
hybridization or sequencing of at least a portion of the IL22RA2
gene locus containing the single nucleotide polymorphism.
36. The method of claim 30, wherein the parasite is a Schistosoma
parasite.
37. The method of claim 30, further comprising detecting in a
biological sample obtained from the subject, an additional single
nucleotide polymorphism at the IL22RA2 gene locus, wherein the
additional single nucleotide polymorphism comprises rs7774663
having a genotype of C, CC, and/or TT.
38. The method of claim 30, further comprising detecting in a
biological sample obtained from the subject at least two additional
single nucleotide polymorphisms at the IL22RA2 gene locus, wherein
the at least two additional single nucleotide polymorphisms
comprise rs7774663 having a genotype of CC or TT, and rs2064501
having a genotype of TT.
39. The method of claim 30, wherein the assay comprises
microsequencing of at least a portion of the IL22RA2 gene locus
containing the single nucleotide polymorphism.
40. The method of claim 30, wherein the assay comprises an
allele-specific amplification of at least a portion of the IL22RA2
gene locus containing the single nucleotide polymorphism.
41. The method of claim 30, wherein the single nucleotide
polymorphism is associated with a risk that a subject will develop
abnormal deposit of extracellular matrix components.
42. The method of claim 30, wherein the fibrosis is hepatic
fibrosis.
43. A method of treating fibrosis in a human subject comprising
administering to the subject a therapeutically effective amount of
an anti-fibrotic therapy, provided one or more single nucleotide
polymorphisms at a IL22RA2 gene locus comprising rs6570136 having a
genotype of GG or AG is detected in a biological sample obtained
from the subject.
44. The method of claim 43, wherein the subject has been infected
with a hepatic virus or a parasite.
45. The method of claim 43, wherein the human subject
self-identifies as being Chinese, Brazilian, or Sudanese.
46. The method of claim 43, wherein the hepatic virus is hepatic C
virus.
47. The method of claim 43, wherein the biological sample comprises
saliva or blood.
48. The method of claim 43, wherein the one or more single
nucleotide polymorphisms at the IL22RA2 gene locus further
comprises rs7774663 having a genotype of C, CC, and/or TT.
49. The method of claim 43, wherein the one or more single
nucleotide polymorphisms at the IL22RA2 gene locus further
comprises rs7774663 having a genotype of CC or TT, and rs2064501
having a genotype of TT.
50. A method of preventing or reducing fibrosis in a human subject,
the method comprising: determining whether the subject is at risk
for developing abnormal deposit of extracellular matrix components
by: (i) obtaining a biological sample from the subject; and (ii)
performing a genotyping assay on the biological sample to determine
if the subject has a rs6570136GG or a rs6570136AG genotype; and if
the subject has the rs6570136GG or the rs6570136AG genotype, then
administering to the subject an anti-fibrotic therapy, and if the
subject does not have the rs6570136GG or the rs6570136AG genotype,
then administering to the subject a therapy other than the
anti-fibrotic therapy.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to the fields of
genetics and medicine. The present invention discloses in
particular the identification of a human susceptibility gene, which
can be used for the diagnosis or prognosis of an abnormal deposit
of Extra Cellular Matrix Proteins (ECMP) in tissue, potentially
resulting in fibrosis, or for the detection of predisposition to
such abnormal ECMP deposit or fibrosis, occurring in liver
diseases, in cirrhosis, cutaneous keloid, obesity and any fibrotic
disease and also in disease of other tissues such as heart, vessels
or brain. The invention more particularly discloses certain alleles
of the IL22RA2 gene on chromosome 6 related to susceptibility to
fibrosis and representing novel targets for the screening of
therapeutically active drugs. The present invention relates more
specifically to particular mutations in the IL22RA2 gene and
expression products, as well as to diagnostic tools and kits based
on these mutations.
BACKGROUND OF THE INVENTION
[0002] Accumulation of Extra Cellular Matrix Proteins in tissue may
have deleterious effects. Abnormal deposit of ECMP in tissue may
result in tissue fibrosis.
[0003] Fibrosis is an excessive growth of fibrous connective tissue
in an organ, any part, or tissue thereof, for example in a liver,
any part or tissue thereof, especially in response to an
injury.
[0004] Abnormal fibrosis occurs in chronic hepatic inflammations of
various aetiologies such as in Hepatitis Virus and Schistosome
infections. It was shown previously that certain subjects infected
by Schistosomes are slow fibrosers whereas others are rapid
fibrosers and that this depends in part on a major gene located on
Chr 6q22-q23 (Dessein et al., 1999; Mohamed-Ali et al., 1999).
International patent application WO2010/094740 identifies CTGF
(CCN2) as a fibrosis susceptibility gene in this region.
[0005] Schistosomiasis is caused by helminths that develop in the
vascular system of their hosts and lay eggs that are for some of
them carried over to the liver where they trigger inflammation in
the periportal space. Since worms live for years in their human
host, chronic liver inflammation associated with much tissue
destruction is common in infected subjects. Tissue repair requires
the deposit of ECMP in the damaged tissues that are later on turned
over and replaced by normal hepatocytes. In some patients ECMP
accumulate in the periportal space forming fibrosis deposits that
reduce blood flow causing varicose veins, ascites. After months or
years of chronic or repeated injury, fibrosis becomes permanent and
irreversible. Subjects die of the consequences of fibrosis.
[0006] In South countries, it is estimated that 5 to 10% of the 350
millions of infected subjects may develop severe hepatic fibrosis.
There is no good marker allowing to predict and follow hepatic
fibrosis progression in Schistosome infected subjects.
[0007] Diagnosis of hepatic fibrosis is mostly based on liver
biopsy, elastometry and ultrasound analysis.
[0008] Biopsies are obtained via percutanous, transjugular,
radiographically-guided fine-needle or laparoscopic route,
depending upon the clinical setting. Histopathological examination
enables the clinician to grade the severity of necroinflammation
and stage the extent of fibrosis. The Metavir scoring system
attributes a score to the stages of fibrosis on a 1-4 scale as
follows: F0=no fibrosis, F1=portal fibrosis without septa,
F2=portal fibrosis and few septae, F3=numerous septae without
cirrhosis, F4=cirrhosis (Bedossa et al., 1996). Liver biopsy is an
invasive and costly procedure, and samples only a small portion of
the liver. Thus it cannot afford a global assessment of hepatic
fibrosis, and is subject to sampling variation and inter- and
intra-observer error. In addition, liver biopsy is associated with
significant morbidity of 3% and a mortality rate of 0.03%.
Potential complications include local hematoma, infection and pain
related to the biopsy.
[0009] Noninvasive tests (i.e., serologic markers, elastometry,
ultrasound analysis) are also used but are not yet ready for
routine clinical use.
[0010] Panels of blood markers have been tested mostly in patients
with chronic hepatitis C or cirrhosis due to viral hepatitis C.
These studies revealed that serum markers can rule on or rule out
fibrosis in approximately 35% of patients (Sebastiani et al.,
2006). However, when looking at patients individually, these
markers could not reliably differentiate between the various stages
of fibrosis. A more recent study incorporated three panels of serum
markers to devise an algorithmic approach that improved diagnostic
accuracy (Parkes et al., 2006). The three panels evaluated were the
APRI (aspartate transaminase to platelet ratio index), the Forns'
index (platelets, gammaglutamyltranspeptidase, cholesterol) and the
Fibrotest (GGT, haptoglobin, bilirubin, apolipoprotein A,
alpha-2-macroglobulin). An algorithm consisting of the APRI
followed by the Fibrotest boosted the diagnostic accuracy of
fibrosis to above 90%. This group estimated that use of this
algorithm could obviate the need for up to 50% of liver biopsies.
However, the individual stages of fibrosis are not distinguishable
using this algorithm. The limitation of these serum markers is the
possibility of false positives when there is highly active hepatic
inflammation.
[0011] Fibroscan is another approach to staging hepatic fibrosis,
which is based on elastography, which provides rapid measurement of
mean hepatic tissue stiffness (Ziol et al., 2005). A probe is
employed to transmit a vibration of low frequency and amplitude
into the liver. This vibration wave triggers an elastic shear wave,
whose velocity through the liver is directly proportional to tissue
stiffness measured in kilopascals (kPa). Sensitivity of the
Fibroscan technique ranged from 79 to 95%, and specificity from 78
to 95%, compared to the liver biopsy. However, the limitations of
this technique are associated with attenuation of elastic waves in
fluid or adipose tissue, which would impair assessment of fibrosis
in patients. In addition, Fibroscan is an extremely expensive
instrument.
[0012] Today's standard-of-care (SOC) for eradication of HCV from
the liver consists of Pegylated type I interferon (PegIFN) and
synthetic nucleoside ribavirin (RBV) therapy (Fried M W et al; N
Engl J Mcd. 2002; 347(13):975-82; EASL Clinical Practice Guideline:
Management of hepatitis C virus infection, J Hepatol. 2011;
55:245-264). However, this standard therapy has limited and
unpredictable efficacy, an extensive toxicity profile frequently
leading to treatment discontinuation and is very expensive. Less
than half of the chronically HCV-infected individuals of genotype 1
and 4 respond to long-term treatment (48 weeks) of standard therapy
(PegIFN/RBV) (Testino G et al; Hepatogastroenterology 2011;
58(106):536-8).
[0013] Thus, there is a need for a method for selecting patients
who have better chances to respond to a treatment in order to
optimize treatment, avoid side effects for non-responders and
reduce treatment costs.
[0014] Altogether there is still a need for an efficient method to
prognose the fibrosis progression and the treatment efficiency.
SUMMARY OF THE INVENTION
[0015] The purpose of the present invention is to provide a new
genetic approach for fibrosis prognosis and treatment. The present
invention now discloses the identification of another human
fibrosis susceptibility gene locus, the IL22RA2 gene locus, which
can be used for detecting predisposition to, diagnosis and
prognosis of an abnormal ECMP deposit, especially fibrosis,
especially hepatic fibrosis, as well as for the screening of
therapeutically active drugs. The invention resides, in particular,
in a method which comprises detecting in a sample from the subject
the presence of an alteration in the IL22RA2 gene locus, the
presence of said alteration being indicative of the presence or
predisposition to an abnormal ECMP deposit or fibrosis.
[0016] A particular object of this invention resides in an in vitro
method of detecting predisposition to or diagnosis and/or prognosis
of an abnormal ECMP deposit or fibrosis occurring in a subject, the
method comprising detecting the presence of an alteration in the
IL22RA2 gene or polypeptide in a sample from the subject, the
presence of said alteration being indicative of the presence of an
abnormal ECMP deposit or a fibrosis or the predisposition to an
abnormal ECMP deposit or fibrosis. A particular object of this
invention resides in a method for assessment (prediction) of the
progression of an abnormal ECMP deposit or fibrosis.
[0017] In a preferred embodiment, said alteration is located within
500 kb, preferably 100kb, preferably 20 kb, upstream the start
codon of the IL22RA2 gene and within 500kb, preferably 100kb,
preferably 20 kb, downstream the 3'UTR of the IL22RA2 gene.
Preferably, the alteration lies in the surrounding sequences of 10
kb region, upstream the starting codon of the IL22RA2 gene and 10
kb region, downstream the untranslated region (3' UTR).
[0018] In another preferred embodiment, said alteration is a
mutation, an insertion or a deletion of one or more bases. In a
more preferred embodiment, said alteration is one or several single
nucleotide polymorphism(s) SNP(s) or a haplotype of SNPs associated
with fibrosis. Preferably, said single nucleotide polymorphisms are
SNPs flanking IL22RA2 gene, which are allelic variants lying close
to the IL22RA2 gene.
[0019] The method of the invention allows for detection and
prognosis of fibrosis which occurs in a human fibrotic disease
selected from hepatic diseases fibrosis, cirrhosis, cutaneous
keloid, hypertrophic scars and obesity, alcoholism, or drug
hepato-toxicity. Especially, the hepatic fibrosis may be caused by
hepatic A virus, hepatic B virus, hepatic C virus (HCV),
Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S.
mansoni) infection.
[0020] In a particular embodiment, the method comprises genotyping
SNPs in the IL22RA2 gene locus in a biological sample of a subject,
preferably infected with a hepatitis virus or parasite, wherein the
presence of genotype GG in SNP rs6570136, TT in SNP rs7774663, TT,
CT in SNP rs11154915 and/or CC in SNP rs2064501, is indicative of a
risk of developing an abnormal ECMP deposit such as a fibrosis or
of the development of an abnormal ECMP deposit such as a fibrosis,
or of a poor prognostic of fibrosis in the subject. The fibrosis is
more particularly hepatic fibrosis.
[0021] Alternatively the method may comprise genotyping any SNP in
Linkage Disequilibrium (LD) with those mentioned herein.
[0022] Preferably, the alteration in the IL22RA2 gene locus is
determined by performing a selective hydridization assay, a
sequencing assay, a microsequencing assay, and/or an
allele-specific amplification assay.
[0023] In another aspect of the invention, said alteration in the
IL22RA2 gene is determined by restriction enzyme digestion, the
detection of at least one said SNP being an indication of
fibrosis.
[0024] This invention also relates to a method for selecting a
therapeutic compound for a subject that has or is predisposed to
develop an abnormal ECMP deposit such as fibrosis, said method
comprising contacting a test compound with a IL22RA2 polypeptide or
gene or a fragment thereof and determining the ability of said test
compound to enhance or reduce biological activity or function of a
pathway related to the IL22RA2 gene.
[0025] A further subject of the invention is an in vitro method for
determining the likelyhood for a patient affected with a viral
infection to respond to a treatment with an antiviral agent and/or
an interferon, which method comprises determining alteration in
IL22RA2 gene locus or in IL22RA2 protein expression or activity in
a biological sample of the patient.
[0026] In a particular embodiment, the method comprises comprising
genotyping SNPs in the IL22RA2 gene locus in a biological sample of
a subject, wherein the presence of a TT genotype with respect to
SNP rs11154915, a AG or GG genotype with respect to SNP rs6570136,
a CT genotype with respect to SNP rs2064501, and/or a AA genotype
with respect to SNP rs1543509, is in favor of a patient's positive
response to the treatment. Alternatively the method may comprise
genotyping any SNP in Linkage Disequilibrium (LD) with those
mentioned herein.
[0027] In a particular embodiment, the treatment comprises an
antiviral agent, optionally with an interferon.
[0028] Preferably said antiviral agent is an inhibitor of viral
replication, such as ribavirin.
LEGEND TO THE FIGURES
[0029] FIGS. 1A and 1B show IL-22 and IL-17 levels in cultures of
PBMC from Sjaponicum endemic subjects Data are obtained in 144 hrs
resting and egg-stimulated cultures from 19 controls and 70 endemic
subjects FIG. 1C shows FACS analysis of IL22+ cells from the blood
of endemic subjects. Data are from one representative experiment
out of 20.
[0030] FIG. 2A shows IL-22 levels in PBMC cultures vary with the
number of anti-schistosome treatments over the past ten years.
Study subjects were more than 30 and less than 65 years old and had
no active HBV infections (HBS Ag-)
[0031] Antischistosome treatment: subjects have taken Praziquantel
over the past ten years after the following regimens: never, 1 to 4
times, 5-10 times, >10 times.
[0032] Controls are subjects who had not been exposed to S.
japonicum and never treated with Praziquantel. Stars: Cultures
stimulated with S. japonicum eggs; Open circles: Resting cultures:
Number of subjects per groups: controls (19), Treatments: no
Treatments (9), 1-4 (30), 5-10 (23), <10 (8)
[0033] FIG. 2B shows that IL-22 levels in PBMC cultures vary with
the degree of hepatic fibrosis.
[0034] Study subjects were more than 30 and less than 65 years old
and had no active HBV infections (HBS Ag-) Controls are subjects
who had not been exposed to S. japonicum; Stars Cultures stimulated
with S. japonicum eggs; Open circles: Resting cultures. Fibrosis
grade was evaluated as described in Methods and are mostly Central
Fibrosis grades, peripheral fibrosis was taken only taken into
account to split subjects with mild Central fibrosis into one group
(CLL) with no or mild peripheral Fibrosis and one group (CLL, GNM)
with mild central fibrosis and advanced to severe (GNM, GNH)
peripheral fibrosis. Number of subjects per groups: controls (19),
CLL (23), CLL GNM (27), CLM (10), CLH (7), D,E,F (3)
[0035] FIG. 2C shows IL-22 levels in subjects with different
hepatic fibrosis grades and different treatment. Study subjects
were more than 30 and less than 65 years old and had no active HBV
infections (HBS Ag-). Controls are subjects who had not been
exposed to S. japonicum. Subjects have been treated either 0 to 4
times (open circles) or more than 5 to 20 times (closed circles).
Number of subjects per groups: Treatments groups were pooled as
follows: 0 to 4 treatments and >5 treatments in order to
increase the number of subjects per point
[0036] Controls: 19; 0-4 Treatments: 39; >5 Treatments:
controls: 31
[0037] FIG. 3A shows the impact of the anti-schistosome treatments
on IL-22, IL-6, IL-1.beta., or IL-23 levels in egg-stimulated
cultures. Study subjects were more than 30 and less than 65 years
old and had no active HBV infections (HBS Ag-) Controls are
subjects who had not been exposed to S. japonicum. PBMC from study
subjects were stimulated with eggs and cytokines were evaluated in
supernatants at 24 hrs (IL-1b, IL-23, IL-6) and at 144 hrs (11-22).
IL-6 levels were multiplied by 0.1.
[0038] FIG. 3B shows the IL-22, IL-6, IL-1.beta. or IL-23 levels in
egg-stimulated PBMC from controls and from subjects with various
degree of Hepatic fibrosis. Study and Number of subjects in each
group as for FIG. 2A.
[0039] FIG. 4 is a map that locates SNPs and correlation bins in
IL22RA2
DETAILED DESCRIPTION OF THE INVENTION
[0040] This invention provides valuable genetic markers to predict
disease progression in fibrosis, especially in hepatic fibrosis, in
humans.
[0041] Early detection of an abnormal accumulation of ECMP or
fibrosis, and regular monitoring of such accumulation or fibrosis,
would allow for initiation of anti-fibrotic therapies capable of
halting and even reversing this process. This would in turn prevent
progression to human fibrosis disease, for example hepatic fibrosis
or hepatic cirrhosis, and the morbidity and mortality this
condition entails. The development of these various early fibrosis
detection techniques bodes well for the future care of patients
with liver disease.
[0042] The inventors have now identified a gene associated with
human fibrosis. They have shown that fibrosis in Chinese, Sudanese
and Brazilian cohorts infected with Schistosoma japonicum and with
Schistosoma mansoni respectively is markedly dependent on allelic
variants lying in the IL22RA2 gene. The IL22RA2 (for
"interleukin-22 receptor alpha-2") gene, also named IL22R-BP,
encodes a soluble form of the IL-22 receptor that competes for the
binding of IL-22 to its receptor.
[0043] More particularly the inventors performed case control
studies on independent samples of Chinese (exposed to S.
japonicum), Sudanese and Brazilians (exposed to S. mansoni) all
living in endemic regions. Hepatic fibrosis (HF) was evaluated
using echography by at least two observers for each sample. All Tag
SNPs in IL22RA2 (Minor Allele Frequency>10%) were tested. To
rule out whether SNPs in linkage disequilibrium with the associated
SNPs could account for the observed associations, the inventors
evaluated SNPs in the 500 Kb regions in 3' and 5' of IL22RA2.
[0044] The invention thus provides a method of determining a risk
of developing a hepatic fibrosis or of the development of a hepatic
fibrosis, or of a poor prognostic of hepatic fibrosis in a subject,
the method comprising detecting the presence of risk-associated
single nucleotide polymorphism (SNP) alleles at the IL22RA2 gene
locus in a sample from said subject.
[0045] The invention more particularly provides a method of
determining a risk of developing a hepatic fibrosis or of the
development of a hepatic fibrosis, or of a poor prognostic of
hepatic fibrosis, the method comprising genotyping a SNP in the
IL22RA2 gene locus in a sample from said subject.
[0046] Another purpose of the present invention is to provide a
genetic approach for predicting the response to viral infection
treatment. The present invention now discloses the identification
of an antiviral treatment response gene locus, the IL22RA2 gene
locus, which can be used for predicting the response to antiviral
treatment of a patient suffering from viral infection, especially
HCV. The invention resides, in particular, in a method which
comprises detecting in a sample from the subject the presence of an
alteration in the IL22RA2 gene locus, the presence of said
alteration being indicative of the response to the treatment, i.e.
being indicative of a level of risk for the patient not to respond
to the treatment
[0047] The method of the invention allows for prediction of the
response to treatment with an antiviral agent such as ribavirin,
and an interferon administered to patient suffering of a viral
infection, especially hepatitis C.
[0048] This invention provides valuable markers to predict response
to antiviral treatment, especially in hepatitis C.
[0049] Early identification of responders and non-responders
subjects to antiviral treatment, would allow for initiation of an
individualized (personalized) treatment based on patients'
genotype. This would in turn help physicians to make more informed
decision, and avoid needless expenditures and unnecessary side
effects. The development of these various early prediction
techniques bodes well for the future care of patients with viral
infection, especially hepatitis C.
[0050] The inventors have now identified a gene associated with
response to an antiviral treatment. They have shown that response
to the antiviral treatment Ribavirin-IFN in various cohorts
infected with HCV is dependent on allelic variants lying in the
IL22RA2 gene.
[0051] Although the experimental data gathered by the inventors did
not allow to confirm association of certain alleles, depending on
the tested population, the present invention is not limited to the
particular SNPs that were found significantly correlated with
fibrosis in all tested populations. Indeed, several reasons could
account for the failure in confirming significant correlation in
some populations, including an insufficient cohort, the incomplete
assessment of confounding variables, a lower frequency of the SNPs
in said populations, etc.
Definitions
[0052] Within the context of this invention, the term "abnormal
deposit of Extra Cellular Matrix Proteins (ECMP)" refers to the
extracellular matrix components (including laminin, fibronectin
EIIIA, collagen I and IV, procollagen III, elastin, tenascin) that
may accumulate in all types of human tissues. Such accumulation may
be deleterious, for instance when it occurs in arteries, heart, or
brain. When the deposition is massive, the accumulation results in
fibrosis of the tissue.
[0053] Within the context of this invention, "fibrosis" designates
all types of human fibrosis occurring in all the fibrotic human
diseases, for example in hepatic diseases, cirrhosis, cutaneous
keloid, hypertrophic scars, sclerodermia, obesity and any fibrotic
disease. Within the context of this invention, "hepatic fibrosis"
or "HF" designates all types of fibrosis occurring in a liver,
tissue thereof or any part of tissue thereof. Hepatic fibrosis
occurs especially in response to an injury. Hepatic fibrosis can be
the common response to chronic liver injury, ultimately leading to
cirrhosis and its complications, portal hypertension, liver
failure, and hepatocellular carcinoma. Hepatic fibrosis is overly
exuberant wound healing in which excessive connective tissue builds
up in the liver. The extracellular matrix is either overproduced,
degraded deficiently, or both. The trigger is chronic injury,
especially if there is an inflammatory component. Various types of
chronic liver injury can cause fibrosis, such as chemical fibrosis
(CCl.sub.4), bacterial (i.e., brucellosis), parasitic (i.e.,
bilharziosis/schistosomiasis caused by Schistosoma species; or
echinococcosis infections) or viral (i.e., hepatitis caused by
hepatic A virus (HAV), hepatic B virus (HBC) or hepatic C virus
(HCV) infections).
[0054] Within the context of this invention, "cutaneous keloid" is
an excessive growth of scar tissue on the skin. More particularly,
keloids and hypertrophic scars (HSc) are dermal fibroproliferative
disorders unique to humans that occur following trauma,
inflammation, surgery, burns and sometimes spontaneously. These are
characterized by excessive deposition of collagen in the dermis and
the subcutaneous tissues. Contrary to the fine line scar
characteristics of normal wound repair, the exuberant scarring of
keloid and HSc results typically in disfigurement, contractures,
pruritis and pain. Keloids occur in individuals with a familial
disposition among the Blacks, Hispanics and Orientals. Unlike HSc,
the keloid scars enlarge and extend beyond the margins of the
original wound and rarely regress. These disorders represent
aberrations in the fundamental processes of wound healing, which
include cell migration and proliferation, inflammation, increased
synthesis and secretion of cytokines and extra cellular matrix
(ECM) proteins and remodelling of the newly synthesized matrix.
Biologically, keloids are fibrotic tissue characterized by a
collection of atypical fibroblasts with excessive deposition of
extracellular matrix components, especially collagen, fibronectin,
elastin, and proteoglycans. Generally, keloids contain relatively
acellular centers and thick, abundant collagen bundles that form
nodules in the deep dermal portion of the lesion. The release and
activation of growth factors during the inflammatory phase of
healing are pre-requisites for the scar processes, including
angiogenesis, reepithelialization, recruitment and proliferation of
fibroblasts and matrix deposition. Then, abnormal production of
activity of the regulating cytokine including IL22RA2, could
contribute to the development of keloids.
[0055] Within the context of this invention, "the IL22RA2 gene
locus" designates all sequences or products in a cell or organism,
including IL22RA2 coding sequences, IL22RA2 non-coding sequences
(e.g., introns), IL22RA2 regulatory sequences controlling
transcription and/or translation (e.g., promoter, enhancer,
terminator, etc.), all corresponding expression products, such as
IL22RA2 RNAs (e.g., mRNAs) and IL22RA2 polypeptides (e.g., a
pre-protein and a mature protein); as well as surrounding sequences
of 500 kb region, preferably 100kb, preferably 20 kb region,
upstream the starting codon of the IL22RA2 gene and 500 kb region,
preferably 100kb, preferably 20 kb region, downstream the
untranslated region (3'UTR). For example, the IL22RA2 locus
comprises surrounding sequences comprising the SNPs of Table 1.
[0056] Within the context of the present invention, the term
"prognosis" includes the detection, monitoring, dosing, comparison,
etc., at various stages, including early, pre-symptomatic stages,
and late stages, in adults, children and pre-birth. Prognosis
typically includes the assessment (prediction) of the progression
of fibrosis and the characterization of a subject to define most
appropriate treatment (pharmaco-genetics), etc. The present
invention provides prognostic methods to determine the speed of the
progression of fibrosis or an associated disorder resulting from a
mutation or a polymorphism in the IL22RA2 gene locus.
[0057] The "sample" may be any biological sample derived from a
patient or subject, which contains nucleic acids or polypeptides.
Examples of such samples include fluids, tissues, cell samples,
organs, biopsies, etc. Most preferred samples are blood, plasma,
saliva, urine, seminal fluid, etc. The sample may be collected
according to conventional techniques and used directly for
diagnosis or stored.
[0058] The "patient" may be any mammal, preferably a human being,
whatever its age or sex. The patient may be infected with a virus,
including a virus which is selected from the group consisting of
virus of the family of Arenaviridae (e.g. Lassa virus),
Coronaviridae (e.g. Sever Acute Respiratory Syndrome virus),
Flaviviridae (e.g. Hepatitis C or B Virus, Dengue virus, West Nil
Virus, Yellow Fever Virus, Tick-Borne Encephalitis virus),
Filoviridae (e.g. Ebola, Marburg), Herpesviridae (e.g. Herpes
Simplex Virus, Cytomegalovirus, Epstein-Barr Virus, Varicella
Zoster Virus), Orthomyxoviridae (e.g. Influenza A and B),
Paramyxoviridae (e.g. Respiratory Syncytial Virus, Paralnfluenza
Virus, PMV, Measles), Poxviridae (e.g. Vaccinia, Variola),
Rhabdoviridae (e.g. Vesicular Stomatitis Virus, Viral Hemorrhagic
Septicemia Virus, Rabies), Retroviridae (e.g. HIV and other
retroviruses), Togaviridae (e.g. Chikungunya, Sindbis, Semliki
Forest Virus, Ross River Virus, Eastern Equine Encephalitis Virus).
In a particular embodiment, the patient is infected with a
Hepatitis C virus, e.g. Hepatitis C virus of genotype 1.
[0059] In a method for determining the likelyhood for a patient
affected with a viral infection to respond to a treatment with an
antiviral agent and/or an interferon, the term "viral infection"
designated all types of human viral infection which may be treated
with Ribavirin and/or IFN, for examples hepatitis C, hepatitis B,
Respiratory Syncytial Virus (RSV) bronchiolitis, adenovirus
disease, influenza and any human viral infection treated with
Ribavirin and/or IFN.
[0060] Within the context of this invention, "responder" refers to
the phenotype of a patient who responds to the treatment with an
antiviral agent, especially Ribavirin, and/or an IFN, i.e. the
viral load is decreased, at least one of his symptoms is
alleviated, or the development of the disease is stopped, or slowed
down.
[0061] Within the context of this invention, "non-responder" refers
to the phenotype of a patient who either does not respond to the
treatment with an antiviral, especially Ribavirin, and/or an IFN,
or who responds but relapses within one or two years. Non response
to treatment refers to a viral load that does not substantially
decrease and patient symptoms are not alleviated, or the disease
progresses. Relapsing patients respond to treatment for a short
period but their viral load and symptoms increase again within one
or two years of the end of the treatment.
[0062] The term "treatment" or "antiviral treatment" refers to
administration of an antiviral agent and/or interferons (IFN).
[0063] Preferably the interferon is interferon gamma. However other
interferons are encompassed, including interferon alpha 2B,
pegylated interferon alpha, consensus interferon, interferon alpha
2A, and lymphoblastoid interferon tau. In a preferred embodiment,
the interferon is PEGylated interferon, such as PEGylated
interferon gamma.
[0064] The "antiviral agent" may be any compound that interferes
with the virus entry into a cell, or its replication, or inhibits
the activity of a viral protein. For instance it may be interfering
RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine
5'-monophospate dehydrogenase inhibitor, amantadine, or
rimantadine. More generally it may be a viral protease
inhibitor.
[0065] When the virus is HCV virus, the viral agent may be an
inhibitor of HCV metalloprotease, HCV serine protease, HCV
polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV
assembly, HCV egress, or HCV NSSA protein.
[0066] In a preferred aspect, the interferon is interferon gamma,
such as PEGylated interferon gamma. In another preferred aspect,
the interferon is interferon alpha, such as PEGylated interferon
alpha. In a specific embodiment, the treatment comprises ribavirin
and interferon gamma or alpha, preferably PEGylated interferon
gamma or alpha.
[0067] Alterations
[0068] The alteration may be determined at the level of the IL22RA2
DNA, RNA or polypeptide. Optionally, the detection is performed by
sequencing all or part of the IL22RA2 gene locus or by selective
hybridization or amplification of all or part of the IL22RA2 gene
locus. More preferably a IL22RA2 gene locus specific amplification
is carried out before the alteration identification step. An
alteration in the IL22RA2 gene locus may be any form of
mutation(s), deletion(s), rearrangement(s) and/or insertions in the
coding and/or non-coding region of the locus, alone or in various
combination(s). Mutations more specifically include point
mutations. Deletions may encompass any region of two or more
residues in a coding or non-coding portion of the gene locus, such
as from two residues up to the entire gene or locus. Typical
deletions affect smaller regions, such as domains (introns) or
repeated sequences or fragments of less than about 50 consecutive
base pairs, although larger deletions may occur as well. Insertions
may encompass the addition of one or several residues in a coding
or non-coding portion of the gene locus. Insertions may typically
comprise an addition of between 1 and 50 base pairs in the gene
locus. Rearrangement includes inversion of sequences. The IL22RA2
gene locus alteration may result in the creation of stop codons,
frameshift mutations, amino acid substitutions, particular RNA
splicing or processing, product instability, truncated polypeptide
production, etc. The alteration may result in the production of a
IL22RA2 polypeptide with altered function, stability, targeting or
structure. The alteration may also cause a reduction in protein
expression or, alternatively, an increase in said production.
[0069] In a preferred embodiment, said alteration is a mutation, an
insertion or a deletion of one or more bases. In a particular
embodiment of the method according to the present invention, the
alteration in the IL22RA2 gene locus is selected from a point
mutation, a deletion and an insertion in the IL22RA2 gene or
corresponding expression product, more preferably a point mutation
and a deletion. The alteration may be determined at the level of
the IL22RA2 DNA, RNA or polypeptide.
[0070] In a most preferred embodiment, the method comprises
genotyping the IL22RA2 gene, to determine the presence of a SNP at
any of the position indicated in Table 1A.
TABLE-US-00001 TABLE 1A Fibrosis-associated SNPs in the IL22RA2
gene locus Taqman MAF (HapMap) Bin SNP Position Assay Number SEQ ID
CEU YRI CHB I rs9376263 137489626 SEQ ID NO: 1 0.41 (T) 0.13 (C)
0.34 (C) rs6570136 137494622 C_2523610_10 SEQ ID NO: 2 0.42 (A)
0.25 (G) 0.34 (G) rs6570137 137498645 SEQ ID NO: 3 0.38 (C) 0.13
(T) 0.37 (T) rs6570138 137501914 SEQ ID NO: 4 0.41 (T) 0.25 (G)
0.34 (G) rs6570139 137502056 SEQ ID NO: 5 0.41 (A) 0.12 (G) 0.31
(G) rs6907167 137503761 SEQ ID NO: 6 0.41 (T) 0.25 (G) 0.33 (G)
rs9402876 137509025 SEQ ID NO: 7 0.41 (C) 0.09 (T) 0.32 (T)
rs9402877 137509075 SEQ ID NO: 8 0.41 (A) 0.13 (T) 0.34 (T)
rs9402878 137509292 SEQ ID NO: 9 0.37 (G) 0.29 (T) 0.33 (T)
rs7774663 137510893 C_30217943_10 SEQ ID NO: 10 0.36 (C) 0.33 (T)
0.38 (T) II rs13217897 137471327 SEQ ID NO: 11 0.18 (A) 0.26 (A)
0.44 (A) rs11154913 137474838 SEQ ID NO: 12 0.17 (G) 0.28 (G) 0.44
(G) rs12664889 137481612 SEQ ID NO: 13 0.18 (A) 0.30 (A) 0.46 (A)
rs13197049 137491211 SEQ ID NO: 14 0.18 (T) 0.26 (T) 0.44 (T)
rs7749054 137500786 C_32241951_10 SEQ ID NO: 15 0.19 (G) 0.26 (G)
0.43 (G) III rs202563 137461492 C_3010272_10 SEQ ID NO: 16 0.49 (G)
0.42 (A) 0.26 (G) rs156751 137463294 SEQ ID NO: 17 0.49 (T) 0.19
(T) 0.26 (T) IV rs85462 137463154 SEQ ID NO: 18 0.21 (G) 0.08 (G)
0.16 (G) rs276467 137464218 SEQ ID NO: 19 0.20 (A) 0.07 (A) 0.16
(A) rs276466 137466614 C_3010277_10 SEQ ID NO: 20 0.21 (G) 0.07 (G)
0.14 (G) rs28366 SEQ ID NO: 21 V rs7750867 137470186 SEQ ID NO: 22
0.16 (T) 0.09 (T) 0.07 (T) rs9389475 137478484 SEQ ID NO: 23 0.17
(T) 0.07 (T) 0.06 (T) rs11154914 137480411 SEQ ID NO: 24 0.17 (G)
0.07 (G) 0.07 (G) rs11154915 137482982 C_9800072_30 SEQ ID NO: 25
0.16 (T) 0.07 (T) 0.05 (T) rs1040622 137483258 SEQ ID NO: 26 0.16
(C) 0.08 (C) 0.07 (C) rs10457018 137484893 SEQ ID NO: 27 0.16 (A)
0.08 (A) 0.07 (A) rs10457019 137484979 SEQ ID NO: 28 0.17 (A) 0.07
(A) 0.07 (A) rs13441747 137488608 SEQ ID NO: 29 0.17 (C) 0.09 (C)
0.07 (C) rs9385786 137497052 SEQ ID NO: 30 0.16 (T) 0.07 (T) 0.06
(T) rs9402875 137498018 SEQ ID NO: 31 0.18 (C) 0.08 (C) 0.06 (C)
rs9385787 137500399 SEQ ID NO: 32 0.17 (C) 0.08 (C) 0.07 (C)
rs9373180 137503455 SEQ ID NO: 33 0.17 (G) 0.04 (G) 0.07 (G)
rs9385789 137505172 SEQ ID NO: 34 0.17 (A) 0.08 (A) 0.07 (A) VI
rs202567 137470844 SEQ ID NO: 35 0.48 (G) 0.06 (A) 0.22 (A)
rs7774349 137475858 SEQ ID NO: 36 0.48 (C) 0.06 (T) 0.21 (T)
rs2064501 137477823 C_11693858_10 SEQ ID NO: 37 0.48 (T) 0.06 (C)
0.23 (C) VII rs1543509 SEQ ID NO: 38 rs17066102 SEQ ID NO: 39
Hapmap: CEU European cohort, YOR African cohort (Yorubas), CHB
Asian cohort (Chinese)
[0071] Preferably the method comprises genotyping a SNP selected in
the group consisting of rs6570136, rs7774663, rs11154915 and
rs2064501.
[0072] The presence of a G allele with respect to SNP rs6570136,
more particularly of a GG genotype, is deleterious for the patient,
i.e. it is indicative of a patient being likely to develop abnormal
deposit of ECMP, or fibrosis, especially hepatic fibrosis.
[0073] The presence of a T allele with respect to SNP rs7774663,
more particularly of a TT genotype, is deleterious for the patient,
i.e. it is indicative of a patient being likely to develop abnormal
deposit of ECMP, or fibrosis, especially hepatic fibrosis.
[0074] The presence of a T allele with respect to SNP rs11154915,
more particularly of a TT or CT genotype, is deleterious for the
patient, i.e. it is indicative of a patient being likely to develop
abnormal deposit of ECMP, or fibrosis, especially hepatic
fibrosis.
[0075] The presence of a C allele with respect to SNP rs2064501,
more particularly of a CC genotype, is deleterious for the patient,
i.e. it is indicative of a patient being likely to develop abnormal
deposit of ECMP, or fibrosis, especially hepatic fibrosis.
[0076] SNPs in the same bins are highly correlated (r2>0.8) and
of similar utility in the methods of the invention. SNPs in strong
linkage disequilibrium (yielding r2>0.6) are encompassed as
well.
[0077] Another method of the invention may comprise determining
whether the patient comprises a genotype of non-response as defined
in Table 1B.
[0078] Analysis was performed on 123 subjects (69 responder
subjects and 54 non responder subjects), all infected with HCV.
TABLE-US-00002 TABLE 1B Antiviral treatment response-associated
alterations in the IL22RA2 gene locus Re- spond- % with % with er
RG RG in SEQ Geno- in Re- Non Re- ID type spond- spond- Bin SNP NO:
(RG) ers ers p OR CI Univariate analysis I rs 10 CT, 89 79.3 0.13
2.1 0.8- 777 TT 5.6 4663 I rs 2 AG, 78.6 66.1 0.12 1.9 0.85- 657 GG
4.2 0136 II rs 15 TT 71.6 58.6 0.1 1.8 0.9- 774 3.7 9054 III rs 16
AG, 87.7 75.4 0.07 2.3 0.9- 20 GG 5.8 2563 IV rs2 21 CC, 44.6 32.1
0.15 1.7 0.8- 8366 TC 3.5 IV rs27 20 0.3 6466 V rs 25 TT 6.8 1.7
0.2 4.2 0.5- 1115 37 4915 VI rs 37 CT 54.8 32.8 0.013 2.5 1.2- 206
5.1 4501 VII rs 38 AA 90.5 73.2 0.012 3.5 1.3- 154 9.3 3509
Multivariate analysis I rs 2 GG 0.16 1.9 0.8- 657 4.7 0136 V rs 25
TT 0.03 13.7 1.3- 1115 146 4915 VI rs 37 CT 0.004 3.6 1.5- 206 8.5
4501 VII rs 38 AA 0.014 3.9 1.3- 154 11.5 3509
[0079] Preferably the method comprises genotyping a SNP selected in
the group consisting of rs11154915, rs6570136, rs2064501 and
rs1543509.
[0080] The presence of a TT genotype with respect to SNP
rs11154915, is in favor of a patient's positive response to the
antiviral treatment.
[0081] The presence of a AG or GG genotype with respect to SNP
rs6570136, is in favor of a patient's positive response to the
antiviral treatment.
[0082] The presence of a CT genotype with respect to SNP rs2064501,
is in favor of a patient's positive response to the antiviral
treatment
[0083] The presence of a AA genotype with respect to SNP rs1543509,
is in favor of a patient's positive response to the antiviral
treatment.
[0084] SNPs in the same bins are highly correlated (r2>0.8) and
of similar utility in the methods of the invention. SNPs in linkage
disequilibrium are encompassed as well.
[0085] Odd ratios associated with each genotype are indicated in
Table 1B. They vary from 1.9 to 4 when each SNP was evaluated
alone; when all SNPs were evaluated together in the same
multivariate model (that takes into account confounding effects
between SNPs) ORs vary from 1.9 to 13, and a subjects who will
carry responder genotypes for all four polymorphisms will be around
50 to 300 times more likely to respond to treatment that a subjects
carrying non responder genotypes for all genotypes.
[0086] Linkage disequilibrium (LD) is defined as the non-random
association of alleles at different loci across the genome. Alleles
at two or more loci are in LD if their combination occurs more or
less frequently than expected by chance in the population.
[0087] When there is a causal locus in a DNA region, due to LD, one
or more SNPs nearby are likely associated with the trait too.
Therefore, any SNPs in strong LD (yielding a r2>0.6) with a
first SNP associated with an abnormal ECMP deposit will be
associated with this trait.
[0088] Identification of additional SNPs in linkage disequilibrium
with a given SNP involves: (a) amplifying a fragment from the
genomic region comprising or surrounding a first SNP from a
plurality of individuals; (b) identifying of second SNPs in the
genomic region harboring or surrounding said first SNP; (c)
conducting a linkage disequilibrium analysis between said first SNP
and second SNPs; and (d) selecting said second SNPs as being in
linkage disequilibrium with said first marker. Subcombinations
comprising steps (b) and (c) are also contemplated.
[0089] Methods to identify SNPs and to conduct linkage
disequilibrium analysis can be carried out by the skilled person
without undue experimentation by using well-known methods.
[0090] It is well known that many SNPs have alleles that show
strong LD with other nearby SNP alleles and in regions of the
genome with strong LD, a selection of evenly spaced SNPs, or those
chosen on the basis of their LD with other SNPs (proxy SNPs or Tag
SNPs), can capture most of the genetic information of SNPs, which
are not genotyped with only slight loss of statistical power. In
association studies, this region of LD are adequately covered using
few SNPs (Tag SNPs) and a statistical association between a SNP and
the phenotype under study means that the SNP is a causal variant or
is in LD with a causal variant. The two metrics most commonly used
to measure LD are D' and r.sup.2 and can be written in terms of
each other and allele frequencies. It is a general consensus that a
proxy (or Tag SNP) is defined as a SNP in LD (r.sup.2.gtoreq.0.8)
with one or more other SNPs. The genotype of the proxy SNP could
predict the genotype of the other SNP via LD and inversely. In
particular, any SNP in LD with one of the SNPs used herein may be
replaced by one or more proxy SNPs defined according to their LD as
r.sup.2>0.8.
[0091] These SNPs in linkage disequilibrium can also be used in the
methods according to the present invention, and more particularly
in the diagnostic methods according to the present invention.
[0092] Alterations in the IL22RA2 gene may be detected by
determining the presence of an altered IL22RA2 RNA expression.
Altered RNA expression includes the presence of an altered RNA
sequence, the presence of an altered RNA splicing or processing,
the presence of an altered quantity of RNA, etc. These may be
detected by various techniques known in the art, including by
sequencing all or part of the IL22RA2 RNA or by selective
hybridisation or selective amplification of all or part of said
RNA, for instance.
[0093] In a further variant, the method comprises detecting the
presence of an altered IL22RA2 polypeptide expression. Altered
IL22RA2 polypeptide expression includes the presence of an altered
polypeptide sequence, the presence of an altered quantity of
IL22RA2 polypeptide, the presence of an altered tissue
distribution, etc. These may be detected by various techniques
known in the art, including by sequencing and/or binding to
specific ligands (such as antibodies), for instance.
[0094] As indicated above, various techniques known in the art may
be used to detect or quantify altered IL22RA2 gene or RNA
expression or sequence, including sequencing, hybridisation,
amplification and/or binding to specific ligands (such as
antibodies). Other suitable methods include allele-specific
oligonucleotide (ASO), allele-specific amplification, Southern blot
(for DNAs), Northern blot (for RNAs), single-stranded conformation
analysis (SSCA), PFGE, fluorescent in situ hybridization (FISH),
gel migration, clamped denaturing gel electrophoresis, heteroduplex
analysis, RNase protection, chemical mismatch cleavage, ELISA,
radio-immunoassays (RIA) and immuno-enzymatic assays (IEMA). Some
of these approaches (e.g., SSCA and CGGE) are based on a change in
electrophoretic mobility of the nucleic acids, as a result of the
presence of an altered sequence. According to these techniques, the
altered sequence is visualized by a shift in mobility on gels. The
fragments may then be sequenced to confirm the alteration. Some
others are based on specific hybridization between nucleic acids
from the subject and a probe specific for wild-type or altered
IL22RA2 gene or RNA. The probe may be in suspension or immobilized
on a substrate. The probe is typically labelled to facilitate
detection of hybrids. Some of these approaches are particularly
suited for assessing a polypeptide sequence or expression level,
such as Northern blot, ELISA and RIA. These latter require the use
of a ligand specific for the polypeptide, more preferably of a
specific antibody.
[0095] In a preferred embodiment, the method comprises detecting
the presence of an altered IL22RA2 gene expression profile in a
sample from the subject. As indicated above, this can be
accomplished more preferably by sequencing, selective hybridisation
and/or selective amplification of nucleic acids present in said
sample.
[0096] Sequencing
[0097] Sequencing can be carried out using techniques well known in
the art, using automatic sequencers. The sequencing may be
performed on the complete IL22RA2 gene locus or, more preferably,
on specific domains thereof, typically those known or suspected to
carry deleterious mutations or other alterations.
[0098] Amplification
[0099] Amplification is based on the formation of specific hybrids
between complementary nucleic acid sequences that serve to initiate
nucleic acid reproduction. Amplification may be performed according
to various techniques known in the art, such as by polymerase chain
reaction (PCR), ligase chain reaction (LCR), strand displacement
amplification (SDA) and nucleic acid sequence based amplification
(NASBA). These techniques can be performed using commercially
available reagents and protocols. Preferred techniques use
allele-specific PCR or PCR-SSCP. Amplification usually requires the
use of specific nucleic acid primers, to initiate the reaction.
Nucleic acid primers useful for amplifying sequences from the
IL22RA2 gene locus are able to specifically hybridize with a
portion of the IL22RA2 gene locus that flank a target region of
said locus, said target region being altered in certain subjects
having fibrosis or associated disorders.
[0100] This invention makes use of nucleic acid primers useful for
amplifying sequences from the IL22RA2 gene or locus including
surrounding regions. Such primers are preferably complementary to,
and hybridize specifically to nucleic acid sequences in the IL22RA2
gene locus. Particular primers are able to specifically hybridize
with a portion of the IL22RA2 gene locus that flank a target region
of said locus, said target region being altered in certain subjects
having fibrosis or associated disorders.
[0101] Selective Hybridization
[0102] Hybridization detection methods are based on the formation
of specific hybrids between complementary nucleic acid sequences
that serve to detect nucleic acid sequence alteration(s). A
particular detection technique involves the use of a nucleic acid
probe specific for wild-type or altered IL22RA2 gene or RNA,
followed by the detection of the presence of a hybrid. The probe
may be in suspension or immobilized on a substrate or support (as
in nucleic acid array or chips technologies). The probe is
typically labeled to facilitate detection of hybrids. In this
regard, a particular embodiment of this invention comprises
contacting the sample from the subject with a nucleic acid probe
specific for an altered IL22RA2 gene locus, and assessing the
formation of a hybrid. In a particular preferred embodiment, the
method comprises contacting simultaneously the sample with a set of
probes that are specific, respectively, for wild type IL22RA2 gene
locus and for various altered forms thereof. In this embodiment, it
is possible to detect directly the presence of various forms of
alterations in the IL22RA2 gene locus in the sample. Also, various
samples from various subjects may be treated in parallel.
[0103] Within the context of this invention, a probe refers to a
polynucleotide sequence which is complementary to and capable of
specific hybridization with a (target portion of a) IL22RA2 gene or
RNA, and which is suitable for detecting polynucleotide
polymorphisms associated with IL22RA2 alleles which predispose to
or are associated with fibrosis. Probes are preferably perfectly
complementary to the IL22RA2 gene, RNA, or target portion thereof.
Probes typically comprise single-stranded nucleic acids of between
8 to 1000 nucleotides in length, for instance of between 10 and
800, more preferably of between 15 and 700, typically of between 20
and 500. It should be understood that longer probes may be used as
well. A preferred probe of this invention is a single stranded
nucleic acid molecule of between 8 to 500 nucleotides in length,
which can specifically hybridize to a region of a IL22RA2 gene
locus or RNA that carries an alteration.
[0104] The method of the invention employs a nucleic acid probe
specific for an altered (e.g., a mutated) IL22RA2 gene or RNA,
i.e., a nucleic acid probe that specifically hybridizes to said
altered IL22RA2 gene or RNA and essentially does not hybridize to a
IL22RA2 gene or RNA lacking said alteration. Specificity indicates
that hybridization to the target sequence generates a specific
signal which can be distinguished from the signal generated through
non-specific hybridization. Perfectly complementary sequences are
preferred to design probes according to this invention. It should
be understood, however, that certain mismatch may be tolerated, as
long as the specific signal may be distinguished from non-specific
hybridization. Particular examples of such probes are nucleic acid
sequences complementary to a target portion of the genomic region
including the IL22RA2 gene locus or RNA carrying a point mutation
as listed in Table 1 above.
[0105] The sequence of the probes can be derived from the sequences
of the IL22RA2 gene and RNA as provided in the present application.
Nucleotide substitutions may be performed, as well as chemical
modifications of the probe. Such chemical modifications may be
accomplished to increase the stability of hybrids (e.g.,
intercalating groups) or to label the probe. Typical examples of
labels include, without limitation, radioactivity, fluorescence,
luminescence, enzymatic labelling, etc. The invention also concerns
the use of a nucleic acid probe as described above in a method of
detecting the presence of or predisposition to fibrosis or an
associated disorder in a subject or in a method of assessing the
response of a subject to a treatment of fibrosis or an associated
disorder.
[0106] Specific Ligand Binding
[0107] As indicated above, alteration in the IL22RA2 gene locus may
also be detected by screening for alteration(s) in IL22RA2
polypeptide sequence or expression levels. In this regard,
contacting the sample with a ligand specific for a IL22RA2
polypeptide and determining the formation of a complex is also
described. Different types of ligands may be used, such as specific
antibodies. In a specific embodiment, the sample is contacted with
an antibody specific for a IL22RA2 polypeptide and the formation of
an immune complex is determined. Various methods for detecting an
immune complex can be used, such as ELISA, radio-immunoassays (RIA)
and immuno-enzymatic assays (IEMA). Within the context of this
invention, an antibody designates a polyclonal antibody, a
monoclonal antibody, as well as fragments or derivatives thereof
having substantially the same antigen specificity. Fragments
include Fab, Fab'2, CDR regions, etc. Derivatives include
single-chain antibodies, humanized antibodies, poly-functional
antibodies, etc. An antibody specific for a IL22RA2 polypeptide
designates an antibody that selectively binds a IL22RA2
polypeptide, i.e., an antibody raised against a IL22RA2 polypeptide
or an epitope-containing fragment thereof. Although non-specific
binding towards other antigens may occur, binding to the target
IL22RA2 polypeptide occurs with a higher affinity and can be
reliably discriminated from non-specific binding.
[0108] It is also disclosed a diagnostic kit comprising products
and reagents for detecting in a sample from a subject the presence
of an alteration in the IL22RA2 gene locus or polypeptide, in the
IL22RA2 gene or polypeptide expression, and/or in IL22RA2 activity.
Said diagnostic kit comprises any primer, any pair of primers, any
nucleic acid probe and/or any ligand, preferably antibody,
described in the present invention. Said diagnostic kit can further
comprise reagents and/or protocols for performing a hybridization,
amplification or antigen-antibody immune reaction.
[0109] Drug Screening
[0110] New methods for the screening of drug candidates or leads
are also described. These methods include binding assays and/or
functional assays, and may be performed in vitro, in cell systems,
in animals, etc. A particular object of this invention resides in a
method of selecting biologically active compounds, said method
comprising contacting in vitro a test compound with a IL22RA2 gene
or polypeptide according to the present invention and determining
the ability of said test compound to bind said IL22RA2 gene or
polypeptide. Binding to said gene or polypeptide provides an
indication as to the ability of the compound to modulate the
activity of said target, and thus to affect a pathway leading to
any abnormal deposit of ECMP or fibrosis in a subject. In a
preferred embodiment, the method comprises contacting in vitro a
test compound with a IL22RA2 polypeptide or a fragment thereof
according to the present invention and determining the ability of
said test compound to bind said IL22RA2 polypeptide or fragment.
The fragment preferably comprises a binding site of the IL22RA2
polypeptide. Preferably, said IL22RA2 gene or polypeptide or a
fragment thereof is an altered or mutated IL22RA2 gene or
polypeptide or a fragment thereof comprising the alteration or
mutation. A particular object of this invention resides in a method
of selecting compounds active on any abnormal deposit of ECMP or
fibrosis, said method comprising contacting in vitro a test
compound with a IL22RA2 polypeptide according to the present
invention or binding site-containing fragment thereof and
determining the ability of said test compound to bind said IL22RA2
polypeptide or fragment thereof. Preferably, said IL22RA2
polypeptide or a fragment thereof is an altered or mutated IL22RA2
polypeptide or a fragment thereof comprising the alteration or
mutation. The method for the screening of drug candidates comprises
contacting a recombinant host cell expressing a IL22RA2 polypeptide
according to the present invention with a test compound, and
determining the ability of said test compound to bind said IL22RA2
and to modulate the activity of IL22RA2 polypeptide. Preferably,
said IL22RA2 polypeptide or a fragment thereof is an altered or
mutated IL22RA2 polypeptide or a fragment thereof comprising the
alteration or mutation. The determination of binding may be
performed by various techniques, such as by labelling of the test
compound, by competition with a labelled reference ligand, etc. The
method of selecting biologically active compounds also comprises
contacting in vitro a test compound with a IL22RA2 polypeptide and
determining the ability of said test compound to modulate the
activity of said IL22RA2 polypeptide. Preferably, said IL22RA2
polypeptide or a fragment thereof is an altered or mutated IL22RA2
polypeptide or a fragment thereof comprising the alteration or
mutation.
[0111] The method of selecting biologically active compounds for a
subject that has or is predisposed to develop any abnormal deposit
of ECMP or fibrosis, also comprises contacting in vitro a test
compound with a IL22RA2 gene according to the present invention and
determining the ability of said test compound to modulate the
expression of said IL22RA2 gene. Preferably, said IL22RA2 gene or a
fragment thereof is an altered or mutated IL22RA2 gene or a
fragment thereof comprising the alteration or mutation.
[0112] The method of screening, selecting or identifying active
compounds, particularly compounds active on any abnormal deposit of
ECMP or fibrosis, also comprises contacting a test compound with a
recombinant host cell comprising a reporter construct, said
reporter construct comprising a reporter gene under the control of
a IL22RA2 gene promoter, and selecting the test compounds that
modulate (e.g. activate or inhibit) expression of the reporter
gene. Preferably, said IL22RA2 gene promoter or a fragment thereof
is an altered or mutated IL22RA2 gene promoter or a fragment
thereof comprising the alteration or mutation.
[0113] The above screening assays may be performed in any suitable
device, such as plates, tubes, dishes, flasks, etc. Typically, the
assay is performed in multi-wells plates. Several test compounds
can be assayed in parallel. Furthermore, the test compound may be
of various origin, nature and composition. It may be any organic or
inorganic substance, such as a lipid, peptide, polypeptide, nucleic
acid, small molecule, etc., in isolated or in mixture with other
substances. The compounds may be all or part of a combinatorial
library of products, for instance.
[0114] Further aspects and advantages of the present invention will
be disclosed in the following experimental section, which should be
regarded as illustrative and not limiting the scope of the present
application.
EXAMPLES
Example 1: Production and Modulation of IL-22 in Human Schistosome
Infections
[0115] Production of IL-22 in Human Schistosome Infections
[0116] The inventors have compared IL-22 levels in cultures of PBMC
from 140 subjects exposed to S. japonicum infections with cultures
of 20 controls who had no previous exposure to schistosome
infections (FIG. 1A) but lived in the same region in comparable
living conditions. IL-22 was detected in resting cultures of
exposed subjects at 72 and 144 hrs and was significantly enhanced
by addition of schistosome eggs at time 0 of the culture. IL-22 was
detected in control resting cultures at 144 hrs only and was not
enhanced by addition of eggs. The inventors detected significant
IL-17A levels in 144 hrs cultures but IL-17 levels were not
enhanced by egg-stimulation (FIG. 1B). Thus it is unlikely that
IL-22 in the cultures was produced by Th17. Analysis by FACS of the
IL22+ cells in the blood of exposed patients showed IL-22 is
produced by CD3+CD4+ and by CD3-CD4- none of these cells
populations produced IL-17 (FIG. 1C). The latter likely are NK
cells. The percentage of CD3+CD4+1L17-IL22+ T cells and
CD3-CD4-IL17-IL22+ in control and endemic subjects are shown on
FIG. 1C.
[0117] Modulation of IL-22 production is modified by the
anti-schistosome treatment and is modulated accordingly to hepatic
fibrosis.
[0118] IL-22 levels in egg-stimulated cultures varied markedly
among exposed subjects. Since anti-schistosome Praziquantel
treatments destroy the worms and shut off egg production until
reinfection occurs, we evaluated whether differences in
Praziquantel treatments could have modulated IL-22 production.
Certain patients had been treated every year for at least 10 years,
others had never been treated and others had received 1 to 10
treatments in the past 10 years. FIG. 2A shows the number of
Praziquantel treatments had a significant impact on IL-22
production by subjects PBMC: IL-22 in egg-stimulated cultures
augmented significantly with the number of treatments over the past
ten years (p=0.005, covariate in the regression model was gender
p=0.08); this effect was however much less for subjects who had
been treated at least once a year every year probably because these
subjects were not getting reinfected (see below). Then the
frequency of Praziquantel treatments over the last ten years had
impacted significantly on IL-22 production by PBMC from exposed
subjects. The inventors then evaluated whether IL-22 levels in
cultures were related to the degree of patient's liver disease.
FIG. 2B shows that IL-22 was low in subjects with mild liver
disease as measured by hepatic fibrosis grades and augmented
steadily with increased fibrosis grades reaching maximum levels in
subjects with advanced central periportal fibrosis. This suggests
that increased production of IL-22 may occur in response to/in
association with severe hepatic disease. Strikingly, however, IL-22
from patients with very severe hepatic fibrosis (HF grades D,E,F)
failed to produce much IL-22.
[0119] The effect of the number of Praziquantel treatments on this
pattern is shown on FIG. 2C. Praziquantel treatments impacted IL-22
produced by cells from all fibrosis groups. Three observations are
most relevant to our study: first the increase IL-22 production in
advanced fibrosis (CLH) is observed at different Praziquantel
regimens and is not due to differences in the frequency of
treatment of this patients; second, Praziquantel treatments
improved IL-22 production in all cultures but in cultures of cells
from subjects with severe fibrosis grades; third, subjects with the
high Praziquantel regimens (>10, once at least every year) are
in the mild fibrosis group and account for the increase of IL-22
production observed in this group. In summary, IL-22 is impacted by
two independent factors the Praziquantel treatments and the degree
of hepatic disease. Moreover subjects with very severe hepatic
disease fail to produce much IL-22 and this was not improved by
Praziquantel treatments whereas the same treatments had a marked
enhancing effect on IL-22 production by subjects with mild to
advanced hepatic fibrosis.
[0120] IL-6 and possibly IL-1.beta. likely are key regulators of
IL-22 production in subjects with different hepatic fibrosis grades
and different treatment regimens.
[0121] The inventors observed that cytokines IL-6, IL-1.beta. and
IL-23 were significantly enhanced (IL-23 (p=3.10-6), IL-6
(p<10-6) and IL-1.beta. (p<10-6) by egg stimulation in 24 hrs
cultures of PBMC from exposed subjects (FIG. 3A). To determine
whether any of these 3 cytokine could play a role in modulating
IL-22 levels, we performed a linear regression analysis with IL-22
levels in egg-stimulated cultures including these 3 cytokines,
patient age and gender. This analysis showed a highly significant
(p=0.0002) association between IL-22 and IL-6 and a weak
association (p=0.06) with IL-1.beta.. IL-23 was excluded from the
regression model. This result is illustrated in FIGS. 3B, 3C that
shows the variations of IL-6, IL-1.beta., and IL-23 with
Praziquantel treatments (FIG. 3B) and with hepatic fibrosis (FIG.
3C). Thus, the link between Praziquantel treatments and IL-22 and
Fibrosis grades and IL-22 is, at least in part, IL-6.
[0122] The results presented above are consistent with the view
that the recruitment of a protective IL-22 response increased with
hepatic damage and that the most severe hepatic disease may result
in part from the inability to recruit such response. To test
further this hypothesis the inventors looked for genetic evidence
indicating the IL-22 was indeed crucial in the control of hepatic
fibrosis and had a significant impact on hepatic disease.
Example 2: Polymorphisms in IL22RA2 Encoding IL22 BP Arc Associated
with Hepatic Fibrosis in Two Samples of Chinese Fishermen and
Farmers Living in an Endemic Area of S. japonicum
[0123] Materials and Methods
[0124] Statistical Analysis
[0125] Multivariate logistic regression was used to analyse the
relationship between the probability of an individual developing
fibrosis and genetic variants including the main covariates known
to affect disease progression in subjects infected with
schistosomes. The statistical SPSS software (version 10.0) was used
for this analysis. Age, gender, and exposure to infection, were
tested in the regression models and kept when they showed an
association (p<0.05) with disease. Since the cohorts were
matched for gender and age, these covariates had little effects on
the association between genetic variants and disease. Infection
with HBV and exposure to infection were included in the regression
models when these covariates could be evaluated accurately as in
the Chinese fishermen (exposure, number of treatments) or in the
Chinese farmers (HBV infection, place of birth).
[0126] DNA Extraction
[0127] Aliquots of 5 to 15 ml of blood were collected on sodium
citrate and kept at -20.degree. C. DNA was extracted using the
standard salting out method (Sambrook et al., 1989).
[0128] DNA Amplification
[0129] All the DNA purified from FTA card were pre amplified before
genotyping. Polymerase chain reactions (whole genome
amplifications) were conducted in 50 .mu.l reactions containing one
punch of biological sample (FTA1-bound buccal cell DNA) or 100 ng
of genomic DNA, 1.5 OD of 15-base totally degenerate random primer
(Genetix, Paris, France), 200 mM dNTPs, 5 mM MgCl.sub.2, 5 ml of
10.times.PCR buffer and 0.5 unit of high fidelity Taq DNA
polymerase (BIOTAQ DNA Polymerase, Bioline London, England).
Samples were amplified in a multiblock thermocycler as follows: a
pre-denaturation step of 3 min at 94.degree. C., 50 cycles
consisting of 1 min at 94.degree. C., 2 min at 37.degree. C., 1 min
of ramp (37-55.degree. C.), and 4 min at 55.degree. C. Final
extension step of 5 min at 72.degree. C.
[0130] Sequencing
[0131] Purified PCR products were sequenced using ABI Prism BigDye
Terminator cycle sequencing system (PE Applied Biosystems, Foster
City, U.S.A.) on ABI Prism automatic sequencer. Sequencing
reactions were performed on both strands Sequencing by GATC biotech
(GATC, Marseille France).
[0132] Polymorphism genotyping by PCR with specific TaqMan
probes
[0133] Allelic discrimination was assessed using TaqMan probe
assays (Applied Biosystems, Lafayette USA). Each reaction contained
12.5 ng of genomic DNA, TaqMan Universal PCR Master Mix (Applied
Biosystems, Lafayette USA), 900 nM of each primer and 200 nM of
each fluorescently-labelled hybridisation probe in a total volume
of 5 .mu.l. RT-PCR was conducted in an ABI Prism Sequence Detection
System 7900 (Applied Biosystems, Lafayette USA) using the following
conditions: 50.degree. C. for 2 min, 95.degree. C. for 10 min and
40 cycles of amplification (95.degree. C. denaturation for 15 s,
60.degree. C. annealing/extension for 1 min).
[0134] Results
[0135] The inventors have selected in HapMap data basis the SNPs
comprise in IL22RA2 (29.7 Kb) and 10 Kb in 3' and 5' of the gene
that had a Minor allele frequency in Chinese greater than 10%.
These SNPs were grouped in six correlation (r.sup.2=0.8) bins
containing n=10 (bin I), 5 (II), 2 (III), 3 (IV), 13 (V) and 3
(VI), and 4 singletons which are positioned as in FIG. 4. The
inventors genotyped one or two SNPs from each bins in a sample of
Chinese fishermen (n=268, 176 subjects with mild HF and 92 patients
with severe HF) who have been fishing for at least 20 years in the
Dong Ting lake where S. japonicum has been endemic for at least 40
years. They found that 3 SNPs belonging to two bins were associated
with HF. SNP rs6570136 GG (p=0.007, OR=2.7 (CI=1.3-5.6)), rs7774663
TT (p=0.006, OR=2.5 (1.3-4.7)) both in bin I and rs7749054 TT
(p=0.045, OR=1.8 (1.1-3.1)) showed some association with HF (Table
2). The significant covariates introduced in the statistical model,
were gender (p<10-3, OR=6.9 (2.8-17)), Exposure (Number of
fishing years) (p=0.05, OR=1.02 (1-1.05)), splenectomy (p=0.008,
OR=6.6 (1.6-27)). Multivariate analysis testing two SNPs
simultaneously in the same models in the presence of the same
covariates indicated that SNPrs 11154915 TC was associated (p=0.04,
OR=1.9 (1-3.5) when tested in the presence of rs 6570136 (p=0.007
OR=2.9 (1.4-6). Interestingly (see study in Sudanese and
Brazilians) SNP rs 2064501 showed a trend to association with HF
that was not reduced when other SNPs were introduced in the
regression model.
[0136] Finally, the association of rs7749054 was likely due to its
LD with SNPs in bin I since the association of rs7749054 with HF
was totally lost in the presence of either SNP rs6570136 or SNP
rs7774663.
TABLE-US-00003 TABLE 2 SNPs of IL22RA2 associated with Hepatic
fibrosis: analysis in Chinese fishermen Chinese fisherman sample
Controls Cases SNP Position Bin Genotype % % OR 95% CI p Univariate
rs6570136 137536315 I GG 13.0 22.1 2.7 1.3-5.6 0.007 analysis
rs7774663 137552586 I TT 18.1 28.4 2.5 1.3-4.7 0.006 rs7749054
137542479 II TT 32.8 41.1 1.8 1.0-2.9 0.045 rs202563 137503185 III
AA 38.7 45.8 0.3 rs276466 137508307 IV AG + GG 24.3 30.2 >0.5
rs11154915 137524675 V CT (no TT) 97.2 99.1 0.16 rs2064501
137519516 VI CC + TT 55.4 62.5 0.17 Multivariate rs6570136 I GG 2.9
1.4-6.0 0.007 analysis rs11154915 V CT (no TT) 1.9 1.0-3.5 0.04
Model 1 (n = 268, 92 cases and 176 controls)
[0137] The inventors then attempted to replicate these results in a
second Chinese sample from farmers from a region endemic for S.
japonicum. This sample differs from the fisherman sample because it
was hospital based recruited from an outpatient clinic caring for
severe hepatic disease including ascites, bleeding from varices and
cirrhosis. 92.2% of the recruited patients were living in a region
where S. japonicum was still endemic, 7.8% had been living in a
schistosome endemic region but transmission in their region had
been interrupted ten to fifteen years ago. A fraction (86.5%) of
these subjects had evidence of previous HBV infection (20.9%
AgHBS+) one patient had been infected with HCV. Thus liver disease
in most farmers of this second sample likely results from both
schistosome and HBV infections.
[0138] All SNPs tested in the Fisherman sample were genotyped on
the Farmer sample (298, 97 subjects with mild hepatic disease and
201 subjects with severe hepatic disease). Association with hepatic
disease was observed with 4 SNPs from 3 different bins: SNP
rs6570136 GG,GA (p=0.009, OR=2 (1.2-3.3)), rs7774663 TT,TC (p=0.01,
OR=2 (1.2-3.3) both in bin I; SNP rs 276466 GA (p=0.01, OR=2.2
(1.2-4)) in bin IV; SNP rs1114915 CC,CT (p=0.04, OR=5.7 (1.1-29.6))
in bin V (Table 3). Trends for association were also observed for
SNP rs202563 AA,GG (p=0.06) in bin III and SNP rs2064501 CT
(p=0.08). Covariates in these association test were Age (p=0.05,
OR=1.03 (1-1.06), gender (p=0.02, OR=2.3 (1.1-4.8) and whether the
patient was living in endemic/non endemic region (p=0.09,
OR=2).
[0139] Multivariate analysis performed on SNPs from different bins
indicated two possible statistical models: one model included SNPs
rs6570136 (or rs7774663) (p=0.03, OR=1.8 (1.1-3)) in bin T and SNP
rs11154915 (p=0.1, OR=4 (0.8-21.2)) in bin V; the other model
included SNP rs 276466 (p=0.02, OR=2 (1.1-3.8)) and SNP rs11154915
(p=0.05, OR=9.2 (1.1-80)). The analysis could not discriminate
between these two models.
TABLE-US-00004 TABLE 3 SNPs of IL22RA2 associated with Hepatic
fibrosis; analysis in Chinese farmers Chinese farmer sample
Controls Cases SNP Position Bin Genotype % % OR 95% CI p Univariate
rs6570136 137536315 I GG + AG 53.6 67.8 2 1.2-3.3 0.009 analysis
rs7774663 137552586 I CT + TT 58.8 72.3 2 1.2-3.3 0.01 rs7749054
137542479 II GG 15.1 18.9 0.5 rs202563 137503185 III AA + GG 46.9
57.3 1.6 0.98-2.7 0.06 rs276466 137508307 IV AG (no GG) 18.7 34.5
2.2 1.2-4.0 0.01 rs11154915 137524675 V CC + CT 93.8 99.3 5.7
1.1-29.6 0.036 rs2064501 137519516 VI CT 40.2 51.2 1.6 0.95-2.7
0.08 Multivariate rs6570136 I GG + AG 1.6 .sup. 1-2.6 0.06 analysis
rs11154915 V CT + TT 4.8 0.93-25.sup. 0.06 Model 1 (n = 298, 201
cases and 97 controls)
Example 3: Extension of the Association to Populations from Sudan
and Brazil Exposed to Schistosoma mansoni
[0140] To assess whether our observation could be extended to
subjects infected with S. mansoni we tested the same SNPs in a
sample from Sudan and in a sample from Brazil. Again a significant
fraction of subjects in the Sudanese sample as in the Chinese
farmer had also been infected with HBV whereas only very few
Brazilian had HBV infections.
[0141] Genotyping the Sudanese sample (n=202, 144 mild HF and 58
severe HF) showed that SNP rs6570136 GG (p=0.01, OR=3.1 (1.3-7.2)),
rs7774663 TT,TC (p=0.01, OR=1.7 (1-3.1), rs11154915 TT (p=0.05,
OR=6.2 (1-35.3)) showed associations with HF whereas a trend for
association was also detected for SNPrs7749054 TT (p=0.07, OR=2
(1-3.6) and for rs2064501 CC (p=0.06, OR=2.7 1-7.3)). See Table
4.
TABLE-US-00005 TABLE 4 Extension of the associations detected in
Chinese to Sudanese infected with S. mansoni Sudanese sample
Controls Cases SNP Position Bin Genotype % % OR 95% CI p Univariate
rs6570136 137536315 I GG 8.3 24.5 3.1 1.3-7.2 0.006 analysis
rs7774663 137552586 I CC + TT 45.5 66.7 1.7 .sup. 1-3.1 0.04
rs7749054 137542479 II TT 0.2 rs202563 137503185 III GG 21.8 34 1.6
0.9-3.0 0.09 rs276466 137508307 IV AG + GG 0.25 rs11154915
137524675 V TT 0.8 5.7 6.2 1-35.3 0.07 rs2064501 137519516 VI CC +
TT 5.3 17 2.6 1.2-5.7 0.02 Multivariate rs6570136 I GG 10 3-34
0.0002 analysis rs2064501 VI TT 3.4 1.2-9.4 0.018 Model 1
rs11154915 V TT 7.4 0.75-74.sup. 0.09 (n = 189, 53 cases and 133
controls)
[0142] Likewise genotyping these same SNPs in the Brazilian sample
(n=161, 119 mild HF and 42 severe HF) showed association with HF
for SNP rs6570136 GG (p=0.0001, OR=6 (2.4-14.7)), rs7774663 TT
(p=0.03, OR=3 (1.4-6.8)) and SNPrs7749054 TT (p=0.03, OR=2.8
(1.2-5.6), Furthermore rs11154915 TT,TC showed a trend for
association with HF (p=0.14, OR=2.4 (0.9-6.5)).
[0143] See Table 5:
TABLE-US-00006 TABLE 5 Replication of the association in Brazilians
infected with S. mansoni Brazilian sample Controls Cases SNP
Position Bin Genotype % % OR 95% CI p Univariate rs6570136
137536315 I GG 11.5 35.6 4.2 1.8-10 0.001 analysis rs7774663
137552586 I TT 24.5 44.2 2.4 1.2-5.1 0.02 rs7749054 137542479 II TT
45.5 67.4 2.5 1.2-5.1 0.01 rs202563 137503185 III AG + GG 73.5 86
0.13 rs276466 137508307 IV AG + GG 26.5 41.9 2 0.9-4.3 0.07
rs11154915 137524675 V CT + TT 74.3 87 2.3 0.9-6.sup. 0.09
rs2064501 137519516 VI CT + TT 52.8 66.7 0.15 Multivariate
rs6570136 I GG 24.8 3-205 0.003 analysis rs2064501 VI CT + TT 10.1
1.1-93 0.04 rs11154915 V CT + TT 2.3 0.8-6.9 0.14
[0144] Multivariate analysis performed in the Sudanese sample
confirmed the independent associations of SNP rs6570136, 20564501
and 11154915. It was most remarkable that the high OR associated
with rs11154915 was confirmed in the multivariate model.
Furthermore subjects bearing the aggravating genotypes for both
SNPs had in both models OR for HF greater than 25. The Multivariate
analysis showed that the association of SNPs rs7749054 was lost in
the presence of SNP rs6570136 confirming that this association was
not independent of SNP rs6570136
[0145] In summary SNPs rs6570136 GG and rs7774663 TT, that belong
to the same correlation bin were associated with HF, in all four
samples tested. SNPrs11154915 TT, CT and rs2064501 CC showed a
trend for association with HF in all samples; more important these
trends were confirmed by multivariate analysis showing that these
SNPs were acting independently of SNP rs6570136; taking into
account these 2 SNPs increased the strength of the association of
SNPrs6570136 with HF.
Example 4: Associations Between SNPs in IL22RA2 and Response to
Anti-HCV Treatment
[0146] The inventors have performed their genetic analysis on 123
subjects (69 responders to treatment with ribavirin+IFN, 54 non
responders) who were or have been infected with HCV genotypes 1 or
4. They tested at least one SNP in each of the 7 bins identified in
IL22RA2 using Hapmap data. Univariate analysis showed associations
with SNP rs2064501 (bin VI, p=0.013) and SNP rs1543509 (bin VII,
p=0.012) but also suggested possible associations with SNPs
rs7774663, rs6570136 (bin I, p<0.13), SNP rs77449054 (bin II,
p=0.1), SNP rs202563 (bin III, p=0.07), SNP rs28366 (bin IV
p=0.15), and SNP rs2064501 (bin VI, p=0.2). This high number of
SNPs in possible associations with response to treatment could be
due to correlations between the tested SNPs, it also suggested that
the different SNPs could exert confounding effects on each others.
Then a step by step multivariate analysis was undertaken.
[0147] Testing all SNPs two by two indicated that the association
of SNP rs202563 and rs6570136 with response to treatment were
equivalent but that SNPs rs276466 and rs28366 were clearly excluded
from the regression model by SNP rs6570136. All tests showed that
the association of SNP rs1154915 with response to treatment was
enhanced by the presence of other SNPs (like SNP rs6570136 or SNP
rs2064501 or SNP rs1543509) in the regression model. The
association of rs6570136 with response to treatment was lost in the
presence of SNPs rs2064501 or rs1543509 but this association was
regained when SNP rs11154915 was added to the model (3 SNPs in the
model). This is due to the strong linkage disequilibrium between
SNP rs11154915 and SNP rs6570136 (or any SNPs in bin I), as a
consequence SNP rs1154915 TT responder genotype is 100% associated
with bin I's non responder genotypes. So the model must include at
least 3 SNPs (rs11154915 (p=0.03), rs7774663 (or rs6570136, p=0.03)
and SNP rs2064501 (p=0.001). Finally SNP rs1543509 and SNPs from
bin I (p=0.15) also enter in this model.
[0148] In summary the inventors have found that SNPs that belong to
four different bins in IL22RA2 are independently associated with
the response to treatment. Importantly, these results that were
obtained testing TagSNPs, can be extended to any SNP in the same
bins. Then it is expected that most if not all SNPs in bins I, V,
VI and VII are genetic markers response to IFN+ribavirin treatment.
It can also be seen that 3 of these identified bins were associated
with fibrosis progression (SNPS in bin VII have not been tested on
fibrosis yet). Interestingly, most genotypes that aggravate hepatic
fibrosis are associated with a better response to treatment.
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Sequence CWU 1
1
3914000DNAHomo sapiens 1acatgacaag gccagagaaa acagaaaggc agaaagagaa
gccaaaagag ctgcaatgac 60agcgataact aagaaggaag aggaaaccct taccatgccc
ttattggagc ttcctcttac 120agaaccccct aactactcct ctaatgaaaa
ggcttggttt gagcaggaaa gtggaagtta 180ccagaaagga agttggtgga
agttctcaaa tgggaggctc gccagctatc ccagaagcaa 240tagcccctgg
ttcataaaac agtttcatca aggaacacat atgggaaaaa ctgcattaga
300gactcttgta ggatggcatt tctattgctg agcctaactg ccatcactcg
agccatttat 360gagtaatgtt taacttgtgc cccaaacaat ccacagcagg
ggccaacatg gcccccaggg 420attcaagaaa ctggagctac accctgtgaa
aacctgcatg tgggctttac tgagctgcct 480cgaaccggag gctaccggtg
catgctagtg tttgtctgca ctttctcagg gtgggttgag 540gcatttccca
ccaggacaaa gaaagctcgg gaagtaacca gaatcttact aaaggacatt
600attcctagat ttcgactgcc tctaacttta ggatcagaca atggcccagc
atttgtggca 660gaaatagtac aacagctaac acagaggtta aaaatcaaat
gaaaactgca tacagcttat 720cacccataga gttctggaaa gttgaaagaa
taaaccggac actcaaacag ccgttaaaaa 780agttttgcca tgaaactcat
ctaagatggg atcaggtgct gcccatggtc cttctctgag 840tcaggtgcac
ccctactaaa ttaactgggt attcacccta taagatagtg tttggccgac
900accctgatca taactcagat aaacggggat ttaaaaaatt ggggaattaa
ccttaagaag 960gcaaatgcaa gccttaggtg aggtctcgca ggaaatgcaa
ggatgggtaa gagaaagaat 1020acctgttagc ctcacagatg cagtacaacc
cttctaacct ggagactctg tctgggtcaa 1080acaatggaac ccaaccactt
tagggccttt atgggatagt ccccatattg tgatcttgtc 1140tactcccact
gctgttaaag ttgcaggtat cataccttgg gttcatcata gccggctgaa
1200accagaagca gccaccaccc aggaccagtg gacaagtcaa caaaacccag
accactcaac 1260atggctgatc ctgtggtgaa accaagccac tgctgacaag
gacaactgcc ctgcttcaac 1320cacaccagag gctggttggt ccacgcacgg
ctgaagcttg aggaaacatc gagccctgtt 1380ctagtcacac aaatggaagc
tgactagtct atgcatggct gaagcctgag gaagtcaatg 1440atacataagt
aaatgtagac taaatttaca aacatagtta tactcttact tgtagtaatt
1500attttgctgt catgttatct ttgcaaatgc tgccaagctt gttgcccaga
aaggtgccca 1560tgcatagtat aagtttaatc atattagtaa tactgaagcc
actgacactt tcacctatgg 1620ttataaaagg ggaccaggat gactgtcatc
actgtatgat agaagcctgg tctggaaaag 1680gtgtgactaa aactctgtta
taccagacct actatgagtg tacagggact catacaggaa 1740cttgttgttt
ataaccagac taattactca gtctgtgatc ctggaaacgg gcagccccaa
1800atatgttatg acccagagtt cttgccctat gacttcttat ttgaagtcca
aatttggtga 1860acccctaatg ccatcatata caaaccccac agaaactggg
gtcagtaaac ttgtaaacaa 1920aacgcaagta ttcacttacg cgcataaagg
gcccgtctcc atatattttg atgcctgcca 1980agctgcacat ctcagtaaay
taaataatat ttggaccatc tgtaaaaatc taggacaaga 2040aagagtcagc
agcagagcca ccaaggccat aataggagag tccgaaaaag agtgccctga
2100ttgtgataat cagtggacca cacatgaatt taatcagcac ctatacactg
gaagggctgc 2160tctgtttgcc agccaagagg agaagatagg gtacacaact
ggaacatgct acccactcaa 2220tctgacaata ctaaagccaa atatgacttt
ctggactaaa gggcataaag gattactaac 2280ctttgatcag gcaggagctc
tcctaggact tggtattcct ctggtcatca caaagaaaac 2340ccaaaggact
caagttcaac ttagcccaat acaacagttc aggttttata aatctttcaa
2400tgaacacttt aattctgaag tatcaaaaat tcaaattcct cctatatcaa
ctgaaaatct 2460gtttgtccag ctagccaaaa gtattgctaa caatttagga
gttacttcct gttatgtatg 2520tggaggtgct aatatgagag atcaatggcc
ctgggaagcc agagaattga tgctgcaaga 2580caattttacc ttgcctgaat
ttgttacaaa attcaatgca aatccaagtg tttggctatt 2640aaggaacccc
atcattggaa aatactgtat tgcctgttgg ggcaagtcct ttcagaacca
2700gataggggaa acaacttgcc taggtcaaca atattttgaa gaatctgaga
acagaacaca 2760atggagaagc tttatagatg attcctctgt gtcactttaa
tccctttttg cagttcccaa 2820cactaaatca atcatggtac caattagaag
ctccaactgt ttggagagca cctgcaggat 2880tatataggat ctgtggaaca
aaggcttatc aattactaac cgataaatgg acaggggcat 2940gtatattagg
aacaataagg ccattctttt tgctactccc cctgcagcaa ggggaagatc
3000taagctatct ggtctatgat gaaggcagaa aaagagtcaa aagaaatgtg
tttacaaaaa 3060taagtactga ggaaaaaata aatactaaca ttaaaaagga
cattgaaata gggggctgga 3120aagataatga atggccccct gggcacaaga
tgggtcatgg ggatactgta ctcctattta 3180tatgttaaac cacatcataa
ggttgcaagc agttctggaa attatagtca atgaaacagc 3240ctgagcctta
gacttgctag ccatacaggc aacccagatg agagatgcca tttatcagaa
3300caggttagta ctgaattatg ttttagcttc agaagggggt ttgtggaaaa
cttaatttaa 3360caaattgctg cttacaaatt gatgacaatg gaaaagctgt
catggaaatc actgccagga 3420tgcggaagtt agctcatgtt ctggttcaga
catggtctgg ttggaacccg agttcactct 3480ttggaggacg gttttcatgg
tttggaggct ttaaaactgt aatactaggc tttgtggcca 3540taaaaggtgg
atgcctactg cttccctgtc tcttgccatt tctaatcgga agcatccaat
3600ccaccataga ctcaatggta gacagacata ccaccatccg aataaaggct
ctgcaaaagt 3660accaactggt atcccaagat gagtatgtac ccactcaaga
agaaatagct aactgtggtg 3720ctctttatta atctacattt gtgtcgagca
ccaaaagggg gaaatgaaga aggaattaat 3780gaaatcaact ataacctaag
agtagtagta atacaaattt taaaatcctt ttaaagttcc 3840tgcaaaatgt
gacccctgcc ttacattcac gttaaaaggg aatattaaca gcctgtcttc
3900tctctgtgga cagtggacct tatctatact ccccaactcc acattcctca
aagtttatta 3960caggcccagt gagttcctgc atgactgcag ggtcacaaga
400021001DNAHomo sapiens 2taactgttga aattgggtgt caggtttatt
atactctact tttgtatgta cttaaaattg 60ttcataacaa agaaaaaaga tttttaaagt
ttatctacaa gatgtggcca gacacggtgg 120ctcacacctg taatctcagc
actttggaag gcggaggtgg gtggatcatt tgaggtgtgg 180agttccagac
cagcctggcc aacatggtgc aaccccgtct gtactaaaaa tacaaaaatt
240agccaggcgt gacggtgtgt gcctgtaatc ccagctactc agtggggctg
aggcaggaga 300attgcttgag tcaaggaggt gaggtttgca gtgagccgag
atcgcgccac tgcgctccag 360tctgggcagc gataaagcga gagtccatct
caaaaaaata aataaataaa taaataaagt 420ttacttacca gatgctgtct
tccttttggt aattttaatg ccattttagt gtcaataata 480agatctaata
attatgggac rccatgttat gtttttccca tattttgtct ttgttaatcc
540tcttatgaag tctaggagat tggtattatt attcatttga tgttacagat
gaagaaactg 600agacatagat agagaggtgg agagaacttg accagggctc
tatagcgagt agtggtaaag 660tgagggctga aatcagatct ggttagcctc
agggcctgag gagtattatg aaactcctct 720tgtgttattc tttgcttgta
atagacattc cataaaggga tagaatgatg tcaaagaaca 780tttgtccatt
ggcttctcga atcgtttatt cagtcaaaca aatgtttatt gagcaactgt
840tatatgccag gcactgtgtt agacatcggg gatgcagaaa tgaacaagac
tacagagcca 900gccctcaggg aaccaacagc attttcttca accaggtctt
ggtagcaaag ggctaagtgt 960ttcttattgt ttttcagaga agtgtttaaa
aactggtgtt c 10013818DNAHomo sapiens 3ccatgggaag gattccaacc
ttcttccaca tccatgttcc ttgcttagcc caacaagacc 60ctggcagagg ctcctgccca
agggccatgc tgggccttgg gctcccctct cggcccttag 120ctggctcctt
gtcctctgag ctgcacttgt tccagcctga ggcatccctc cctcccaccc
180ttcatccaca agaccccagc yctgcctcct caatgtttta tttgcattct
gagttcctac 240tatattgtat tcccaagaca tatctcttct aaatttctaa
attacagtaa aacaacttct 300aaatttcatg tgtgatatgg tttggctgtg
tccccaccaa aatcttgtct tgcattgtag 360cttccataat ccccatatat
tgtgggaggg acctggtggg aggtaaatga atcatggggg 420tgtttttttc
ccatgctgtt ctcatgatag tgaataagtc ttacaagatc tgatgatttt
480ataaagggca gttcccctgc acacatctct tgcctgccac catgtaagac
gtgcctttgc 540ttctcctcct tctgccatga ttgtgaggcc tacccagtca
tggggaactg ttaatccatt 600aaacctcttt ttatttataa attacccagt
cttgggtatg tctttattag aagtgtgaga 660aaggactaat acactgtgcc
tcagtttcct cactggaaaa aaatgtataa tactagtctt 720accagatagc
taggagtgtc aataagagaa actttgccaa ccatctgcct atagtagagg
780ctcaggcgca ttagttctcc ctcccatttc tttccact 81847142DNAHomo
sapiens 4tgagcagggg gcacagcaaa gccccaaggc tgaggccaga tgaaggagca
ggaggcaatg 60tggctggaga ggagggagca aggggcagag tgttggtggt gaggtcaggg
gcccagcagc 120ctgatccagg ggacttgaac aggatggaag gactttgggt
gcgttctgaa gaaggggaag 180ccactggaag gcattaagta gaaaaaattg
gaagtgagag taattatatg tgaaagttgt 240tagagtcaca atggagtgac
gatgaggcag gacaggtagt caaggaagta agtgcagtta 300acacaatgag
ccccagtatt cgcattgtaa tccagctcat gcaagcacag ctatctcctg
360cagggaatat ttcccataga cagcatttgc actttgattt tacctcttct
caaacggacc 420ctgttctcat gataatagta aaaaacacac ccctaggtgg
agatttaaga tgctgatgaa 480ttatgagatg tatgaacaag catgtacagc
tactgcacat gtgcacccag aggaccaccg 540aggacatgct tactagcaac
accttttctc accctcttat gaataatcat gtaagagtcc 600cataaaagga
tttctccagc aataatcagt gctgtccatt cagtggctca tgcctgtaac
660ccagcacttt gggaggccga ggtgggtgga tcacctgagg tcaggagttt
gagaccagcc 720tggtcaacat ggtgaaacct cgtttctatt aaaaatacaa
aaaaagtagc caggtgtaat 780ggcacatgcc tgtaatccca gctacttggg
aggctgaagc aggagaactg attgaacctg 840ggaggtggag gttgcagtga
gtcatgactg tgccactgca ctccagccaa cagagtaaga 900ctctgttccc
cctcggcccc ctgcaaaaaa aaataataac aatgataaga ggcaagatca
960atggccacca aaattttatt ttttcccata gcgttgctgg ggtggcatgg
ctgcctgccc 1020tgggttcatc ctgtccctaa gtggaactcc ctatggctga
gggactcaga atcaaatgac 1080ttatagccaa ttaaatgttc tagtccagat
gcccaattaa atgggcatgg acagacattc 1140attagccttt aaattatttt
ctaagtaaaa agtcaacaaa caaaaagtta aaggtgaggt 1200tacaaaactg
acttttcttt aacttctatg ctactgtaat cttgggtttt gttatggact
1260tatagcaatt atttatacaa aacataagaa ttgttctgaa aaaattaaaa
aatatatacc 1320tgcatggctc ataactggaa atattatacc aggaggcttt
gtcacttggt atctttatcc 1380ttttacttat tattttcttt taattctaca
ggaagcagta aattctttat ggttggagtg 1440gatgaagagg tgccatgtaa
tagctcagaa ggcaaagtcc cttgttttac cagctgttta 1500ggcatccatg
tactcatcct tgatttgaag ggtttgagtt aattctatcc ttccaaatca
1560gcccttacaa tctcacgtgc ccacctcttc tgcaacagtc tctgggccta
gagggaggac 1620gcttgcaata caggattttt tgcatgttcc cagtggctcc
accccattct cccagtgcac 1680atgcaggccc ttagtctgaa cccackctac
attgatttat ttcccttact gagcatgtgt 1740taagggatgg aatttttcac
catgggcatg tttaggcaag ccccctgtac acaatgtcct 1800ggatggcatt
tggctgtctt ctgcctctat cattccccca tctaaaagag tacatctaac
1860tgccattaga ataaggataa gaagaaagac aaagacccat cttaactgct
ttctgctgac 1920agagggcact gttttggaaa gacagcagtt gggtctccct
cagaggccta tctaagggta 1980tctggtaaaa gggaccatca ttcgaggctc
tggttgcata actgtttgga gtttgagggc 2040ctgaaggcga gaagagacaa
accaggttat tagaagacat gtaccaaaat gaaatggggg 2100aagggtaagg
acagttcaaa aatcctgagg ctgctgacat gcccagataa ctggtagctg
2160tagttgtgcc tgctaagatt tgggtgcatg ggacttggct ttggttagct
cccgtagttt 2220attttcccaa aaaagaaacc tctgggttat gggcacccta
tttactccca ttatctggca 2280ggatttgtag gataattgtt cagaactaga
atactgttcc agatttttac attacccatg 2340ccttttgttt cttctgagct
gcagccagag atcactggtt agttcacagg aataagcagg 2400gttaatttaa
aatgtaggca aaaaacttaa aaacaactaa tgagtctaga atttaatgac
2460aaatgtatga taagttttga aacataattt ctttctcccc agtcctcatt
tttgttaaaa 2520acaaatcata ataggagtga gttgtttgta aaataaactt
tagtcttaca cttggtctgc 2580ttatttgcac aaagtacaac aagaataatt
atttttacat aggcttttta aattggcttt 2640gatggaactc tgttccacaa
ggaatttcag ataggacttc ataaaaatga gcccagccat 2700gggtttgtac
cctctaatac ctatgagttg ggtgaattgc tctcttcttg aggtcccaag
2760aatatgcggt tcctggccct gttagaaagt gacattcttt actcactaca
ggttagggaa 2820cctgtatggg gactgtgtag acaaagtatg aggctggttt
acccaagggg cttttattgg 2880ctctgcaagt tgagcttgat tccttaaagg
gaaacatacc cttccagtca aagttacagt 2940tactggttgg taaagttaaa
gttacagcta ctggttgcta aagcaaccag tttctccaat 3000tgcatcctgt
tgcaaaagaa agtggattct tactgcactg atgcaaataa ccgtattgcc
3060ctaagttaag aatactcaca gatagtttcc aaattctaga ggaagcaggc
agagagaaaa 3120aaaagtgcta aattttgttc ataggagtct gcattactca
attattaaag attgtgtata 3180gctcaaaaaa aaagatcagc actgttttaa
gctaaagttt aaaaaagatt acttcaattt 3240tctattagtt cagtctgttc
agttaactct tgttctgctt gatatttgtg aacatttcag 3300ctcttcatga
gtcctgtacg tttttccatt attccaatgt cacaatctcc aaagttatca
3360gaaacctgca tttgagagca cctgttacgt ttctatagct gattataaat
cctatttgaa 3420gaagatcaaa acaaaacaat ggtctgtgaa tagcaaaatg
tccatggtag ttacagtcaa 3480aaacacaatt gacaaagaaa ttttgttatc
tctgtggctt ataatcacct aacataacac 3540ctttaattgt gagtgatagc
atatacttag atattagaat tttagaaatc ccatacagtt 3600ttggagcata
tattattatt cactaaaata taacccaaag aagattaaat atcattttgg
3660caatcccatg tacataaatt tgtcaggtaa tcctatttac ctctcttctg
gatgctccag 3720ggatgctagg ggtcaggaaa gacaaccttg aagctgacat
ttgattttgg gaagcccatt 3780aaatatgtta gaggtttaaa acaatgttat
gaagtagaat tccagattac cataaattac 3840ttattttgcc aaaatgatga
ctcaaaaatt ttaaaacaag ccaaaaactt ttactcattt 3900agagggaaga
cttagatttc caaagaattt gtctcctgtc ttcactttca tttccttggc
3960agtctatctg gaagacaaac tgaaatattt aattatcctt tactattaca
tgaaaatctt 4020atacaaggga gagaaagcca aattttaccc tcacattagt
ttactattaa tgtcaacccc 4080aattttttaa tgaaacctta tagacaattc
tatccaatct taaccagttt gatcatgagg 4140taagattcct gtaagccttt
tataaccttt tacaaattac taatttacta atctgctaaa 4200gagcagatta
gggctttaag aaaaccttgt tgtgctttca tttcaatgct cagtttgtag
4260aaaaaccata taatagagtt ttggatttaa tcaatgttca cacacagaat
ttcttttgca 4320agattaattt ttagaaacct cccacaactt gtttaaacct
ttagtttatc ttatctaatt 4380tataatagtc ctttaacctt aggcaaaaac
ttacatttcc atgcattctt ataatctttg 4440actaataaca cattttactg
ttcttacata ccttgcatgt aaatctattt tcagtggtct 4500caattacatg
ttataatggt acctcttagc actttttaat tttagtttaa aacctggtaa
4560gtcgttttaa ttacgcacta ggtgctgata aagtttgatt ccttccagca
taattaaggg 4620tgtggttaat tccatatgtc cctgtgcctt accaagttgt
aaagcaggca gattgaacag 4680ttttcaaagg caaaagaagc cgtttacaac
cttaaaacat ttagccacct agtgcctgac 4740ttgcataatt tagaccagct
atttacattt taagaacatt tgcattttat caattatctt 4800taagactact
tttatttctc agagattaaa gtcacaagaa ctaaaaggca ttatagcttt
4860tatctttcct ccaaaaatat ttgatcttag tgctgatttt tctttaagcc
aattaattag 4920agctcttttt tataactaca cagatggaga agaagattga
gtgttataag atttttcatt 4980tgcccatctc ctaattggat tcttggtctc
tgggtgggac cctttaagag cagggctaag 5040aaagcatgca gtttattttc
tttttttctt tttcttttct ttttttttga gaaagagttt 5100cactcttgtt
gcccaggctg gagtgcaatg gtgcgatctc agctcactgc aacctctgcc
5160tcccaggttc aagcgattct cttacctcag cctcccaagt ggctgcatgc
agtttctagg 5220gcctaataaa caggcatagc tggaaaacaa aaacggattt
tgagagcgat ctatttgcct 5280ctaattcctg gggttccatg aggaaaacag
aggtttctcc caaaatggaa tccatggtgc 5340cttttctgtt tttaccaagc
agccctatgc catcagaaat tatcttaggg cctctcatgt 5400gcgcattaac
actggcaaga caaggtggag aaaagtaatt cagtcaactg agaaaaaaat
5460ctttttccag caaaacaaga tccaagaaga gaaaaacata aaggcctttc
aaatatacgt 5520atagcttgga tatccacttt taattaagct gagctctctt
taagaaagtc cttttaaatc 5580ccacattacc tgacttcagc catgccaagc
agccaatatt tctggctttg gaagtttatc 5640aaaagaacct caaggttcaa
ccaacaagcc tcaattaaga cacgcgaagc acaccagatt 5700ggctacacct
taagaccagc ctcataaaac ctttttcact aatggaaact ttacagggaa
5760tatcaacagt gatccttatc attcttttca ccagtttaca cagggagaga
gaggccaaaa 5820gtctgactgg ttaaaaaact tttatccttt tgctggcatg
tcatgcttct gggttccctt 5880cccctgagct caattctaag ccaaccagtt
taaggtttgg gaaattaact tttctcagtt 5940tggaggatgc atcctatggg
aatgtccttt agtacaggga cacagtcacc catctgtgaa 6000gagaggacaa
aggaggaaaa agtaaaaaaa gatttttttc aaaggctccc caggggttca
6060ggatgcattt gaaaggggga cagattgaag atgaatggct actcatctag
aaagagggga 6120gccagacatc cctggttcct ttctctttct aggaaatagc
cagggtatgt gagggaaaga 6180aggaacaagc atccattttc cttcttccgt
ccttatgtcc ccaagtcctg acaacctcga 6240cagggtgcca cccatgggtg
ccaatacggt tctcacccat ggtaacaggg gacctagtgg 6300atgggattat
ccactgttac ccacaaactg tctttccccc tgctctcaat agccttcaag
6360tgccctagac ctcatttagg ccattgatac tagtatgacc tttatccatg
aaacaagagg 6420cttggcttaa ttgtcaggaa ttagtcatgc tcacctatac
tgtgcttttt aatttttgtt 6480gttgtctgcc tctggatccc tccgatgcag
ttatctttcc tagggcttct acatgaagct 6540tggaattgag tttgggacaa
aagaactgcc tcagtaggtg ggtgcatgga ctcatcaatc 6600cccaggtgtc
cctcaccagt ctggctgctg ccgccttatc ataagctgaa ggctaaggtg
6660caactgtgaa attaggtcct tctcaaacaa gggagggaaa atggtgtcct
gtgaattagg 6720gtcctggtct aataagatgc cttccaaaag gaagaaaact
tctggcacag agaagacccc 6780tctacccgca gggctgtgtt attaggttgg
tgcgaaagca attgtggtgc ccatcattct 6840aagtaatgac aaaaaccaca
actactttca caccagccta ctaactcatg acttggtgga 6900caaaagaaaa
taacaacaac aacaacagct taaatgcagg gctgtgttta ctgctgacaa
6960ggtggagaaa agaaaaatat gcctgagaaa tgcaaatgta tttctccaac
aggcagagaa 7020acttaattgc tattgcactg agctggaccc cttggcttgg
ggtggggaag actctgtgga 7080tacatggcag gggacactgg ccagttggct
gcatggggcc caggcccctg agatcaccct 7140gg 714257142DNAHomo sapiens
5gaaggagcag gaggcaatgt ggctggagag gagggagcaa ggggcagagt gttggtggtg
60aggtcagggg cccagcagcc tgatccaggg gacttgaaca ggatggaagg actttgggtg
120cgttctgaag aaggggaagc cactggaagg cattaagtag aaaaaattgg
aagtgagagt 180aattatatgt gaaagttgtt agagtcacaa tggagtgacg
atgaggcagg acaggtagtc 240aaggaagtaa gtgcagttaa cacaatgagc
cccagtattc gcattgtaat ccagctcatg 300caagcacagc tatctcctgc
agggaatatt tcccatagac agcatttgca ctttgatttt 360acctcttctc
aaacggaccc tgttctcatg ataatagtaa aaaacacacc cctaggtgga
420gatttaagat gctgatgaat tatgagatgt atgaacaagc atgtacagct
actgcacatg 480tgcacccaga ggaccaccga ggacatgctt actagcaaca
ccttttctca ccctcttatg 540aataatcatg taagagtccc ataaaaggat
ttctccagca ataatcagtg ctgtccattc 600agtggctcat gcctgtaacc
cagcactttg ggaggccgag gtgggtggat cacctgaggt 660caggagtttg
agaccagcct ggtcaacatg gtgaaacctc gtttctatta aaaatacaaa
720aaaagtagcc aggtgtaatg gcacatgcct gtaatcccag ctacttggga
ggctgaagca 780ggagaactga ttgaacctgg gaggtggagg ttgcagtgag
tcatgactgt gccactgcac 840tccagccaac agagtaagac tctgttcccc
ctcggccccc tgcaaaaaaa aataataaca 900atgataagag gcaagatcaa
tggccaccaa aattttattt tttcccatag cgttgctggg 960gtggcatggc
tgcctgccct gggttcatcc tgtccctaag tggaactccc tatggctgag
1020ggactcagaa tcaaatgact tatagccaat taaatgttct agtccagatg
cccaattaaa 1080tgggcatgga cagacattca ttagccttta aattattttc
taagtaaaaa gtcaacaaac 1140aaaaagttaa aggtgaggtt acaaaactga
cttttcttta acttctatgc tactgtaatc 1200ttgggttttg ttatggactt
atagcaatta tttatacaaa acataagaat tgttctgaaa 1260aaattaaaaa
atatatacct gcatggctca taactggaaa tattatacca ggaggctttg
1320tcacttggta tctttatcct tttacttatt attttctttt aattctacag
gaagcagtaa 1380attctttatg gttggagtgg atgaagaggt gccatgtaat
agctcagaag gcaaagtccc 1440ttgttttacc agctgtttag gcatccatgt
actcatcctt gatttgaagg gtttgagtta 1500attctatcct tccaaatcag
cccttacaat ctcacgtgcc cacctcttct gcaacagtct 1560ctgggcctag
agggaggacg cttgcaatac aggatttttt gcatgttccc agtggctcca
1620ccccattctc ccagtgcaca tgcaggccct tagtctgaac ccacgctaca
ttgatttatt 1680tcccttactg agcatgtgtt aagggatgga atttttcacc
atgggcatgt ttaggcaagc 1740cccctgtaca caatgtcctg gatggcattt
ggctgtcttc tgcctctatc attcccccat 1800ctaaaaragt acatctaact
gccattagaa taaggataag aagaaagaca aagacccatc 1860ttaactgctt
tctgctgaca
gagggcactg ttttggaaag acagcagttg ggtctccctc 1920agaggcctat
ctaagggtat ctggtaaaag ggaccatcat tcgaggctct ggttgcataa
1980ctgtttggag tttgagggcc tgaaggcgag aagagacaaa ccaggttatt
agaagacatg 2040taccaaaatg aaatggggga agggtaagga cagttcaaaa
atcctgaggc tgctgacatg 2100cccagataac tggtagctgt agttgtgcct
gctaagattt gggtgcatgg gacttggctt 2160tggttagctc ccgtagttta
ttttcccaaa aaagaaacct ctgggttatg ggcaccctat 2220ttactcccat
tatctggcag gatttgtagg ataattgttc agaactagaa tactgttcca
2280gatttttaca ttacccatgc cttttgtttc ttctgagctg cagccagaga
tcactggtta 2340gttcacagga ataagcaggg ttaatttaaa atgtaggcaa
aaaacttaaa aacaactaat 2400gagtctagaa tttaatgaca aatgtatgat
aagttttgaa acataatttc tttctcccca 2460gtcctcattt ttgttaaaaa
caaatcataa taggagtgag ttgtttgtaa aataaacttt 2520agtcttacac
ttggtctgct tatttgcaca aagtacaaca agaataatta tttttacata
2580ggctttttaa attggctttg atggaactct gttccacaag gaatttcaga
taggacttca 2640taaaaatgag cccagccatg ggtttgtacc ctctaatacc
tatgagttgg gtgaattgct 2700ctcttcttga ggtcccaaga atatgcggtt
cctggccctg ttagaaagtg acattcttta 2760ctcactacag gttagggaac
ctgtatgggg actgtgtaga caaagtatga ggctggttta 2820cccaaggggc
ttttattggc tctgcaagtt gagcttgatt ccttaaaggg aaacataccc
2880ttccagtcaa agttacagtt actggttggt aaagttaaag ttacagctac
tggttgctaa 2940agcaaccagt ttctccaatt gcatcctgtt gcaaaagaaa
gtggattctt actgcactga 3000tgcaaataac cgtattgccc taagttaaga
atactcacag atagtttcca aattctagag 3060gaagcaggca gagagaaaaa
aaagtgctaa attttgttca taggagtctg cattactcaa 3120ttattaaaga
ttgtgtatag ctcaaaaaaa aagatcagca ctgttttaag ctaaagttta
3180aaaaagatta cttcaatttt ctattagttc agtctgttca gttaactctt
gttctgcttg 3240atatttgtga acatttcagc tcttcatgag tcctgtacgt
ttttccatta ttccaatgtc 3300acaatctcca aagttatcag aaacctgcat
ttgagagcac ctgttacgtt tctatagctg 3360attataaatc ctatttgaag
aagatcaaaa caaaacaatg gtctgtgaat agcaaaatgt 3420ccatggtagt
tacagtcaaa aacacaattg acaaagaaat tttgttatct ctgtggctta
3480taatcaccta acataacacc tttaattgtg agtgatagca tatacttaga
tattagaatt 3540ttagaaatcc catacagttt tggagcatat attattattc
actaaaatat aacccaaaga 3600agattaaata tcattttggc aatcccatgt
acataaattt gtcaggtaat cctatttacc 3660tctcttctgg atgctccagg
gatgctaggg gtcaggaaag acaaccttga agctgacatt 3720tgattttggg
aagcccatta aatatgttag aggtttaaaa caatgttatg aagtagaatt
3780ccagattacc ataaattact tattttgcca aaatgatgac tcaaaaattt
taaaacaagc 3840caaaaacttt tactcattta gagggaagac ttagatttcc
aaagaatttg tctcctgtct 3900tcactttcat ttccttggca gtctatctgg
aagacaaact gaaatattta attatccttt 3960actattacat gaaaatctta
tacaagggag agaaagccaa attttaccct cacattagtt 4020tactattaat
gtcaacccca attttttaat gaaaccttat agacaattct atccaatctt
4080aaccagtttg atcatgaggt aagattcctg taagcctttt ataacctttt
acaaattact 4140aatttactaa tctgctaaag agcagattag ggctttaaga
aaaccttgtt gtgctttcat 4200ttcaatgctc agtttgtaga aaaaccatat
aatagagttt tggatttaat caatgttcac 4260acacagaatt tcttttgcaa
gattaatttt tagaaacctc ccacaacttg tttaaacctt 4320tagtttatct
tatctaattt ataatagtcc tttaacctta ggcaaaaact tacatttcca
4380tgcattctta taatctttga ctaataacac attttactgt tcttacatac
cttgcatgta 4440aatctatttt cagtggtctc aattacatgt tataatggta
cctcttagca ctttttaatt 4500ttagtttaaa acctggtaag tcgttttaat
tacgcactag gtgctgataa agtttgattc 4560cttccagcat aattaagggt
gtggttaatt ccatatgtcc ctgtgcctta ccaagttgta 4620aagcaggcag
attgaacagt tttcaaaggc aaaagaagcc gtttacaacc ttaaaacatt
4680tagccaccta gtgcctgact tgcataattt agaccagcta tttacatttt
aagaacattt 4740gcattttatc aattatcttt aagactactt ttatttctca
gagattaaag tcacaagaac 4800taaaaggcat tatagctttt atctttcctc
caaaaatatt tgatcttagt gctgattttt 4860ctttaagcca attaattaga
gctctttttt ataactacac agatggagaa gaagattgag 4920tgttataaga
tttttcattt gcccatctcc taattggatt cttggtctct gggtgggacc
4980ctttaagagc agggctaaga aagcatgcag tttattttct ttttttcttt
ttcttttctt 5040tttttttgag aaagagtttc actcttgttg cccaggctgg
agtgcaatgg tgcgatctca 5100gctcactgca acctctgcct cccaggttca
agcgattctc ttacctcagc ctcccaagtg 5160gctgcatgca gtttctaggg
cctaataaac aggcatagct ggaaaacaaa aacggatttt 5220gagagcgatc
tatttgcctc taattcctgg ggttccatga ggaaaacaga ggtttctccc
5280aaaatggaat ccatggtgcc ttttctgttt ttaccaagca gccctatgcc
atcagaaatt 5340atcttagggc ctctcatgtg cgcattaaca ctggcaagac
aaggtggaga aaagtaattc 5400agtcaactga gaaaaaaatc tttttccagc
aaaacaagat ccaagaagag aaaaacataa 5460aggcctttca aatatacgta
tagcttggat atccactttt aattaagctg agctctcttt 5520aagaaagtcc
ttttaaatcc cacattacct gacttcagcc atgccaagca gccaatattt
5580ctggctttgg aagtttatca aaagaacctc aaggttcaac caacaagcct
caattaagac 5640acgcgaagca caccagattg gctacacctt aagaccagcc
tcataaaacc tttttcacta 5700atggaaactt tacagggaat atcaacagtg
atccttatca ttcttttcac cagtttacac 5760agggagagag aggccaaaag
tctgactggt taaaaaactt ttatcctttt gctggcatgt 5820catgcttctg
ggttcccttc ccctgagctc aattctaagc caaccagttt aaggtttggg
5880aaattaactt ttctcagttt ggaggatgca tcctatggga atgtccttta
gtacagggac 5940acagtcaccc atctgtgaag agaggacaaa ggaggaaaaa
gtaaaaaaag atttttttca 6000aaggctcccc aggggttcag gatgcatttg
aaagggggac agattgaaga tgaatggcta 6060ctcatctaga aagaggggag
ccagacatcc ctggttcctt tctctttcta ggaaatagcc 6120agggtatgtg
agggaaagaa ggaacaagca tccattttcc ttcttccgtc cttatgtccc
6180caagtcctga caacctcgac agggtgccac ccatgggtgc caatacggtt
ctcacccatg 6240gtaacagggg acctagtgga tgggattatc cactgttacc
cacaaactgt ctttccccct 6300gctctcaata gccttcaagt gccctagacc
tcatttaggc cattgatact agtatgacct 6360ttatccatga aacaagaggc
ttggcttaat tgtcaggaat tagtcatgct cacctatact 6420gtgcttttta
atttttgttg ttgtctgcct ctggatccct ccgatgcagt tatctttcct
6480agggcttcta catgaagctt ggaattgagt ttgggacaaa agaactgcct
cagtaggtgg 6540gtgcatggac tcatcaatcc ccaggtgtcc ctcaccagtc
tggctgctgc cgccttatca 6600taagctgaag gctaaggtgc aactgtgaaa
ttaggtcctt ctcaaacaag ggagggaaaa 6660tggtgtcctg tgaattaggg
tcctggtcta ataagatgcc ttccaaaagg aagaaaactt 6720ctggcacaga
gaagacccct ctacccgcag ggctgtgtta ttaggttggt gcgaaagcaa
6780ttgtggtgcc catcattcta agtaatgaca aaaaccacaa ctactttcac
accagcctac 6840taactcatga cttggtggac aaaagaaaat aacaacaaca
acaacagctt aaatgcaggg 6900ctgtgtttac tgctgacaag gtggagaaaa
gaaaaatatg cctgagaaat gcaaatgtat 6960ttctccaaca ggcagagaaa
cttaattgct attgcactga gctggacccc ttggcttggg 7020gtggggaaga
ctctgtggat acatggcagg ggacactggc cagttggctg catggggccc
7080aggcccctga gatcaccctg gggctggggc agcagctgtg gctcaatcct
gcactggatg 7140gc 714267142DNAHomo sapiens 6gaaggagcag gaggcaatgt
ggctggagag gagggagcaa ggggcagagt gttggtggtg 60aggtcagggg cccagcagcc
tgatccaggg gacttgaaca ggatggaagg actttgggtg 120cgttctgaag
aaggggaagc cactggaagg cattaagtag aaaaaattgg aagtgagagt
180aattatatgt gaaagttgtt agagtcacaa tggagtgacg atgaggcagg
acaggtagtc 240aaggaagtaa gtgcagttaa cacaatgagc cccagtattc
gcattgtaat ccagctcatg 300caagcacagc tatctcctgc agggaatatt
tcccatagac agcatttgca ctttgatttt 360acctcttctc aaacggaccc
tgttctcatg ataatagtaa aaaacacacc cctaggtgga 420gatttaagat
gctgatgaat tatgagatgt atgaacaagc atgtacagct actgcacatg
480tgcacccaga ggaccaccga ggacatgctt actagcaaca ccttttctca
ccctcttatg 540aataatcatg taagagtccc ataaaaggat ttctccagca
ataatcagtg ctgtccattc 600agtggctcat gcctgtaacc cagcactttg
ggaggccgag gtgggtggat cacctgaggt 660caggagtttg agaccagcct
ggtcaacatg gtgaaacctc gtttctatta aaaatacaaa 720aaaagtagcc
aggtgtaatg gcacatgcct gtaatcccag ctacttggga ggctgaagca
780ggagaactga ttgaacctgg gaggtggagg ttgcagtgag tcatgactgt
gccactgcac 840tccagccaac agagtaagac tctgttcccc ctcggccccc
tgcaaaaaaa aataataaca 900atgataagag gcaagatcaa tggccaccaa
aattttattt tttcccatag cgttgctggg 960gtggcatggc tgcctgccct
gggttcatcc tgtccctaag tggaactccc tatggctgag 1020ggactcagaa
tcaaatgact tatagccaat taaatgttct agtccagatg cccaattaaa
1080tgggcatgga cagacattca ttagccttta aattattttc taagtaaaaa
gtcaacaaac 1140aaaaagttaa aggtgaggtt acaaaactga cttttcttta
acttctatgc tactgtaatc 1200ttgggttttg ttatggactt atagcaatta
tttatacaaa acataagaat tgttctgaaa 1260aaattaaaaa atatatacct
gcatggctca taactggaaa tattatacca ggaggctttg 1320tcacttggta
tctttatcct tttacttatt attttctttt aattctacag gaagcagtaa
1380attctttatg gttggagtgg atgaagaggt gccatgtaat agctcagaag
gcaaagtccc 1440ttgttttacc agctgtttag gcatccatgt actcatcctt
gatttgaagg gtttgagtta 1500attctatcct tccaaatcag cccttacaat
ctcacgtgcc cacctcttct gcaacagtct 1560ctgggcctag agggaggacg
cttgcaatac aggatttttt gcatgttccc agtggctcca 1620ccccattctc
ccagtgcaca tgcaggccct tagtctgaac ccacgctaca ttgatttatt
1680tcccttactg agcatgtgtt aagggatgga atttttcacc atgggcatgt
ttaggcaagc 1740cccctgtaca caatgtcctg gatggcattt ggctgtcttc
tgcctctatc attcccccat 1800ctaaaagagt acatctaact gccattagaa
taaggataag aagaaagaca aagacccatc 1860ttaactgctt tctgctgaca
gagggcactg ttttggaaag acagcagttg ggtctccctc 1920agaggcctat
ctaagggtat ctggtaaaag ggaccatcat tcgaggctct ggttgcataa
1980ctgtttggag tttgagggcc tgaaggcgag aagagacaaa ccaggttatt
agaagacatg 2040taccaaaatg aaatggggga agggtaagga cagttcaaaa
atcctgaggc tgctgacatg 2100cccagataac tggtagctgt agttgtgcct
gctaagattt gggtgcatgg gacttggctt 2160tggttagctc ccgtagttta
ttttcccaaa aaagaaacct ctgggttatg ggcaccctat 2220ttactcccat
tatctggcag gatttgtagg ataattgttc agaactagaa tactgttcca
2280gatttttaca ttacccatgc cttttgtttc ttctgagctg cagccagaga
tcactggtta 2340gttcacagga ataagcaggg ttaatttaaa atgtaggcaa
aaaacttaaa aacaactaat 2400gagtctagaa tttaatgaca aatgtatgat
aagttttgaa acataatttc tttctcccca 2460gtcctcattt ttgttaaaaa
caaatcataa taggagtgag ttgtttgtaa aataaacttt 2520agtcttacac
ttggtctgct tatttgcaca aagtacaaca agaataatta tttttacata
2580ggctttttaa attggctttg atggaactct gttccacaag gaatttcaga
taggacttca 2640taaaaatgag cccagccatg ggtttgtacc ctctaatacc
tatgagttgg gtgaattgct 2700ctcttcttga ggtcccaaga atatgcggtt
cctggccctg ttagaaagtg acattcttta 2760ctcactacag gttagggaac
ctgtatgggg actgtgtaga caaagtatga ggctggttta 2820cccaaggggc
ttttattggc tctgcaagtt gagcttgatt ccttaaaggg aaacataccc
2880ttccagtcaa agttacagtt actggttggt aaagttaaag ttacagctac
tggttgctaa 2940agcaaccagt ttctccaatt gcatcctgtt gcaaaagaaa
gtggattctt actgcactga 3000tgcaaataac cgtattgccc taagttaaga
atactcacag atagtttcca aattctagag 3060gaagcaggca gagagaaaaa
aaagtgctaa attttgttca taggagtctg cattactcaa 3120ttattaaaga
ttgtgtatag ctcaaaaaaa aagatcagca ctgttttaag ctaaagttta
3180aaaaagatta cttcaatttt ctattagttc agtctgttca gttaactctt
gttctgcttg 3240atatttgtga acatttcagc tcttcatgag tcctgtacgt
ttttccatta ttccaatgtc 3300acaatctcca aagttatcag aaacctgcat
ttgagagcac ctgttacgtt tctatagctg 3360attataaatc ctatttgaag
aagatcaaaa caaaacaatg gtctgtgaat agcaaaatgt 3420ccatggtagt
tacagtcaaa aacacaattg acaaagaaat tttgttatct ctgtggctta
3480taatcaccta acataacacc tttaattgtg aktgatagca tatacttaga
tattagaatt 3540ttagaaatcc catacagttt tggagcatat attattattc
actaaaatat aacccaaaga 3600agattaaata tcattttggc aatcccatgt
acataaattt gtcaggtaat cctatttacc 3660tctcttctgg atgctccagg
gatgctaggg gtcaggaaag acaaccttga agctgacatt 3720tgattttggg
aagcccatta aatatgttag aggtttaaaa caatgttatg aagtagaatt
3780ccagattacc ataaattact tattttgcca aaatgatgac tcaaaaattt
taaaacaagc 3840caaaaacttt tactcattta gagggaagac ttagatttcc
aaagaatttg tctcctgtct 3900tcactttcat ttccttggca gtctatctgg
aagacaaact gaaatattta attatccttt 3960actattacat gaaaatctta
tacaagggag agaaagccaa attttaccct cacattagtt 4020tactattaat
gtcaacccca attttttaat gaaaccttat agacaattct atccaatctt
4080aaccagtttg atcatgaggt aagattcctg taagcctttt ataacctttt
acaaattact 4140aatttactaa tctgctaaag agcagattag ggctttaaga
aaaccttgtt gtgctttcat 4200ttcaatgctc agtttgtaga aaaaccatat
aatagagttt tggatttaat caatgttcac 4260acacagaatt tcttttgcaa
gattaatttt tagaaacctc ccacaacttg tttaaacctt 4320tagtttatct
tatctaattt ataatagtcc tttaacctta ggcaaaaact tacatttcca
4380tgcattctta taatctttga ctaataacac attttactgt tcttacatac
cttgcatgta 4440aatctatttt cagtggtctc aattacatgt tataatggta
cctcttagca ctttttaatt 4500ttagtttaaa acctggtaag tcgttttaat
tacgcactag gtgctgataa agtttgattc 4560cttccagcat aattaagggt
gtggttaatt ccatatgtcc ctgtgcctta ccaagttgta 4620aagcaggcag
attgaacagt tttcaaaggc aaaagaagcc gtttacaacc ttaaaacatt
4680tagccaccta gtgcctgact tgcataattt agaccagcta tttacatttt
aagaacattt 4740gcattttatc aattatcttt aagactactt ttatttctca
gagattaaag tcacaagaac 4800taaaaggcat tatagctttt atctttcctc
caaaaatatt tgatcttagt gctgattttt 4860ctttaagcca attaattaga
gctctttttt ataactacac agatggagaa gaagattgag 4920tgttataaga
tttttcattt gcccatctcc taattggatt cttggtctct gggtgggacc
4980ctttaagagc agggctaaga aagcatgcag tttattttct ttttttcttt
ttcttttctt 5040tttttttgag aaagagtttc actcttgttg cccaggctgg
agtgcaatgg tgcgatctca 5100gctcactgca acctctgcct cccaggttca
agcgattctc ttacctcagc ctcccaagtg 5160gctgcatgca gtttctaggg
cctaataaac aggcatagct ggaaaacaaa aacggatttt 5220gagagcgatc
tatttgcctc taattcctgg ggttccatga ggaaaacaga ggtttctccc
5280aaaatggaat ccatggtgcc ttttctgttt ttaccaagca gccctatgcc
atcagaaatt 5340atcttagggc ctctcatgtg cgcattaaca ctggcaagac
aaggtggaga aaagtaattc 5400agtcaactga gaaaaaaatc tttttccagc
aaaacaagat ccaagaagag aaaaacataa 5460aggcctttca aatatacgta
tagcttggat atccactttt aattaagctg agctctcttt 5520aagaaagtcc
ttttaaatcc cacattacct gacttcagcc atgccaagca gccaatattt
5580ctggctttgg aagtttatca aaagaacctc aaggttcaac caacaagcct
caattaagac 5640acgcgaagca caccagattg gctacacctt aagaccagcc
tcataaaacc tttttcacta 5700atggaaactt tacagggaat atcaacagtg
atccttatca ttcttttcac cagtttacac 5760agggagagag aggccaaaag
tctgactggt taaaaaactt ttatcctttt gctggcatgt 5820catgcttctg
ggttcccttc ccctgagctc aattctaagc caaccagttt aaggtttggg
5880aaattaactt ttctcagttt ggaggatgca tcctatggga atgtccttta
gtacagggac 5940acagtcaccc atctgtgaag agaggacaaa ggaggaaaaa
gtaaaaaaag atttttttca 6000aaggctcccc aggggttcag gatgcatttg
aaagggggac agattgaaga tgaatggcta 6060ctcatctaga aagaggggag
ccagacatcc ctggttcctt tctctttcta ggaaatagcc 6120agggtatgtg
agggaaagaa ggaacaagca tccattttcc ttcttccgtc cttatgtccc
6180caagtcctga caacctcgac agggtgccac ccatgggtgc caatacggtt
ctcacccatg 6240gtaacagggg acctagtgga tgggattatc cactgttacc
cacaaactgt ctttccccct 6300gctctcaata gccttcaagt gccctagacc
tcatttaggc cattgatact agtatgacct 6360ttatccatga aacaagaggc
ttggcttaat tgtcaggaat tagtcatgct cacctatact 6420gtgcttttta
atttttgttg ttgtctgcct ctggatccct ccgatgcagt tatctttcct
6480agggcttcta catgaagctt ggaattgagt ttgggacaaa agaactgcct
cagtaggtgg 6540gtgcatggac tcatcaatcc ccaggtgtcc ctcaccagtc
tggctgctgc cgccttatca 6600taagctgaag gctaaggtgc aactgtgaaa
ttaggtcctt ctcaaacaag ggagggaaaa 6660tggtgtcctg tgaattaggg
tcctggtcta ataagatgcc ttccaaaagg aagaaaactt 6720ctggcacaga
gaagacccct ctacccgcag ggctgtgtta ttaggttggt gcgaaagcaa
6780ttgtggtgcc catcattcta agtaatgaca aaaaccacaa ctactttcac
accagcctac 6840taactcatga cttggtggac aaaagaaaat aacaacaaca
acaacagctt aaatgcaggg 6900ctgtgtttac tgctgacaag gtggagaaaa
gaaaaatatg cctgagaaat gcaaatgtat 6960ttctccaaca ggcagagaaa
cttaattgct attgcactga gctggacccc ttggcttggg 7020gtggggaaga
ctctgtggat acatggcagg ggacactggc cagttggctg catggggccc
7080aggcccctga gatcaccctg gggctggggc agcagctgtg gctcaatcct
gcactggatg 7140gc 714273609DNAHomo sapiens 7cagacagtca tgcaccccag
ccaggaggga agggggaatg gggagatgct gtcttcctat 60ccatcctaca catgtgccta
tggccattgg gttgggagtg gaacaccccc aatattgtaa 120aagaaaagat
aggtgccatt acaatccccc taaaaagaag gaaaatgcca tagaaaagac
180tgggttggac tgaggccgat gttcctgacc cctgagagca atggggggtt
gaagggtggg 240gtgcaatttc ccccatcctt agaaaacacc tgagaacaag
aaagctcaga aacaaaaggg 300aaagaaatgt tctgggttca cattttactc
acccaggcaa tgtcagcttt ctcattataa 360cttttggctt ttgatttttt
ttttttaatt ttacaatctg gacaaatagt gttttaaata 420cctttgtttt
aaccccctca atttccattc tatttatttc atttcttaac aaccatccaa
480agatttctat cacccttctg gggcgactcc tttgactctc ttttgccttt
ctcatttttt 540tttaaattac ctcaacattt tattaaggat ctgtaagacc
cacaagggac agcaaatttg 600atacaacttg tcaaacaatt gtatggttct
gtcggagaaa tgtcacctgg gatgcctatg 660taaaagggac ctctttaacc
cccaaattta ccatgacctg ggtaataggc atataaagtg 720ggagaatatc
ctggtcatca taaagccagt accatgtggc ttgcttatga atcatatcta
780ctgcttcatc tgggttactc cacttggcat tttataggga gagttgggca
gtccctttct 840tggggtaaac agactttaca gtggcattta tccagtccac
tagggttgga tgttctctca 900ggaataacct cctatgcatt tggatcactt
atactcatta gagatttaat agtgagctgt 960gggtcatgga tcaaactaaa
gaagctcttt cactctgtag catttaaaat taaggattct 1020atccttaaat
tagttatttt taaatccatt atagtaaaag tgtctcagga agctgactat
1080accaatctac aaaatggaac aattccttta cattatagcc tctggtttta
atagttgttt 1140tgccctgccc ctacatttac tatcttcttg gtaaccacag
gtctcagagg taaactttgt 1200tgccccggtt taatttatat ttttgtgagt
agcttggatg ctagaggctt gagctgagac 1260agacccactt ctggtcttgg
tccactctta aggaccaacc caacactctt ttactctcat 1320ttcagctttt
acagataata accaaaggat gaaacatttt tcttccttat tagcttgcct
1380tcccttatgc attcagggaa ctaactccct gggagtatga gtaggatcca
tctctaattc 1440cactggtaac ttttactttt agtaactgac tatagcccag
ctgcagctcc ttaagatggg 1500caaccacatg gctactcaag agtcaggatt
tctcatttca caccctttta tttttttctt 1560tatccattta gttttatcta
tataattttt tcctttattt tagagtgayt cataaatagt 1620ctctagaaaa
aaattacatt ttctttagca aaaactagtt ccttgtgttt tcagaaacct
1680caccaaaaac accttttatt cacctactag tttaagtctt attaactcaa
attcccagtg 1740gaaaaaaaac tcataggttt acttaattta aacattacat
gacttattaa cccaaatccc 1800cagtggggga aaaaagtaac ctaggtttac
ttaatttaaa cataacatga ctttaagatt 1860ttaaattact ggaaataatt
gagattaaat ttaccaaatt aatcttacca aagattacta 1920gtcatgtgag
ctaaaaggca tctgagctag gttccatcag tctgataagc attaacattc
1980tccaagccaa ttgattagag ctcttttgta ccacttgtta gtgaaatatc
acttccacat 2040ggcacatgta aacatgtaga tataacagac atatagaaaa
cggcaggtcc aaaagatttt 2100tcatttgcct cttttcaaaa attctctccc
ctactttaga ttattaattt aaaaaagtta 2160taaggccaaa caaaagttga
aggagagagt taccatccta ggccttttca aaagcgaaaa 2220aaggactgag
atatcaattt gaataatttc aaaaagaaac attacagaat ttaaaaatta
2280aaaactttgt gcattgagta actcaatatt ttaaataaaa tcttgttcta
accaaatctt 2340tagttattta ttagtgtatt tttttttgag acagagtctt
gctcttgttg ctcaggctgg 2400agtgcaatgg tgcgatctca gctcactgca
acttctgcct cccaggttca agtgattctc 2460ctgcctcagc ttcccaagta
gctgggatta caggcacctg
ccaccatgcc cagctaattt 2520tttaattttt agtagagaca gggtttcacc
atgttggcca ggctggtctc gaactcctga 2580cctatatgat ctgctcgcct
cggcctccca aagtgctagg attacaggcg tgagcaccgc 2640acccagtcta
gtgtattttt aacataaaag ttcaatttaa aaaaaagatt ataattttct
2700gtaattatgg acaacttaat cacataacat ttgtataaat ttctttttta
ctaactttat 2760tatgacttac acagaccatt cacaacatgc ttggactttc
tgctttgacc taagtgtcac 2820tctttctgga ataactcggt cattttatct
taggacaaaa attcaccaaa caatattttt 2880ctcatacaaa attacttttc
ttttaagctt tcttaccaaa aatacctctg tatatctata 2940cttttcttta
tattggtcta tttcctggtt cctttcacat tcttatttat acaggacttt
3000taaataagct ttgaattaga caaaaattat ttacctttta ataagaacat
attttaaaaa 3060aagaataaaa tataattttt tgaattggaa aatacccaga
tatttaatta aatatctatt 3120attgaattta atataatttt atattctaaa
ttatgacaag tttatttaca ggtatttatc 3180cctttacatt tacctgatta
ttttatttta atattttatg tagactatga aaactgtgat 3240agtcatcatt
taaagttatt tccctgtcaa tgatttttat agcctatgaa gttcaggtgt
3300ttacctaagt aagaacctca ggattaaata tatggttatt ttaccaataa
ttccaagttt 3360agctgttttc attaaaccaa caatatttga tatcttgttt
gtcaaaaact acacaagcaa 3420agatcattct gttttgggtt ggtgtattag
tctgttctca cattgttatt aaaaaatcct 3480ggaattgggt aatctataaa
gaaaagaggt ttaattggct tacagtttta caggctatat 3540aggaagcata
gcagcttttg cttggaaact tataatcatg gtgaaaggtg aaggtgaagc
3600aggcatgtc 360983659DNAHomo sapiens 8cagacagtca tgcaccccag
ccaggaggga agggggaatg gggagatgct gtcttcctat 60ccatcctaca catgtgccta
tggccattgg gttgggagtg gaacaccccc aatattgtaa 120aagaaaagat
aggtgccatt acaatccccc taaaaagaag gaaaatgcca tagaaaagac
180tgggttggac tgaggccgat gttcctgacc cctgagagca atggggggtt
gaagggtggg 240gtgcaatttc ccccatcctt agaaaacacc tgagaacaag
aaagctcaga aacaaaaggg 300aaagaaatgt tctgggttca cattttactc
acccaggcaa tgtcagcttt ctcattataa 360cttttggctt ttgatttttt
ttttttaatt ttacaatctg gacaaatagt gttttaaata 420cctttgtttt
aaccccctca atttccattc tatttatttc atttcttaac aaccatccaa
480agatttctat cacccttctg gggcgactcc tttgactctc ttttgccttt
ctcatttttt 540tttaaattac ctcaacattt tattaaggat ctgtaagacc
cacaagggac agcaaatttg 600atacaacttg tcaaacaatt gtatggttct
gtcggagaaa tgtcacctgg gatgcctatg 660taaaagggac ctctttaacc
cccaaattta ccatgacctg ggtaataggc atataaagtg 720ggagaatatc
ctggtcatca taaagccagt accatgtggc ttgcttatga atcatatcta
780ctgcttcatc tgggttactc cacttggcat tttataggga gagttgggca
gtccctttct 840tggggtaaac agactttaca gtggcattta tccagtccac
tagggttgga tgttctctca 900ggaataacct cctatgcatt tggatcactt
atactcatta gagatttaat agtgagctgt 960gggtcatgga tcaaactaaa
gaagctcttt cactctgtag catttaaaat taaggattct 1020atccttaaat
tagttatttt taaatccatt atagtaaaag tgtctcagga agctgactat
1080accaatctac aaaatggaac aattccttta cattatagcc tctggtttta
atagttgttt 1140tgccctgccc ctacatttac tatcttcttg gtaaccacag
gtctcagagg taaactttgt 1200tgccccggtt taatttatat ttttgtgagt
agcttggatg ctagaggctt gagctgagac 1260agacccactt ctggtcttgg
tccactctta aggaccaacc caacactctt ttactctcat 1320ttcagctttt
acagataata accaaaggat gaaacatttt tcttccttat tagcttgcct
1380tcccttatgc attcagggaa ctaactccct gggagtatga gtaggatcca
tctctaattc 1440cactggtaac ttttactttt agtaactgac tatagcccag
ctgcagctcc ttaagatggg 1500caaccacatg gctactcaag agtcaggatt
tctcatttca caccctttta tttttttctt 1560tatccattta gttttatcta
tataattttt tcctttattt tagagtgatt cataaatagt 1620ctctagaaaa
aaattacatt ttctttagca aaaactagwt ccttgtgttt tcagaaacct
1680caccaaaaac accttttatt cacctactag tttaagtctt attaactcaa
attcccagtg 1740gaaaaaaaac tcataggttt acttaattta aacattacat
gacttattaa cccaaatccc 1800cagtggggga aaaaagtaac ctaggtttac
ttaatttaaa cataacatga ctttaagatt 1860ttaaattact ggaaataatt
gagattaaat ttaccaaatt aatcttacca aagattacta 1920gtcatgtgag
ctaaaaggca tctgagctag gttccatcag tctgataagc attaacattc
1980tccaagccaa ttgattagag ctcttttgta ccacttgtta gtgaaatatc
acttccacat 2040ggcacatgta aacatgtaga tataacagac atatagaaaa
cggcaggtcc aaaagatttt 2100tcatttgcct cttttcaaaa attctctccc
ctactttaga ttattaattt aaaaaagtta 2160taaggccaaa caaaagttga
aggagagagt taccatccta ggccttttca aaagcgaaaa 2220aaggactgag
atatcaattt gaataatttc aaaaagaaac attacagaat ttaaaaatta
2280aaaactttgt gcattgagta actcaatatt ttaaataaaa tcttgttcta
accaaatctt 2340tagttattta ttagtgtatt tttttttgag acagagtctt
gctcttgttg ctcaggctgg 2400agtgcaatgg tgcgatctca gctcactgca
acttctgcct cccaggttca agtgattctc 2460ctgcctcagc ttcccaagta
gctgggatta caggcacctg ccaccatgcc cagctaattt 2520tttaattttt
agtagagaca gggtttcacc atgttggcca ggctggtctc gaactcctga
2580cctatatgat ctgctcgcct cggcctccca aagtgctagg attacaggcg
tgagcaccgc 2640acccagtcta gtgtattttt aacataaaag ttcaatttaa
aaaaaagatt ataattttct 2700gtaattatgg acaacttaat cacataacat
ttgtataaat ttctttttta ctaactttat 2760tatgacttac acagaccatt
cacaacatgc ttggactttc tgctttgacc taagtgtcac 2820tctttctgga
ataactcggt cattttatct taggacaaaa attcaccaaa caatattttt
2880ctcatacaaa attacttttc ttttaagctt tcttaccaaa aatacctctg
tatatctata 2940cttttcttta tattggtcta tttcctggtt cctttcacat
tcttatttat acaggacttt 3000taaataagct ttgaattaga caaaaattat
ttacctttta ataagaacat attttaaaaa 3060aagaataaaa tataattttt
tgaattggaa aatacccaga tatttaatta aatatctatt 3120attgaattta
atataatttt atattctaaa ttatgacaag tttatttaca ggtatttatc
3180cctttacatt tacctgatta ttttatttta atattttatg tagactatga
aaactgtgat 3240agtcatcatt taaagttatt tccctgtcaa tgatttttat
agcctatgaa gttcaggtgt 3300ttacctaagt aagaacctca ggattaaata
tatggttatt ttaccaataa ttccaagttt 3360agctgttttc attaaaccaa
caatatttga tatcttgttt gtcaaaaact acacaagcaa 3420agatcattct
gttttgggtt ggtgtattag tctgttctca cattgttatt aaaaaatcct
3480ggaattgggt aatctataaa gaaaagaggt ttaattggct tacagtttta
caggctatat 3540aggaagcata gcagcttttg cttggaaact tataatcatg
gtgaaaggtg aaggtgaagc 3600aggcatgtct tacatggctg gagaaggagg
aagagaaggt tgttggggag gtgccacac 365993876DNAHomo sapiens
9cagacagtca tgcaccccag ccaggaggga agggggaatg gggagatgct gtcttcctat
60ccatcctaca catgtgccta tggccattgg gttgggagtg gaacaccccc aatattgtaa
120aagaaaagat aggtgccatt acaatccccc taaaaagaag gaaaatgcca
tagaaaagac 180tgggttggac tgaggccgat gttcctgacc cctgagagca
atggggggtt gaagggtggg 240gtgcaatttc ccccatcctt agaaaacacc
tgagaacaag aaagctcaga aacaaaaggg 300aaagaaatgt tctgggttca
cattttactc acccaggcaa tgtcagcttt ctcattataa 360cttttggctt
ttgatttttt ttttttaatt ttacaatctg gacaaatagt gttttaaata
420cctttgtttt aaccccctca atttccattc tatttatttc atttcttaac
aaccatccaa 480agatttctat cacccttctg gggcgactcc tttgactctc
ttttgccttt ctcatttttt 540tttaaattac ctcaacattt tattaaggat
ctgtaagacc cacaagggac agcaaatttg 600atacaacttg tcaaacaatt
gtatggttct gtcggagaaa tgtcacctgg gatgcctatg 660taaaagggac
ctctttaacc cccaaattta ccatgacctg ggtaataggc atataaagtg
720ggagaatatc ctggtcatca taaagccagt accatgtggc ttgcttatga
atcatatcta 780ctgcttcatc tgggttactc cacttggcat tttataggga
gagttgggca gtccctttct 840tggggtaaac agactttaca gtggcattta
tccagtccac tagggttgga tgttctctca 900ggaataacct cctatgcatt
tggatcactt atactcatta gagatttaat agtgagctgt 960gggtcatgga
tcaaactaaa gaagctcttt cactctgtag catttaaaat taaggattct
1020atccttaaat tagttatttt taaatccatt atagtaaaag tgtctcagga
agctgactat 1080accaatctac aaaatggaac aattccttta cattatagcc
tctggtttta atagttgttt 1140tgccctgccc ctacatttac tatcttcttg
gtaaccacag gtctcagagg taaactttgt 1200tgccccggtt taatttatat
ttttgtgagt agcttggatg ctagaggctt gagctgagac 1260agacccactt
ctggtcttgg tccactctta aggaccaacc caacactctt ttactctcat
1320ttcagctttt acagataata accaaaggat gaaacatttt tcttccttat
tagcttgcct 1380tcccttatgc attcagggaa ctaactccct gggagtatga
gtaggatcca tctctaattc 1440cactggtaac ttttactttt agtaactgac
tatagcccag ctgcagctcc ttaagatggg 1500caaccacatg gctactcaag
agtcaggatt tctcatttca caccctttta tttttttctt 1560tatccattta
gttttatcta tataattttt tcctttattt tagagtgatt cataaatagt
1620ctctagaaaa aaattacatt ttctttagca aaaactagtt ccttgtgttt
tcagaaacct 1680caccaaaaac accttttatt cacctactag tttaagtctt
attaactcaa attcccagtg 1740gaaaaaaaac tcataggttt acttaattta
aacattacat gacttattaa cccaaatccc 1800cagtggggga aaaaagtaac
ctaggtttac ttaatttaaa cataacatga ctttaagatt 1860ttaaattact
ggaaakaatt gagattaaat ttaccaaatt aatcttacca aagattacta
1920gtcatgtgag ctaaaaggca tctgagctag gttccatcag tctgataagc
attaacattc 1980tccaagccaa ttgattagag ctcttttgta ccacttgtta
gtgaaatatc acttccacat 2040ggcacatgta aacatgtaga tataacagac
atatagaaaa cggcaggtcc aaaagatttt 2100tcatttgcct cttttcaaaa
attctctccc ctactttaga ttattaattt aaaaaagtta 2160taaggccaaa
caaaagttga aggagagagt taccatccta ggccttttca aaagcgaaaa
2220aaggactgag atatcaattt gaataatttc aaaaagaaac attacagaat
ttaaaaatta 2280aaaactttgt gcattgagta actcaatatt ttaaataaaa
tcttgttcta accaaatctt 2340tagttattta ttagtgtatt tttttttgag
acagagtctt gctcttgttg ctcaggctgg 2400agtgcaatgg tgcgatctca
gctcactgca acttctgcct cccaggttca agtgattctc 2460ctgcctcagc
ttcccaagta gctgggatta caggcacctg ccaccatgcc cagctaattt
2520tttaattttt agtagagaca gggtttcacc atgttggcca ggctggtctc
gaactcctga 2580cctatatgat ctgctcgcct cggcctccca aagtgctagg
attacaggcg tgagcaccgc 2640acccagtcta gtgtattttt aacataaaag
ttcaatttaa aaaaaagatt ataattttct 2700gtaattatgg acaacttaat
cacataacat ttgtataaat ttctttttta ctaactttat 2760tatgacttac
acagaccatt cacaacatgc ttggactttc tgctttgacc taagtgtcac
2820tctttctgga ataactcggt cattttatct taggacaaaa attcaccaaa
caatattttt 2880ctcatacaaa attacttttc ttttaagctt tcttaccaaa
aatacctctg tatatctata 2940cttttcttta tattggtcta tttcctggtt
cctttcacat tcttatttat acaggacttt 3000taaataagct ttgaattaga
caaaaattat ttacctttta ataagaacat attttaaaaa 3060aagaataaaa
tataattttt tgaattggaa aatacccaga tatttaatta aatatctatt
3120attgaattta atataatttt atattctaaa ttatgacaag tttatttaca
ggtatttatc 3180cctttacatt tacctgatta ttttatttta atattttatg
tagactatga aaactgtgat 3240agtcatcatt taaagttatt tccctgtcaa
tgatttttat agcctatgaa gttcaggtgt 3300ttacctaagt aagaacctca
ggattaaata tatggttatt ttaccaataa ttccaagttt 3360agctgttttc
attaaaccaa caatatttga tatcttgttt gtcaaaaact acacaagcaa
3420agatcattct gttttgggtt ggtgtattag tctgttctca cattgttatt
aaaaaatcct 3480ggaattgggt aatctataaa gaaaagaggt ttaattggct
tacagtttta caggctatat 3540aggaagcata gcagcttttg cttggaaact
tataatcatg gtgaaaggtg aaggtgaagc 3600aggcatgtct tacatggctg
gagaaggagg aagagaaggt tgttggggag gtgccacaca 3660cttttaaaca
accagatctc atgagaactt actatcacca tgacagcccc aagggggatg
3720gtgttaaacc atgagaaact accccatgat ccaatcacct tccaccaggt
tcctcctcca 3780acactgggga ttacaatttg acatgagatt tgggtgggga
tacagatcca accataacgg 3840ttgggtttac agttttataa actttatgtc aaattt
3876106995DNAHomo sapiens 10tgtcttccta tccatcctac acatgtgcct
atggccattg ggttgggagt ggaacacccc 60caatattgta aaagaaaaga taggtgccat
tacaatcccc ctaaaaagaa ggaaaatgcc 120atagaaaaga ctgggttgga
ctgaggccga tgttcctgac ccctgagagc aatggggggt 180tgaagggtgg
ggtgcaattt cccccatcct tagaaaacac ctgagaacaa gaaagctcag
240aaacaaaagg gaaagaaatg ttctgggttc acattttact cacccaggca
atgtcagctt 300tctcattata acttttggct tttgattttt tttttttaat
tttacaatct ggacaaatag 360tgttttaaat acctttgttt taaccccctc
aatttccatt ctatttattt catttcttaa 420caaccatcca aagatttcta
tcacccttct ggggcgactc ctttgactct cttttgcctt 480tctcattttt
ttttaaatta cctcaacatt ttattaagga tctgtaagac ccacaaggga
540cagcaaattt gatacaactt gtcaaacaat tgtatggttc tgtcggagaa
atgtcacctg 600ggatgcctat gtaaaaggga cctctttaac ccccaaattt
accatgacct gggtaatagg 660catataaagt gggagaatat cctggtcatc
ataaagccag taccatgtgg cttgcttatg 720aatcatatct actgcttcat
ctgggttact ccacttggca ttttataggg agagttgggc 780agtccctttc
ttggggtaaa cagactttac agtggcattt atccagtcca ctagggttgg
840atgttctctc aggaataacc tcctatgcat ttggatcact tatactcatt
agagatttaa 900tagtgagctg tgggtcatgg atcaaactaa agaagctctt
tcactctgta gcatttaaaa 960ttaaggattc tatccttaaa ttagttattt
ttaaatccat tatagtaaaa gtgtctcagg 1020aagctgacta taccaatcta
caaaatggaa caattccttt acattatagc ctctggtttt 1080aatagttgtt
ttgccctgcc cctacattta ctatcttctt ggtaaccaca ggtctcagag
1140gtaaactttg ttgccccggt ttaatttata tttttgtgag tagcttggat
gctagaggct 1200tgagctgaga cagacccact tctggtcttg gtccactctt
aaggaccaac ccaacactct 1260tttactctca tttcagcttt tacagataat
aaccaaagga tgaaacattt ttcttcctta 1320ttagcttgcc ttcccttatg
cattcaggga actaactccc tgggagtatg agtaggatcc 1380atctctaatt
ccactggtaa cttttacttt tagtaactga ctatagccca gctgcagctc
1440cttaagatgg gcaaccacat ggctactcaa gagtcaggat ttctcatttc
acaccctttt 1500atttttttct ttatccattt agttttatct atataatttt
ttcctttatt ttagagtgat 1560tcataaatag tctctagaaa aaaattacat
tttctttagc aaaaactagt tccttgtgtt 1620ttcagaaacc tcaccaaaaa
caccttttat tcacctacta gtttaagtct tattaactca 1680aattcccagt
ggaaaaaaaa ctcataggtt tacttaattt aaacattaca tgacttatta
1740acccaaatcc ccagtggggg aaaaaagtaa cctaggttta cttaatttaa
acataacatg 1800actttaagat tttaaattac tggaaataat tgagattaaa
tttaccaaat taatcttacc 1860aaagattact agtcatgtga gctaaaaggc
atctgagcta ggttccatca gtctgataag 1920cattaacatt ctccaagcca
attgattaga gctcttttgt accacttgtt agtgaaatat 1980cacttccaca
tggcacatgt aaacatgtag atataacaga catatagaaa acggcaggtc
2040caaaagattt ttcatttgcc tcttttcaaa aattctctcc cctactttag
attattaatt 2100taaaaaagtt ataaggccaa acaaaagttg aaggagagag
ttaccatcct aggccttttc 2160aaaagcgaaa aaaggactga gatatcaatt
tgaataattt caaaaagaaa cattacagaa 2220tttaaaaatt aaaaactttg
tgcattgagt aactcaatat tttaaataaa atcttgttct 2280aaccaaatct
ttagttattt attagtgtat ttttttttga gacagagtct tgctcttgtt
2340gctcaggctg gagtgcaatg gtgcgatctc agctcactgc aacttctgcc
tcccaggttc 2400aagtgattct cctgcctcag cttcccaagt agctgggatt
acaggcacct gccaccatgc 2460ccagctaatt ttttaatttt tagtagagac
agggtttcac catgttggcc aggctggtct 2520cgaactcctg acctatatga
tctgctcgcc tcggcctccc aaagtgctag gattacaggc 2580gtgagcaccg
cacccagtct agtgtatttt taacataaaa gttcaattta aaaaaaagat
2640tataattttc tgtaattatg gacaacttaa tcacataaca tttgtataaa
tttctttttt 2700actaacttta ttatgactta cacagaccat tcacaacatg
cttggacttt ctgctttgac 2760ctaagtgtca ctctttctgg aataactcgg
tcattttatc ttaggacaaa aattcaccaa 2820acaatatttt tctcatacaa
aattactttt cttttaagct ttcttaccaa aaatacctct 2880gtatatctat
acttttcttt atattggtct atttcctggt tcctttcaca ttcttattta
2940tacaggactt ttaaataagc tttgaattag acaaaaatta tttacctttt
aataagaaca 3000tattttaaaa aaagaataaa atataatttt ttgaattgga
aaatacccag atatttaatt 3060aaatatctat tattgaattt aatataattt
tatattctaa attatgacaa gtttatttac 3120aggtatttat ccctttacat
ttacctgatt attttatttt aatattttat gtagactatg 3180aaaactgtga
tagtcatcat ttaaagttat ttccctgtca atgattttta tagcctatga
3240agttcaggtg tttacctaag taagaacctc aggattaaat atatggttat
tttaccaata 3300attccaagtt tagctgtttt cattaaacca acaatatttg
atatcttgtt tgtcaaaaac 3360tacacaagca aagatcattc tgttttgggt
tggtgtatta gtctgttctc acattgttat 3420taaaaaaycc tggaattggg
taatctataa agaaaagagg tttaattggc ttacagtttt 3480acaggctata
taggaagcat agcagctttt gcttggaaac ttataatcat ggtgaaaggt
3540gaaggtgaag caggcatgtc ttacatggct ggagaaggag gaagagaagg
ttgttgggga 3600ggtgccacac acttttaaac aaccagatct catgagaact
tactatcacc atgacagccc 3660caagggggat ggtgttaaac catgagaaac
taccccatga tccaatcacc ttccaccagg 3720ttcctcctcc aacactgggg
attacaattt gacatgagat ttgggtgggg atacagatcc 3780aaccataacg
gttgggttta cagttttata aactttatgt caaattttga cacagagtat
3840ttgtcaggga taagtatgaa attgctgatc aataaatgca aacaaaaata
tatgttgaca 3900atttataaga catttctaat attacttgac caataatttt
aagccagttt atttataaaa 3960ggttttactt gtcacatgac cttgaaaagc
atttgggctt attgtttaat gtatgagtac 4020ccttcaactt taagccattt
tagtaccttg tggccaaaaa cacataataa aatacatgtt 4080tgtacacata
aacacacata tacacactca tacaaagatc ctgttgcttt cacttcaaaa
4140ttttagctat gagatattaa tataaactta ccagtttgca aaaacaataa
caaaaagaaa 4200cggttggatg caaacagtgg attttatctc agtagaaatg
tgttaataat agcagacaaa 4260gcaggtggaa aagaaaacag agatagagaa
cttaggaact ttagagttgc aggttgaact 4320ttaggttctg aattttcctt
gatgtaattt gcccatcagt ttaaaatgcg cacaagaaca 4380gacctaatgt
gtaaccagct ggagtattag aaaacctggc acgcccttcc atttacacaa
4440ccacttgcaa gtagaggcac catgaaacga aatgaggtgc ctgagaggcc
ttgttcttgt 4500ttttccatat ccttaattta ttccccacat attttcttaa
aaggaggaac tgagctgtgg 4560cctaagtttt agtttagtgg gtcaaaatat
gctgattctg ggtggggctc cacagtgtgt 4620caccagtgag tcgttgccac
cctcttatgt atctcagttt ctctctctgg aggtttagac 4680ctccgagtgc
tcaaaacatg gagttcctac atgagcttcc tggatgaacc tttttaaact
4740aattttgctg ggggttccct gtagggcggc tgcatttcat ggggttggta
gtcaacccct 4800taggctccac cccagtaacc cagggatgcc ttttggctgg
aaggagcaaa atgccctttc 4860ttttcagagc ttaggaaact cagtctgaca
tttatctaca aaaacaacag tttagttgct 4920ctcacaaata cacagacaag
ccaatcgaga ttaattttgg gagagaagac aatgagaaag 4980ctctttagaa
tgcacctctg aactagaatt aggatcctaa acaacaactt cattggtggg
5040ggcagcgggg tggaaaaagc taagaccagc tgtaaactgt cctcagccac
tcctaacttt 5100atagctcttg tctgccatta cacactccaa ggtcacatct
tctcacagta caaggtaatc 5160tctggtgccc gcaaaagcca agagggtcag
gtaatgcaat acaggaaagc agagttttaa 5220atctaagaag aatctgccca
tgactcttga aaccccacaa agaaaacaga acaccccaaa 5280agggggtggg
agtggtgcct ttgttctgag ttctttaagg ggtctgagac attagaaccc
5340ttctgtagat ttttcttggt accagagatg gtgaaggggg aaggaaaaat
agagtggaac 5400aaaagtaaac agaagaataa ctgttttttg tttttttttt
ttaagaaagg aagtgaacac 5460agaaaccaag cacatgtttt tgtttttgtt
tgtgcagctg ccaggaattt tagccaattc 5520agaggccttg tttcccctaa
tttggaattc tcattggaat ttgaccaagt ctgttatagt 5580tgatcaaatc
ctatgggaga aagatcagaa caacaaaaac cccaacaata tgattactga
5640gtgctctaac ggtaaggaga aattaaaacc agctgcttgt caatttcaac
ttgtagtcat 5700taaggagaat ttccaagaca aaaaaatccc aattcttgct
acttacctag gaatagagcc 5760ctggcacaag attgctcttt accatcttag
aagcaggaaa aatacctgga aaggtgcaca 5820ggaacagaca taaggttctt
gccttcccta tcggaaacta gctgaaactc cagaaatgag 5880ttacctgcta
tgcatcatca tggaagcaga aaaacttgct ttccttgttg gaatcaagta
5940aaactccaga aaaggagttg tagagcaaaa taagctttag atctcgacca
aattttgaga 6000gatcagggat tctctggagg gggaactccc aggcctcagc
aaattgtcct tctgatttga 6060gccataagga tagctcaagc tggtaccaag
caccaataga ttcatcaaag gtcaggggca 6120cctccactca gaatcccttc
atcaccaatt tgtgaactca aaagtatctg agacagatct 6180caatacattt
agacggttta ttttgccaag gttaaggatg tgcccatgac acatgtgccc
6240atgacacagc ctcaggaggt cctgatgaca tgtgcccacg
gtggtcaggg tacaacttgc 6300ttttatactt tttagggagg cataatacat
caatcaatac ctgtaagatg tacactggtt 6360caatctggaa aagcaggaca
acttgaagtg ggggcttcca ggttataggt agatttaaga 6420attttctgat
tggcaatttg ttgaaagagt tatgttgtta cccaaagacc cagaatcaat
6480agaaatacct gggttatgat gataaggggt tgtagagacc aaagtttatc
aggcagatga 6540agcctccagg tagcagattt cagagagaat agattgaaaa
tgtttcttat cagacgtaag 6600tttaatgctg gtcagctttt cctaagttcc
aaaagggagg agggtatact gagttatatc 6660caactctccc ttcccatcat
ggcctgaact agtttttcag gttaacttta caatgcgctt 6720ggccaagagg
gggcgtccgt ttagatggtt tgaggtgggg agggcttaca attttatttt
6780tggcttacat agtaaaggtt aattatctca atacaattag gtcatcttca
tttttctttt 6840aaaaactttt gtcttccttt atctccctga atacacaggc
agtttactat tttctcattg 6900caagacccat tctcaaatat tattttcttt
tagagagact cttgctgtta tttaggttca 6960caagatggtg tcagaagtga
aataaaagtg gcctc 699511601DNAHomo sapiens 11tgaaatgctc tattctttgc
ctcaagtgat cctcctacct cggcctccca aagtgctggg 60attacaggca tggagccaac
acacctggcc ttcacatcta tttttaatcc aagtaattct 120agggtcaaat
aatactgaaa tctcgctaag tatcaaacgc tgcttttaac tgaagaaagt
180ttactttgtt ttattttatt tttaaaatct tgctttgtct ctagatagac
accataaatc 240agaacttctt aatctaagat aacatcctgc tgctcaaaaa
caggtgtcag aggaggcaat 300rcatgcagct ggctcattag tctatatcac
agatgccaca aacatgctgt cttgaggaac 360tagaaacgtg cttttttgaa
atatgttctt cagaagttct taggagctgt ggtgggagag 420cgcaagcctg
ggggtgagga ggcagctgag tgggtgattc ttctcactat tgcatcaaca
480agagtagtag ctatagactg ggtttcttat tcttctacta agaggccccg
aaataaaatg 540gctttttaaa ggacctggtc taaagctttt ttcttttctt
ttcttttctg attttttttt 600t 601122429DNAHomo sapiens 12aaataaaaag
atttgattaa attttttaaa tgggcaaagg atctcaatgg acaattctcc 60aaggaaggta
caaaatagcc aataagcata aaacagaagc tcaacatcat taattagcag
120gtaaatgcaa ataaaaacca catgagttac cattttatac ctattaggat
ggctatagtc 180aaaaaagatt ggtaaaaatg tggaaaaatc aaaactctca
tatattgctg atgggaatgt 240aaaatagtgc agatgctttg aaagtagtct
ggcatttcct caaatgatta aatatagagt 300tactatgaga cccagcaatt
ccactcctat gtatatattg aagagaaata taaaggtatg 360cccagctatg
tgtggtggcg tatgcctgat agtccttggt acttgggagg ctgaggtgga
420aggattgctg gagcccaggg gttcaagact gaagtgagct atgtttgtgc
cactgcgctc 480cagcccaggt gacagagcag gatcctgtct ctcaaaaaaa
caaacaagaa aaaaaaacaa 540aaaaactcac actcaaaaat ttttacatga
ctgtttatag tagcattatt cataatagcc 600aaaaagtgga aactacccaa
atgtctatca actgaagaaa ggataaataa tatgtggtat 660atccatataa
tgtattattt ggtcacaaaa aagaatgaag tactgataca tactacaatc
720tgaatgaact ttgaaaacac gttaagtgaa agaagccagt caaaaaaatc
atgtattata 780ttagtctatc tagaacaggg aactctatag agacagaaag
attagtagtt gccggggctg 840agggctaagg gaatggtgag actggaaggt
gatagccaaa gggtatggag ttgctttttg 900aggtgataaa aatgttctaa
aattgactgt gagtgatggt tgtacatatt tgtgaatata 960gtaaaaacca
ttaaactgta tgctatatgc ttaaagtata ggctgtgtga attatatctc
1020aataaggctg tttaaaaaaa tctaagtgga tgcagtgacc atctatttcc
ccagtgtcct 1080gtagttgctc tatgggctct tgaacaaaat agttgcatga
tggaggctat atatagactt 1140aacaatatgg atctcctctt accaaagttg
gtctgacctg cagagtgtcc aactttccag 1200taaggaagat caatgttgaa
cccctagtat agtgccatat tccaggggct ctcatcttcc 1260atctcgttgc
aggtaggttt atttttgttc ccttccaaaa gggagggggc aagagacatt
1320ggttatagat tttctttact gctggatata gattctggtt acagattttg
tttatagatt 1380tttatttact gcttcaatgc ttttattagc agacccctaa
ccactcctgg gaccacacat 1440acacccatag atgtagtcaa tgccttgttc
atgagcatag tactccacaa tacattgctt 1500atgacaaaga acttaagtta
atgtgaaagg agtgaagcaa ggtctcaaga cccataggac 1560aaatatatat
catatatttg tcgctcagaa atccatgact ttataggaag gtgaaatgga
1620taattgaaaa ctcagtttga gagacgtctt gtgaattggc atatgaattg
gtaaatgctc 1680caattggtaa atgcttcact aagcctaggg ccaatatatg
gtgctatttc ttccacagac 1740agaattcact ggtctaggat acaagaagta
gaagtgggag gggcaactct gactgttacc 1800catagtgaac aacttatgac
atgtttttgt ttcccatatg cttggccttg aattcttctg 1860gtttataaca
aaaatggttt ccaaaaattg gaagtcgagg ctctctcctg accatttgga
1920gcgcctcatg ccatttaact aacaaaaaga aaatgaggtt cttatattgt
ctagggtgat 1980tcattctgat tttcaaggcr taatatagtt ataaatacaa
tggggtcagg tggaagaatt 2040cttggtatcc tctggtgtgc ctcttagagc
ttctctattc agtgataaaa attaatgtaa 2100ggttaggtca agcggagaca
ggaaacacca aaaggactca aactcctcgt ggataaagag 2160ctgaagtgct
ggctggaaag aaagtgaatg ttgagtttat aatgaaggaa gaagtcataa
2220atattaacta cagcttcatg actagttgac ttgttgcaat tatgaggact
gtggtaaata 2280tctttttttt ttcttgttct atttatgcac atctttatat
ctatacatta aaccccttct 2340ctctctctct ctactatttt atccaatgtc
tgttggtaat ggttaatttt aacacctatg 2400tcttagatta tattattcta
tggttgtga 242913778DNAHomo sapiens 13tcactgcctg atcagtcatc
tttagaacat aaacattcca gaagttttca ggagatgaca 60ggcacaattt cctgaaggcc
tgcctagaat tgatttgcta acatgaagat agatggctta 120atgcccttaa
tctctctgtc tatggatttc ttctctcatt tttgtaacat cagtgctacc
180accaccaaca gtaataacac tgcaccaggc actgagggac ttttatctgc
attcactcat 240ttaatttgcc cagctcttct gtgaggaagg tactgtgcat
tatggtcttc ctcttacaga 300ctgaaaaaac gaagccttgg acacctgaag
gagattgcca ggcagccaat ggtgaagctg 360attttgtacc cagacagtct
gagtgcagag mctgccatta ccctccaaca gaaaaccaag 420agcaaagcca
tgggagagag gagctaatga aagaggcaga ccaattagaa gctgaggcta
480tactttatct tcttccttct tccctcctcc tcctccttct ggccggcatt
catcaaacat 540tgaacatata tgaacattaa cttatgttag gcactatgtt
caaagcttta caacttactt 600aattcccaca gccaccaagt aaggtaaata
tttttattat cgcattctac agatgaggaa 660gctgaggctt tagaaagttg
catctcttac tcgaggttac aggtttggta agatgcagag 720ccaggaacat
tttggtagca tttgaattcc tgccgtattt tgctaaatgt gcccttgc
778141001DNAHomo sapiens 14ctaacattaa aaaggacatt gaaatagggg
gctggaaaga taatgaatgg ccccctgggc 60acaagatggg tcatggggat actgtactcc
tatttatatg ttaaaccaca tcataaggtt 120gcaagcagtt ctggaaatta
tagtcaatga aacagcctga gccttagact tgctagccat 180acaggcaacc
cagatgagag atgccattta tcagaacagg ttagtactga attatgtttt
240agcttcagaa gggggtttgt ggaaaactta atttaacaaa ttgctgctta
caaattgatg 300acaatggaaa agctgtcatg gaaatcactg ccaggatgcg
gaagttagct catgttctgg 360ttcagacatg gtctggttgg aacccgagtt
cactctttgg aggacggttt tcatggtttg 420gaggctttaa aactgtaata
ctaggctttg tggccataaa aggtggatgc ctactgcttc 480cctgtctctt
gccatttcta wtcggaagca tccaatccac catagactca atggtagaca
540gacataccac catccgaata aaggctctgc aaaagtacca actggtatcc
caagatgagt 600atgtacccac tcaagaagaa atagctaact gtggtgctct
ttattaatct acatttgtgt 660cgagcaccaa aagggggaaa tgaagaagga
attaatgaaa tcaactataa cctaagagta 720gtagtaatac aaattttaaa
atccttttaa agttcctgca aaatgtgacc cctgccttac 780attcacgtta
aaagggaata ttaacagcct gtcttctctc tgtggacagt ggaccttatc
840tatactcccc aactccacat tcctcaaagt ttattacagg cccagtgagt
tcctgcatga 900ctgcagggtc acaagactga taagtttagg ctgcaagaca
tgtctttctc aaaatgtaac 960aaacgttgta atactgcctt tgtttcttgc
ttctgtaact c 1001157028DNAHomo sapiens 15catatgaaca aaggtctgag
ttgggtgagg caggatgcca cacagacatt ggaggaggaa 60aatctgagca gggggcacag
caaagcccca aggctgaggc cagatgaagg agcaggaggc 120aatgtggctg
gagaggaggg agcaaggggc agagtgttgg tggtgaggtc aggggcccag
180cagcctgatc caggggactt gaacaggatg gaaggacttt gggtgcgttc
tgaagaaggg 240gaagccactg gaaggcatta agtagaaaaa attggaagtg
agagtaatta tatgtgaaag 300ttgttagagt cacaatggag tgacgatgag
gcaggacagg tagtcaagga agtaagtgca 360gttaacacaa tgagccccag
tattcgcatt gtaatccagc tcatgcaagc acagctatct 420cctgcaggga
atatttccca tagacagcat ttgcactttg attttacctc ttctcaaacg
480gaccctgttc tcatgataat agtaaaaaac acacccctag gtggagattt
aagatgctga 540tgaattatga gatgtatgaa caagcatgta cagctactgc
acatgtgcac ccagaggacc 600accgaggaca tgcttactag caacaccttt
tctcaccctc tkatgaataa tcatgtaaga 660gtcccataaa aggatttctc
cagcaataat cagtgctgtc cattcagtgg ctcatgcctg 720taacccagca
ctttgggagg ccgaggtggg tggatcacct gaggtcagga gtttgagacc
780agcctggtca acatggtgaa acctcgtttc tattaaaaat acaaaaaaag
tagccaggtg 840taatggcaca tgcctgtaat cccagctact tgggaggctg
aagcaggaga actgattgaa 900cctgggaggt ggaggttgca gtgagtcatg
actgtgccac tgcactccag ccaacagagt 960aagactctgt tccccctcgg
ccccctgcaa aaaaaaataa taacaatgat aagaggcaag 1020atcaatggcc
accaaaattt tattttttcc catagcgttg ctggggtggc atggctgcct
1080gccctgggtt catcctgtcc ctaagtggaa ctccctatgg ctgagggact
cagaatcaaa 1140tgacttatag ccaattaaat gttctagtcc agatgcccaa
ttaaatgggc atggacagac 1200attcattagc ctttaaatta ttttctaagt
aaaaagtcaa caaacaaaaa gttaaaggtg 1260aggttacaaa actgactttt
ctttaacttc tatgctactg taatcttggg ttttgttatg 1320gacttatagc
aattatttat acaaaacata agaattgttc tgaaaaaatt aaaaaatata
1380tacctgcatg gctcataact ggaaatatta taccaggagg ctttgtcact
tggtatcttt 1440atccttttac ttattatttt cttttaattc tacaggaagc
agtaaattct ttatggttgg 1500agtggatgaa gaggtgccat gtaatagctc
agaaggcaaa gtcccttgtt ttaccagctg 1560tttaggcatc catgtactca
tccttgattt gaagggtttg agttaattct atccttccaa 1620atcagccctt
acaatctcac gtgcccacct cttctgcaac agtctctggg cctagaggga
1680ggacgcttgc aatacaggat tttttgcatg ttcccagtgg ctccacccca
ttctcccagt 1740gcacatgcag gcccttagtc tgaacccacg ctacattgat
ttatttccct tactgagcat 1800gtgttaaggg atggaatttt tcaccatggg
catgtttagg caagccccct gtacacaatg 1860tcctggatgg catttggctg
tcttctgcct ctatcattcc cccatctaaa agagtacatc 1920taactgccat
tagaataagg ataagaagaa agacaaagac ccatcttaac tgctttctgc
1980tgacagaggg cactgttttg gaaagacagc agttgggtct ccctcagagg
cctatctaag 2040ggtatctggt aaaagggacc atcattcgag gctctggttg
cataactgtt tggagtttga 2100gggcctgaag gcgagaagag acaaaccagg
ttattagaag acatgtacca aaatgaaatg 2160ggggaagggt aaggacagtt
caaaaatcct gaggctgctg acatgcccag ataactggta 2220gctgtagttg
tgcctgctaa gatttgggtg catgggactt ggctttggtt agctcccgta
2280gtttattttc ccaaaaaaga aacctctggg ttatgggcac cctatttact
cccattatct 2340ggcaggattt gtaggataat tgttcagaac tagaatactg
ttccagattt ttacattacc 2400catgcctttt gtttcttctg agctgcagcc
agagatcact ggttagttca caggaataag 2460cagggttaat ttaaaatgta
ggcaaaaaac ttaaaaacaa ctaatgagtc tagaatttaa 2520tgacaaatgt
atgataagtt ttgaaacata atttctttct ccccagtcct catttttgtt
2580aaaaacaaat cataatagga gtgagttgtt tgtaaaataa actttagtct
tacacttggt 2640ctgcttattt gcacaaagta caacaagaat aattattttt
acataggctt tttaaattgg 2700ctttgatgga actctgttcc acaaggaatt
tcagatagga cttcataaaa atgagcccag 2760ccatgggttt gtaccctcta
atacctatga gttgggtgaa ttgctctctt cttgaggtcc 2820caagaatatg
cggttcctgg ccctgttaga aagtgacatt ctttactcac tacaggttag
2880ggaacctgta tggggactgt gtagacaaag tatgaggctg gtttacccaa
ggggctttta 2940ttggctctgc aagttgagct tgattcctta aagggaaaca
tacccttcca gtcaaagtta 3000cagttactgg ttggtaaagt taaagttaca
gctactggtt gctaaagcaa ccagtttctc 3060caattgcatc ctgttgcaaa
agaaagtgga ttcttactgc actgatgcaa ataaccgtat 3120tgccctaagt
taagaatact cacagatagt ttccaaattc tagaggaagc aggcagagag
3180aaaaaaaagt gctaaatttt gttcatagga gtctgcatta ctcaattatt
aaagattgtg 3240tatagctcaa aaaaaaagat cagcactgtt ttaagctaaa
gtttaaaaaa gattacttca 3300attttctatt agttcagtct gttcagttaa
ctcttgttct gcttgatatt tgtgaacatt 3360tcagctcttc atgagtcctg
tacgtttttc cattattcca atgtcacaat ctccaaagtt 3420atcagaaacc
tgcatttgag agcacctgtt acgtttctat agctgattat aaatcctatt
3480tgaagaagat caaaacaaaa caatggtctg tgaatagcaa aatgtccatg
gtagttacag 3540tcaaaaacac aattgacaaa gaaattttgt tatctctgtg
gcttataatc acctaacata 3600acacctttaa ttgtgagtga tagcatatac
ttagatatta gaattttaga aatcccatac 3660agttttggag catatattat
tattcactaa aatataaccc aaagaagatt aaatatcatt 3720ttggcaatcc
catgtacata aatttgtcag gtaatcctat ttacctctct tctggatgct
3780ccagggatgc taggggtcag gaaagacaac cttgaagctg acatttgatt
ttgggaagcc 3840cattaaatat gttagaggtt taaaacaatg ttatgaagta
gaattccaga ttaccataaa 3900ttacttattt tgccaaaatg atgactcaaa
aattttaaaa caagccaaaa acttttactc 3960atttagaggg aagacttaga
tttccaaaga atttgtctcc tgtcttcact ttcatttcct 4020tggcagtcta
tctggaagac aaactgaaat atttaattat cctttactat tacatgaaaa
4080tcttatacaa gggagagaaa gccaaatttt accctcacat tagtttacta
ttaatgtcaa 4140ccccaatttt ttaatgaaac cttatagaca attctatcca
atcttaacca gtttgatcat 4200gaggtaagat tcctgtaagc cttttataac
cttttacaaa ttactaattt actaatctgc 4260taaagagcag attagggctt
taagaaaacc ttgttgtgct ttcatttcaa tgctcagttt 4320gtagaaaaac
catataatag agttttggat ttaatcaatg ttcacacaca gaatttcttt
4380tgcaagatta atttttagaa acctcccaca acttgtttaa acctttagtt
tatcttatct 4440aatttataat agtcctttaa ccttaggcaa aaacttacat
ttccatgcat tcttataatc 4500tttgactaat aacacatttt actgttctta
cataccttgc atgtaaatct attttcagtg 4560gtctcaatta catgttataa
tggtacctct tagcactttt taattttagt ttaaaacctg 4620gtaagtcgtt
ttaattacgc actaggtgct gataaagttt gattccttcc agcataatta
4680agggtgtggt taattccata tgtccctgtg ccttaccaag ttgtaaagca
ggcagattga 4740acagttttca aaggcaaaag aagccgttta caaccttaaa
acatttagcc acctagtgcc 4800tgacttgcat aatttagacc agctatttac
attttaagaa catttgcatt ttatcaatta 4860tctttaagac tacttttatt
tctcagagat taaagtcaca agaactaaaa ggcattatag 4920cttttatctt
tcctccaaaa atatttgatc ttagtgctga tttttcttta agccaattaa
4980ttagagctct tttttataac tacacagatg gagaagaaga ttgagtgtta
taagattttt 5040catttgccca tctcctaatt ggattcttgg tctctgggtg
ggacccttta agagcagggc 5100taagaaagca tgcagtttat tttctttttt
tctttttctt ttcttttttt ttgagaaaga 5160gtttcactct tgttgcccag
gctggagtgc aatggtgcga tctcagctca ctgcaacctc 5220tgcctcccag
gttcaagcga ttctcttacc tcagcctccc aagtggctgc atgcagtttc
5280tagggcctaa taaacaggca tagctggaaa acaaaaacgg attttgagag
cgatctattt 5340gcctctaatt cctggggttc catgaggaaa acagaggttt
ctcccaaaat ggaatccatg 5400gtgccttttc tgtttttacc aagcagccct
atgccatcag aaattatctt agggcctctc 5460atgtgcgcat taacactggc
aagacaaggt ggagaaaagt aattcagtca actgagaaaa 5520aaatcttttt
ccagcaaaac aagatccaag aagagaaaaa cataaaggcc tttcaaatat
5580acgtatagct tggatatcca cttttaatta agctgagctc tctttaagaa
agtcctttta 5640aatcccacat tacctgactt cagccatgcc aagcagccaa
tatttctggc tttggaagtt 5700tatcaaaaga acctcaaggt tcaaccaaca
agcctcaatt aagacacgcg aagcacacca 5760gattggctac accttaagac
cagcctcata aaaccttttt cactaatgga aactttacag 5820ggaatatcaa
cagtgatcct tatcattctt ttcaccagtt tacacaggga gagagaggcc
5880aaaagtctga ctggttaaaa aacttttatc cttttgctgg catgtcatgc
ttctgggttc 5940ccttcccctg agctcaattc taagccaacc agtttaaggt
ttgggaaatt aacttttctc 6000agtttggagg atgcatccta tgggaatgtc
ctttagtaca gggacacagt cacccatctg 6060tgaagagagg acaaaggagg
aaaaagtaaa aaaagatttt tttcaaaggc tccccagggg 6120ttcaggatgc
atttgaaagg gggacagatt gaagatgaat ggctactcat ctagaaagag
6180gggagccaga catccctggt tcctttctct ttctaggaaa tagccagggt
atgtgaggga 6240aagaaggaac aagcatccat tttccttctt ccgtccttat
gtccccaagt cctgacaacc 6300tcgacagggt gccacccatg ggtgccaata
cggttctcac ccatggtaac aggggaccta 6360gtggatggga ttatccactg
ttacccacaa actgtctttc cccctgctct caatagcctt 6420caagtgccct
agacctcatt taggccattg atactagtat gacctttatc catgaaacaa
6480gaggcttggc ttaattgtca ggaattagtc atgctcacct atactgtgct
ttttaatttt 6540tgttgttgtc tgcctctgga tccctccgat gcagttatct
ttcctagggc ttctacatga 6600agcttggaat tgagtttggg acaaaagaac
tgcctcagta ggtgggtgca tggactcatc 6660aatccccagg tgtccctcac
cagtctggct gctgccgcct tatcataagc tgaaggctaa 6720ggtgcaactg
tgaaattagg tccttctcaa acaagggagg gaaaatggtg tcctgtgaat
6780tagggtcctg gtctaataag atgccttcca aaaggaagaa aacttctggc
acagagaaga 6840cccctctacc cgcagggctg tgttattagg ttggtgcgaa
agcaattgtg gtgcccatca 6900ttctaagtaa tgacaaaaac cacaactact
ttcacaccag cctactaact catgacttgg 6960tggacaaaag aaaataacaa
caacaacaac agcttaaatg cagggctgtg tttactgctg 7020acaaggtg
7028161656DNAHomo sapiens 16gggtatatac ccaaaggaaa taaagtcatt
acctcgtgaa gatatctgta ttcctatgtt 60aactgcagca ttattgacaa tagccaagat
atggaaacaa actagatgtc cttcaatgga 120taaactatga tatgtacata
caatggaata ttattcagcc tttaaaaaga ggaaaatgag 180gaaatcttgc
tattttccac aacatggatt gacctggagg acattatact aggagaaata
240agccagagac aaaaagaaaa atattgtata atttcactta tatgtggtat
tcttcccaaa 300agatcaaata tatagagaga atgaaacagg gttaccagtg
ctggagtctg ggaggggaga 360atggggagat ctaggtaaaa ggttacaaag
tagcaaatat atagaataaa caagtcaaaa 420aatgtgttgt acagcaacat
gtggattaaa attaataata gtgttatata caggattttt 480tctaaactaa
gtatattata gctgtttgcc acaaggagaa acatggtata ttagctcatt
540ttgcattgct gtaaaggaat acctgagatt aggtaattta taaagaaaag
agattgattt 600ggctcaccgt tctacaaacc gtacaagagg ctcatggttc
cacaaaccgt gcagcttctg 660cttctggtga agacttcagg aagctttcaa
tcatggtgga aggtgaaggg aagcaggtgt 720gtcgcatggt gaagggaagc
aggtgtgttg catgatgaag gtgggagcga gggcaagggg 780tgaggtccca
ggatgtttaa gaaccagctt tcatgtgaac aaacagagca agaacccatt
840cattactgca aagagggcag caagccattc atgaaacatc cacccccagg
actcaaacac 900ctcccaccaa gcctcacctc cagcactggg gatcacattt
caacatgagg tttggagggg 960acaaactata tcaaatggta actgagaaga
ttaataaatt rttccactat agtaaccatt 1020ttactacaca catgcatctt
ataacatcac gttttatacc ttaaatatac acaatacaat 1080ttttttttaa
aaaagctagt tagatatgga atttaccaat gagtgaatgt tttccagtaa
1140ttgtgtagac ttcagagctc tttctggcga gtacatatgg cctccaactt
aataaggttc 1200gacttaaggt tttttgactt acgatggatt catcaggatg
taacctcaca ataagctgag 1260gagcatccat atgtacctcc attcatgctg
gataaatgga ttcttttttt tttttttttt 1320tttttttttg agacacagtc
ttgctctgtc actaggctgg agtgcagtgg catgatcttg 1380gctcattgca
gcctccgcct cccggattca agcaattctc ctgcctcagc ctcccgagca
1440gctgggatta gaggtgcatg ccaccacacc agctaatttt tgtattttta
gtagagacgg 1500ggttttgcca cgttggcccg gatggtctca atctcttgac
ctcgtgatcc gcccgcctcg 1560gcctcccaaa gtgctgagat tacaggcatg
agccaccgcg cctggccaac aaataggctc 1620tttaaggcac tgctcttctt
tgtccctgag agcaga 165617936DNAHomo sapiens 17tgagtgtcac ttcctaggta
ttgtttcttc tccctggctg gtggtcaagt ccagaagtcc 60tgtcccagaa tttcttcaaa
aggagagagg gagtaaaatt gggtatggaa aaaagactca 120cattgacaaa
aaagaatttt agagtcttct ctaaaatgtt gcggcaagta gataaaacca
180tgaaaaacca ggatgcccta tgtgattgtt aatattaagt gtcaacttga
ttggattgaa 240ggatgcaaag tattattcct gaatgtgtct atgaggatgt
tgccaataga gattaatatt 300tgagtcagtg actgggagag gcagacccac
cctctatctc agtgggcacc atctgagcag 360ctgccagcgc agctagagta
aagcaggtag aagaagatgg aaagaacaga cctgccgagt 420cttctggcct
ccaccyttct cccttgctgg atgcttcctg ccctcgaata tcagactcca
480agttcttcag cttttggact
cctgcactta catcagtggc ttaccagggg ttctcaggcc 540ttcagccaca
gactgaaggc tgcactgtca ctttcgaggt tttgagactc ggactggctt
600ccctgctcct cagtttgcac acggcctatt gtgggacttc actttgtgat
tgtgtgagtc 660aatactcctt aataaactcc ctttcatata tacatctatc
ctattagtcc tgtccctcag 720gaaaccctga ctaatacacc ctataggcag
atgagcctat tttacctggg gttagatcaa 780agttgtttga gggaaggggc
aacagaagag agctaacttc tcatgtgcca atgagaccga 840aggaaagatt
ctaatggaca cacaagatgc aatacagaaa tctggagaaa tggttcaata
900gggaacacac agctcctagt gaggattaag cacccc 93618938DNAHomo sapiens
18tgggggtgct taatcctcac taggagctgt gtgttcccta ttgaaccatt tctccagatt
60tctgtattgc atcttgtgtg tccattagaa tctttccttc ggtctcattg gcacatgaga
120agttagctct cttctgttgc cccttccctc aaacaacttt gatctaaccc
caggtaaaat 180aggctcatct gcctataggg tgtattagtc agggtttcct
gagggacagg actaatagga 240tagatgtata tatgaaaggg agtttattaa
ggagtattga ctcacacaat cacaaagtga 300agtcccacaa taggccgtgt
gcaaactgag gagcagggaa gccagtccga gtctcaaaac 360ctsgaaagtg
acagtgcagc cttcagtctg tggctgaagg cctgagaacc cctggtaagc
420cactgatgta agtgcaggag tccaaaagct gaagaacttg gagtctgata
ttcgagggca 480ggaagcatcc agcaagggag aaaggtggag gccagaagac
tcggcaggtc tgttctttcc 540atcttcttct acctgcttta ctctagctgc
gctggcagct gctcagatgg tgcccactga 600gatagagggt gggtctgcct
ctcccagtca ctgactcaaa tattaatctc tattggcaac 660atcctcatag
acacattcag gaataatact ttgcatcctt caatccaatc aagttgacac
720ttaatattaa caatcacata gggcatcctg gtttttcatg gttttatcta
cttgccgcaa 780cattttagag aagactctaa aattcttttt tgtcaatgtg
agtctttttt ccatacccaa 840ttttactccc tctctccttt tgaagaaatt
ctgggacagg acttctggac ttgaccacca 900gccagggaga agaaacaata
cctaggaagt gacactca 938191239DNAHomo sapiens 19tctctgctgt
ggcaccagga ctgcacgaga tctggtctct gcacatcttg gtgtctgcat 60cctggtaaaa
aatggccccc tttcccacac ctacccatgg aggaagatga ggcagcaagt
120tgtaagaaat taccagaaaa gcctcactcc tgatctcctg acccaccccc
tcatgctctc 180agtgcttcta ctcttgcttc attaatttat ccaacaaata
ctaattgtcg gctaggtacc 240aagttctgtt atagataatg aagatatggc
tgtggaaaaa gaaccagaaa cctgccttta 300cattctagtg gaagaggagg
aagataaaca ataaacaagg tcaacaagta actacagcat 360gtcaggtgat
ttaagtgctg ggaaggaaac tgagtggtat agatcattgc agagggtagg
420ttgcaatttt aaatggaata gtgaagttag cctcactrat aaggcagtct
tccagcaaag 480atctgacaga ggtgaggaag tgaatctatg gaaacctggg
ggtacagcct tccagcaaat 540aacaggtgca aaggcccaga agcctagggc
atttgtattt gagggcaagc aaggggtctg 600tgtgctggag aagagtgagg
aaggtgagaa ttagggagtg aggcctggga gattatgagg 660aaaggaaaca
gatcatacag cgccttggag gccattataa agactttggt ttttaccctt
720atgagatggg aagctattgg cggttttaga gcaggaaagt gacatgatct
gatttatgtt 780ccaaggctca tgctggccac cttgttaaga caaaactgga
gggaggcaag cagagcgggg 840acaccaatga ggtaaccata gtgaccatcc
agaggagaaa tgatggtggc ctggaatagg 900tagttctgag aagtgttgta
ttttggaggt agatcaatag aatttattgg tgcattgaat 960atatatgatg
tgaaagaaag cggggagaca aagataacct caacgctttt ggcctgagca
1020gctgtaagac tgggattgca tttgatcaca gggcaagctc agtcgggctc
aaaactgttt 1080gctccttcct ggctggaact tcgtgtgggc ctaagatgtt
taactggaat ttcatctggc 1140agacttaaac attgtgttct tcttttaaaa
gctcaaataa caaatattcc aaaatgtaaa 1200gcaaaaaaag gatttattga
aatcatgtga caatatatc 123920801DNAHomo sapiens 20aaatatttaa
taataataaa tatataaaaa gtatattcat ataaaataga aatgtatgaa 60aaatattcac
ctttatagaa gttttaaatt gtcaaagcaa tgtcaattta attggctcaa
120taagagagtg aaaaaccatt gcttcaggac cgcctcagtc tgtaatgcta
ttttaaaaaa 180attatttcaa cattttctta aatactattc cttggttgtt
aaatttttat tttgctgtat 240tagaagaatg aaggttgtta ttagggatgt
tacattcaga aataaagttc tgaatttcat 300agaacacttt attctctgcc
tcatctttac atttcaattt ttcgggggga atgtcgttca 360aatatagttt
acaaatgaaa tataaaggat aaaagaatgg rtaaacaaag aagtccccaa
420ggtgtaacag tgaatattgc tttaagaaaa tacaaaaaca attttaaata
agatccttca 480aacacgagtc atcctgttct cagggagctt tagaatttcc
acattgctga atgccaaatt 540ccacaagtca tggaatttcc acacatctct
cttcacttct ctgacttctt ctgtctaaca 600tgggctgata tatttcagcc
actacacagt agctggagtg tggtgttaga gcttcaattt 660caaccgctct
gtgagcccct tcataaacct tttgctccta cacacgagag agaaaataat
720cagttggtaa atggctgcca ttaagtcaca gctgcatttt tgtttaaatt
aacaagttgt 780acatggtcac agcagtagat g 801211715DNAHomo sapiens
21tcctatatag agatgaggaa ggcgccacaa gcaagacact cttggccaga aggattgagt
60aatgaggttt cctttcttct ttgtcactaa aaaaattaca tttaattttg agaataaaga
120taagttcttc taagacagga ttaaaaacta aacaaaacaa aaacaaacag
aaaagaaaag 180cttaatatat cttttaaatg agggacaatt gtacagagya
gacttccttg ttgttgatag 240ttttaattca gatatcaatc cagaaatcat
aagatttttt tccccaaaac ctgttcttat 300ttacataaag tagactttaa
aacaaaattt tgattcatta agtagaaata tttaataata 360ataaatatat
aaaaagtata ttcatataaa atagaaatgt atgaaaaata ttcaccttta
420tagaagtttt aaattgtcaa agcaatgtca atttaattgg ctcaataaga
gagtgaaaaa 480ccattgcttc aggaccgcct cagtctgtaa tgctatttta
aaaaaattat ttcaacattt 540tcttaaatac tattccttgg ttgttaaatt
tttattttgc tgtattagaa gaatgaaggt 600tgttattagg gatgttacat
tcagaaataa agttctgaat ttcatagaac actttattct 660ctgcctcatc
tttacatttc aatttttcgg ggggaatgtc gttcaaatat agtttacaaa
720tgaaatataa aggataaaag aatggataaa caaagaagtc cccaaggtgt
aacagtgaat 780attgctttaa gaaaatacaa aaacaatttt aaataagatc
cttcaaacac gagtcatcct 840gttctcaggg agctttagaa tttccacatt
gctgaatgcc aaattccaca agtcatggaa 900tttccacaca tctctcttca
cttctctgac ttcttctgtc taacatgggc tgatatattt 960cagccactac
acagtagctg gagtgtggtg ttagagcttc aatttcaacc gctctgtgag
1020ccccttcata aaccttttgc tcctacacac gagagagaaa ataatcagtt
ggtaaatggc 1080tgccattaag tcacagctgc atttttgttt aaattaacaa
gttgtacatg gtcacagcag 1140tagatgggtt gtggggtttc ttcccagaca
catccttctt ttctagagtc ctaggccata 1200gcctggtaaa gggacaaggc
aagtggctgt gtaggtgcaa cttgacttct ccttgagggc 1260tgttggctgg
ttgaccccat ggtcagagtc ttgtttttaa gaattttgtt tgttttttga
1320gatacagttt cactccatca tccagcctgg agtgcagtgt caccatctcg
gctcactgca 1380acctctgcct ctcaggttca agagattctc gtgcctcagc
ctcctgagta gctgggattg 1440cagacgcata ccaccacgcc tggctaattt
ttgtattttc agtagagatg gagtttcacc 1500atgttgacca ggcaggtctt
gaactcctga cctcaaatga tttgcctgcc tcagcctccc 1560aaagtgctgg
gattacaggc atgaaccacc ccacctggcc ttctttttaa gaatttgaag
1620tgtgcagtga gaatgatgtg cagcgagatg agcagagata actgcaggca
tgaaactgtg 1680gccacataga gacagaaagt ctgagagaca gagca
1715221231DNAHomo sapiens 22agctgcggac atcacagggc tcctggctta
tgatctgtga tgctagattt tgcaattgat 60tgcaaaatca gttttgcaat cagttgcaag
tttcttgacc cattcactgg attgtgattg 120tgttacaaga ccaagtcaag
attatttgac ctcatagcac tttactcttt aacagctctc 180tccttgaaat
attaccttcc ygcactattc atgaacatat cagcccacag atttcctcct
240acctctttgg ctattccttc tcagtctcct tttaagattt ttcttactca
ggcatctttg 300ggtgaaagtc cctcaatatc tggtcttact caaaactgcc
tctcactcac tactctctcc 360ctaggcaatc ctatcaatgt ccactgtact
gtatgcatga aatgactcac aaatttttgt 420ctctaataaa gactttactt
tgagtcttgg atctgaagag atatgtcccc tggatctctt 480aaaagcatat
taagcttaac atattcaaaa ccaaactcat aatctctatt accttgcatc
540ccaccaaact ggtctttttc atcaaacccc atcaaaaaga tctcagcaat
tcatctaatt 600atgcatgcaa gaaacttaga ggtcatcttt gacatgtcct
cttcaccatt atatccgatc 660tatcacctgg tcctgccaat gttgcttact
aaatgtccct ccaggaataa attttctcta 720gtccttttca taagccaaat
tcggtctcct gtagactatt attagtaacc tgctacttca 780cttatctgca
tccaacctgt tccccaaaat atagtcaaaa tgatcttttc tatacacaag
840tctgatcata tggctcctaa ataaaattat gtttttctgg aggaagtcac
aactccttaa 900aaaattcttg tacctgccta cctttccagt cccatctcat
tatggactcc ttcctgcatg 960ctcttcttca atatattggt tatctttcag
tcccttgagt ttgctatgcc agagggcctt 1020tgcaaatgct ggtcccttgc
ttgaaatgct ctattctttg cctcaagtga tcctcctacc 1080tcggcctccc
aaagtgctgg gattacaggc atggagccaa cacacctggc cttcacatct
1140atttttaatc caagtaattc tagggtcaaa taatactgaa atctcgctaa
gtatcaaacg 1200ctgcttttaa ctgaagaaag tttactttgt t 123123511DNAHomo
sapiens 23tttcaacatg aattttggtg gagacaaact caaaccatag cagcttggga
gtcctcttta 60ggaaaagatt tataaatata aaatccttgc attggggtcc tgaagtttaa
tcttcattag 120attcatggta aaacagtttc taatcttctt agtactttgg
accacaaata ggtccacttt 180tgacctattt atactactcc aggggaagca
taaaaagagt accaatcttt actttctgca 240tgctgaaagt atctcyagca
atgcacaaat ctacttttgt aatggagaaa ccttcattgt 300aaagatttgt
acattttaca atcgctacat aaaatatgta gagagaagtc gtagcggtta
360aagatggaga tgcttctggg gatattcctt ccgaaattaa ttagcaggaa
aatctgacct 420aggacctacc ccatgctgga gagacatgga tgaatttatg
ggataaaaat tgctactttg 480gccatagctg catttgattt cctgaatttc t
51124701DNAHomo sapiens 24tcatgctaat gaggaaaact gcccaagacc
ctgctggggg gtagtgtttc tgagactaat 60catggcatgg catgggataa ttttgcactg
gcatgacttg tgctttcttc ctcaaatcag 120gcaacatagg tggtacaacc
ttgcttgcct ttagttgcat ggaggcaaga gaattttggc 180aaaattttac
ttagggttca rggtttttta taagggataa gaagttgggc agaaggagga
240gtcaagaagc atatcttttt tttttggatg gagtttcact cttgtcgccc
tggctggagt 300gcagtggcgt gatctcagct cactgcaacc tctgcctccc
ggattcaagc gattctcctg 360cctcagcctc ctgagtagct gggattacag
gtgcccgcca ccatgcctgg ctaatttttt 420tgtattttta gtagagatgg
ggttttgcca tgttgggcag gctggtctcg aactcctgac 480ctcaagtgat
ccgcccacct cggcctccca aagtgctggg attacaggcg tgagccactg
540cacccggcca ggaagcatat cttctgtttt ctccctgacc tcatcttctg
tcaccccgac 600ccctgtgttt gcagtgttga ctccttcact tgctccacca
tgactccagt gactctgcct 660tagggcctct gcactggccc ttcccttttc
ctggtctgct c 70125801DNAHomo sapiens 25ttgttctgta tgaagtctct
gcaccctcta gagagccttt tctttagtgg gaactcatta 60agtacatgtg gggtcattca
agctgcagat agacactaac cccatgcctg ctctgatcat 120ttagtgacat
caaaagctgc agcctttata aagttcaaaa aagcaccagt gccatttcca
180acagatcctt gattggactc agatgacaaa gctatgagca attaaaaaga
aacaaagcac 240ttacctgcta caccagtaag gaagaaactg atgaggaagc
ctagaaagca atgtttaggc 300atcatggttg caagtgtgac tgttcaggca
accagtgttc cttttaacca gctcaggacc 360aaagaggaaa ctgtaaaatc
cacaaacaga caatcactcc ygggtttaag gcagatggtt 420ccttgaagca
actacaattt tattttgata ctacattata ttattttatt ttaggaaaaa
480tatgaaagta taaaaatcac ttcaaaaaac atttgctgtc acttttatgt
ggaagctcgt 540tttattggga agctcgtttt ttgttggggc ttcattagct
gcagaaaggt aaaacactga 600ggatgggcag atctgaaggg cagggcagtg
cagggattgt gcaagtggca agcaggtgag 660tgaatgaaac aactagtggg
gccttaaggg aatctggccc caggaggcgg agaggctgcc 720aaggactagg
acttggctgc cagggtgatt ttgagtaatg tgcttggcat ttgcagctat
780cggggcccct ggcagtggtt c 801262172DNAHomo sapiens 26tgcctgatca
gtcatcttta gaacataaac attccagaag ttttcaggag atgacaggca 60caatttcctg
aaggcctgcc tagaattgat ttgctaacat gaagatagat ggcttaatgc
120ccttaatctc tctgtctatg gatttcttct ctcatttttg taacatcagt
gctaccacca 180ccaacagtaa taacactgca ccaggcactg agggactttt
atctgcattc actcatttaa 240tttgcccagc tcttctgtga ggaaggtact
gtgcattatg gtcttcctct tacagactga 300aaaaacgaag ccttggacac
ctgaaggaga ttgccaggca gccaatggtg aagctgattt 360tgtacccaga
cagtctgagt gcagagcctg ccattaccct ccaacagaaa accaagagca
420aagccatggg agagaggagc taatgaaaga ggcagaccaa ttagaagctg
aggctatact 480ttatcttctt ccttcttccc tcctcctcct ccttctggcc
ggcattcatc aaacattgaa 540catatatgaa cattaactta tgttaggcac
tatgttcaaa gctttacaac ttacttaatt 600cccacagcca ccaagtaagg
taaatatttt tattatcgca ttctacagat gaggaagctg 660aggctttaga
aagttgcatc tcttactcga ggttacaggt ttggtaagat gcagagccag
720gaacattttg gtagcatttg aattcctgcc gtattttgct aaatgtgccc
ttgctgttac 780caagtaccag agtcttctca aatccaaaca cttctggaag
atgaaggctt gaattgcttt 840tatgtattag tcactggaca actgcaccat
cttggcaagt tacttaaatc acttacactg 900agaggtaccc atttgttaac
ttgcattctt acaggcttgc tcagaagtat gtggtgctga 960taagatgctc
tacactcctg cagtttcctc cacgaatacc agaagcaaat tctcacctgt
1020tgtttgtggt ccctatcctg tgccaggcac ttctctaagc atttggcata
tattaattga 1080tttaatcttc acagtgacct agaatcccca ttctactaat
gaggaaattg agggtgttaa 1140gtaaatttcc caagttttcc tagatggtaa
atggcagatc tgaaatccag accatgatag 1200cttggcttag gagcctgtgc
tggtaaccac catgatttag tgttccttca aggtaaaaga 1260cattctaagg
tgagtgagag ccagagagaa agagagaggg agagaaagaa agagggaggg
1320agggaaggag agagagagag agaaatggat gtacatttgt tctgtatgaa
gtctctgcac 1380cctctagaga gccttttctt tagtgggaac tcattaagta
catgtggggt cattcaagct 1440gcagatagac actaacccca tgcctgctct
gatcatttag tgacatcaaa agctgcagcc 1500tttataaagt tcaaaaaagc
accagtgcca tttccaacag atccttgatt ggactcagat 1560gacaaagcta
tgagcaatta aaaagaaaca aagcacttac ctgctacacc agtaaggaag
1620aaactgatga ggaagcctag aaagcaatgt ttaggcatca tggttgcaag
tgtgactgtt 1680caggcaacca gtgttccttt taaccagctc aggaccaaag
aggaaactgt aaaatccaca 1740aacagacaat cactcccggg tttaaggcag
atggttcctt gaagcaacta caattttatt 1800ttgatactac attatattat
tttattttag gaaaaatatg aaagtataaa aatcacttca 1860aaaaacattt
gctgtcactt ttatgtggaa gctcgtttta ttgggaagct cgttttttgt
1920tggggcttca ttagctgcag aaaggtaaaa cactgaggat gggcagatct
gaagggcagg 1980gcagtgcagg gattgtgcaa gtggcaagca ggtgagtgaa
tgaaacaact agyggggcct 2040taagggaatc tggccccagg aggcggagag
gctgccaagg actaggactt ggctgccagg 2100gtgattttga gtaatgtgct
tggcatttgc agctatcggg gcccctggca gtggttcaaa 2160gcaagagggg tc
2172273078DNAHomo sapiens 27aaaaaagtca tgttccatag tgaacaggtc
tgtgcaaacc tacccttaaa gtccaaggaa 60gctgagaggt caaagaaaaa ggctgacata
tccagtttct cagaaagaaa catttcgtag 120ggacttatga acagagccat
gtgtgtgtcc tggacagtgg caagacaaga tggtggaccc 180tcatgccatt
accctgtaga cctgaagaag gaattaagga aatcaactat aacctaatag
240tagtagtagt aatagaaatt ttaaaatcct cttaaagttg ctgcaaagtg
tgacccccca 300ccttacactc aagttaaaag ggaatattaa cagcctgtct
tctctctgtg gacagtggac 360cttatctata cttcccaaat ccacattcct
cagagtttat tacaggccca gtgagttcct 420gcatgactgc agggtcacaa
gactgataag tttaggttgc aagacatgtc tttctcaaaa 480tataacaaat
gttgtaatgc tgcctttgtt tcttgcttct gtatctcgct tcctgcctca
540tgtagttccc accttaagat gtttaaacgt aggaaaagcc ctttgctcag
ggctcagact 600ttctggacat atgtgctact gatcacctta atttagtaaa
ctctcctgaa cctttttcgg 660tctctccaat ctttggttgt cccacaacat
ttccggggac cagtctggga ttggagatgg 720cagattttcg tctcctttgc
ctgtgggtta gagccccagg acatgggaaa tctggggtcc 780ttggtgccac
cgggagagtt ttagcccaga aggagaacag cccttccacg ttctggagcc
840ttcctccaac agtgcaaatg gaaccagtgg aaagggttgc aggacagtca
caagaacagt 900gcatagacat atgaactgca gtaaggtttg ggccctaagg
caagacccgt cccataagga 960tggaagggga gcctggtcac ctccaagggc
atgacaacta gtctgacccg agggggttgg 1020gacaatggga gaggcccatt
gattcagatg aaactcacac cctaattgac accagacrta 1080agtggggctc
atgagtcggt cagaaaggaa aaccattttg gggatggggg aggtgtgtga
1140aagtgtgtaa aagagatggt ctcgggagag accaaggcgg ggttgatgtg
gggaggcaca 1200gatctcttag cgtggactgt gtgctcccag gcgagtgtgg
gaaaaaccag acctaggaca 1260ctgcatacgg cccagaggac cagctccaca
gctgcagcta gctgtgacag gaattaaggc 1320atgctcctgg ctaagcagtg
tccgaacctc ctgtaatagg acccagtctg gtggatccaa 1380gagtgaaagt
gagagtgaaa gtgcatcaca agggaggaaa caggaggaaa agcgtcaaag
1440cctattccac tggagtgcgt gctgaaaaac tttaaaaaaa gttttaatgg
tgactatggg 1500gttaagctaa cttcacagaa actgagaact tttttgagat
aaaatagcca tcttttaatg 1560tagggtggcc agccaagggg acaatagaca
gggagataat tggccgagtg tttcgggtgg 1620tcaccaggct tggagaacag
cccgggcacc tggatcagtt tccgtatatt gactcctggc 1680taagtataat
tcagaccctc cctaagtggc tgcaggccta ctttgagatc tactgtaaga
1740ctctaacggc caagacaaaa ccaggaacaa tagaaagaaa ctgcaaggca
tcagaaaaag 1800aaaagtcaca ggaaaagcag taaaaacctg tcctacaggc
cccgcctgaa gagttagaaa 1860ttccacccca ctatgcacca atttatccac
ctctggcaaa gcttagacag aaggctgccc 1920cggctgcctc cggagactca
gactcagaag gaagcacccc tcaggcaaca ccacgcagag 1980aggagccaga
gcccttgact gaaaagccaa gggaggaact ccagggtgat gaggtcggcc
2040gccttaggtc ggtccgtgcc caagcaatgc agatgccact ctgagaaaca
tggggacaaa 2100tttatttgaa tgcacagaat gaagtccaag ggggagaaca
gctcttcttt tatcagccct 2160tctctactac tgatctctta aattggagac
aacatactcc ctcctataga gagaagcctc 2220aggctcttat agatctaatg
cagtccattt tcctaactca caatcctacc tgggttgatt 2280gtaaacattt
ttttctgtca ttatttaata tggaagagca ccgtagagtt atacaagctg
2340ctctccagtg gctggagaaa aatgcatctt caagcacagg agatatcagg
cagtatacac 2400aacaagcact cctgatagag gctgacccag gctgggaccc
taaccaggct caagggctac 2460aagtttgcag cagtattgag aggcactcct
aaatggaata aacgctggag agaaaaaggc 2520caccaatatc ggaaaggtct
cagaggttcg ccagaagcca gataaaagtc ccggtgaatt 2580ttatgagagg
ctgtgcgagg cttaccagct ttacatgcca cttgacccag aggctgcggg
2640taatcagtgt atggttaatg tggcatttgt aagccaggtg caagaagaca
tcggaagtta 2700gaagggtttg aaggtgtgaa tattacccag cttatccagg
tggctactaa ggtgtttgta 2760aatcagaagg aggaggccaa gagaaaagct
agatgcagag ctaaggaaaa ggcagacttg 2820ctggcggtgg ccttagttgg
aagagaaact ggttttgtga gaggatgtgg tcgtggttgc 2880ggtcatgata
gaggacaaac taggtaaaac caggaagcta agccaggaca agagggccaa
2940cttaggctta agggagatca atgtgtgaga tgcaagcaga tgggacacta
gaagaatgaa 3000tgccaaattt tccggtgccc ttgttaggaa gagatttcct
ccagaaattg caagcacaaa 3060tctcctttat accagaag 3078283164DNAHomo
sapiens 28aaaaaagtca tgttccatag tgaacaggtc tgtgcaaacc tacccttaaa
gtccaaggaa 60gctgagaggt caaagaaaaa ggctgacata tccagtttct cagaaagaaa
catttcgtag 120ggacttatga acagagccat gtgtgtgtcc tggacagtgg
caagacaaga tggtggaccc 180tcatgccatt accctgtaga cctgaagaag
gaattaagga aatcaactat aacctaatag 240tagtagtagt aatagaaatt
ttaaaatcct cttaaagttg ctgcaaagtg tgacccccca 300ccttacactc
aagttaaaag ggaatattaa cagcctgtct tctctctgtg gacagtggac
360cttatctata cttcccaaat ccacattcct cagagtttat tacaggccca
gtgagttcct 420gcatgactgc agggtcacaa gactgataag tttaggttgc
aagacatgtc tttctcaaaa 480tataacaaat gttgtaatgc tgcctttgtt
tcttgcttct gtatctcgct tcctgcctca 540tgtagttccc accttaagat
gtttaaacgt aggaaaagcc ctttgctcag ggctcagact 600ttctggacat
atgtgctact gatcacctta atttagtaaa ctctcctgaa cctttttcgg
660tctctccaat ctttggttgt cccacaacat ttccggggac cagtctggga
ttggagatgg 720cagattttcg tctcctttgc ctgtgggtta gagccccagg
acatgggaaa tctggggtcc 780ttggtgccac cgggagagtt ttagcccaga
aggagaacag cccttccacg ttctggagcc 840ttcctccaac agtgcaaatg
gaaccagtgg aaagggttgc
aggacagtca caagaacagt 900gcatagacat atgaactgca gtaaggtttg
ggccctaagg caagacccgt cccataagga 960tggaagggga gcctggtcac
ctccaagggc atgacaacta gtctgacccg agggggttgg 1020gacaatggga
gaggcccatt gattcagatg aaactcacac cctaattgac accagacgta
1080agtggggctc atgagtcggt cagaaaggaa aaccattttg gggatggggg
aggtgtgtga 1140aagtgtgtaa aagagatggt ctcrggagag accaaggcgg
ggttgatgtg gggaggcaca 1200gatctcttag cgtggactgt gtgctcccag
gcgagtgtgg gaaaaaccag acctaggaca 1260ctgcatacgg cccagaggac
cagctccaca gctgcagcta gctgtgacag gaattaaggc 1320atgctcctgg
ctaagcagtg tccgaacctc ctgtaatagg acccagtctg gtggatccaa
1380gagtgaaagt gagagtgaaa gtgcatcaca agggaggaaa caggaggaaa
agcgtcaaag 1440cctattccac tggagtgcgt gctgaaaaac tttaaaaaaa
gttttaatgg tgactatggg 1500gttaagctaa cttcacagaa actgagaact
tttttgagat aaaatagcca tcttttaatg 1560tagggtggcc agccaagggg
acaatagaca gggagataat tggccgagtg tttcgggtgg 1620tcaccaggct
tggagaacag cccgggcacc tggatcagtt tccgtatatt gactcctggc
1680taagtataat tcagaccctc cctaagtggc tgcaggccta ctttgagatc
tactgtaaga 1740ctctaacggc caagacaaaa ccaggaacaa tagaaagaaa
ctgcaaggca tcagaaaaag 1800aaaagtcaca ggaaaagcag taaaaacctg
tcctacaggc cccgcctgaa gagttagaaa 1860ttccacccca ctatgcacca
atttatccac ctctggcaaa gcttagacag aaggctgccc 1920cggctgcctc
cggagactca gactcagaag gaagcacccc tcaggcaaca ccacgcagag
1980aggagccaga gcccttgact gaaaagccaa gggaggaact ccagggtgat
gaggtcggcc 2040gccttaggtc ggtccgtgcc caagcaatgc agatgccact
ctgagaaaca tggggacaaa 2100tttatttgaa tgcacagaat gaagtccaag
ggggagaaca gctcttcttt tatcagccct 2160tctctactac tgatctctta
aattggagac aacatactcc ctcctataga gagaagcctc 2220aggctcttat
agatctaatg cagtccattt tcctaactca caatcctacc tgggttgatt
2280gtaaacattt ttttctgtca ttatttaata tggaagagca ccgtagagtt
atacaagctg 2340ctctccagtg gctggagaaa aatgcatctt caagcacagg
agatatcagg cagtatacac 2400aacaagcact cctgatagag gctgacccag
gctgggaccc taaccaggct caagggctac 2460aagtttgcag cagtattgag
aggcactcct aaatggaata aacgctggag agaaaaaggc 2520caccaatatc
ggaaaggtct cagaggttcg ccagaagcca gataaaagtc ccggtgaatt
2580ttatgagagg ctgtgcgagg cttaccagct ttacatgcca cttgacccag
aggctgcggg 2640taatcagtgt atggttaatg tggcatttgt aagccaggtg
caagaagaca tcggaagtta 2700gaagggtttg aaggtgtgaa tattacccag
cttatccagg tggctactaa ggtgtttgta 2760aatcagaagg aggaggccaa
gagaaaagct agatgcagag ctaaggaaaa ggcagacttg 2820ctggcggtgg
ccttagttgg aagagaaact ggttttgtga gaggatgtgg tcgtggttgc
2880ggtcatgata gaggacaaac taggtaaaac caggaagcta agccaggaca
agagggccaa 2940cttaggctta agggagatca atgtgtgaga tgcaagcaga
tgggacacta gaagaatgaa 3000tgccaaattt tccggtgccc ttgttaggaa
gagatttcct ccagaaattg caagcacaaa 3060tctcctttat accagaaggg
cacatgactc taaatctagg tcaaagaaaa gccatgataa 3120agacccttac
tgtcccaaca acagaggaat ggtaataatt tggg 3164291001DNAHomo sapiens
29gaaccggagg ctaccggtgc atgctagtgt ttgtctgcac tttctcaggg tgggttgagg
60catttcccac caggacaaag aaagctcggg aagtaaccag aatcttacta aaggacatta
120ttcctagatt tcgactgcct ctaactttag gatcagacaa tggcccagca
tttgtggcag 180aaatagtaca acagctaaca cagaggttaa aaatcaaatg
aaaactgcat acagcttatc 240acccatagag ttctggaaag ttgaaagaat
aaaccggaca ctcaaacagc cgttaaaaaa 300gttttgccat gaaactcatc
taagatggga tcaggtgctg cccatggtcc ttctctgagt 360caggtgcacc
cctactaaat taactgggta ttcaccctat aagatagtgt ttggccgaca
420ccctgatcat aactcagata aacggggatt taaaaaattg gggaattaac
cttaagaagg 480caaatgcaag ccttaggtga sgtctcgcag gaaatgcaag
gatgggtaag agaaagaata 540cctgttagcc tcacagatgc agtacaaccc
ttctaacctg gagactctgt ctgggtcaaa 600caatggaacc caaccacttt
agggccttta tgggatagtc cccatattgt gatcttgtct 660actcccactg
ctgttaaagt tgcaggtatc ataccttggg ttcatcatag ccggctgaaa
720ccagaagcag ccaccaccca ggaccagtgg acaagtcaac aaaacccaga
ccactcaaca 780tggctgatcc tgtggtgaaa ccaagccact gctgacaagg
acaactgccc tgcttcaacc 840acaccagagg ctggttggtc cacgcacggc
tgaagcttga ggaaacatcg agccctgttc 900tagtcacaca aatggaagct
gactagtcta tgcatggctg aagcctgagg aagtcaatga 960tacataagta
aatgtagact aaatttacaa acatagttat a 100130701DNAHomo sapiens
30acctttgcaa aatcatgcaa tgttgcagtc agctcgtcag ttggataaat taatctgagt
60gacctaggaa ttatctgctt cttaaggata catagatttc cctgagaaat catctgggtg
120cttttggaat ttgggggcag aaaatacagg atagtattat ctgacaattt
tctaattctt 180ctatggtaat tagtgtgttt ygattttttt tttatctcat
ctagattcag ttgctacaaa 240gtatattttc tttagaagac tatccttttt
attcatgcct ttaaatttat tggtacagag 300ttgtgcaagt tattccttta
tgatttattt aattctcctt tttctgtgac ttccctttta 360taattttctg
ttttgagtaa tgattttccc cttgttttct tagtaaattg gctggatatt
420tattttcaaa tttcttttca aggaactaaa ttttgtagtt ttgtattcta
ctttaaaaaa 480agtcatgtct catttttatc tcctttacct ttaaaaattc
cttccttttg tttttgtttt 540atttaatttg ttggattttt caaaaaacaa
aaactcctga gtcagatatt tgttctgttt 600gttttattct ttattttata
ccaatacaaa tttttacact aggaatttct ctgaaatgta 660taagctccct
cattggctct aaaatgtgat gttttctttt t 70131501DNAHomo sapiens
31ctctcttttt gctttgattt ctgggaggtg gattagcatt tactattaga ttcactattt
60aatttactct ttaagaacaa agataaagtg tagccagaca actgcttagg agtgtatcag
120tccaacaaga tgtacattga gctctaaaca aaatttaaaa atcttcatga
gccttagaat 180aagaaaaata ccttttacat tttaaaacag tgacttaaat
tttttttttt ttttactgta 240gcatatgagc mgccaccata actaacttat
tttgtatttc tagcttcacc taaagctatt 300tctggatgtg gctgctagtt
tgtcaaagtt aaataaagcg tgacgcatat tgttcaaagg 360caagcggaag
atctaacgtt tctttttgaa atataggaaa ctggagatat caggcaacag
420tggaaaagca tgcactttgg agaaaggtga aacctgaatt caattctctc
aaaatgtact 480tcgagcttca tccatttgca t 501321486DNAHomo sapiens
32tgtttctttc tctataatac ataaaataaa ttatattaat attctaggtt atatataata
60acacatataa ataaatataa aattatatta tatatagaaa tatatttttt atttttataa
120gtacgtattt atttgtaaac tgtaaaacca taataaagga gtaaaactga
catgaatata 180agtgaaatgg agggggttgt gtagacaata tgtttagctg
acaaatattt attgagcact 240tgtcctatgc caggcactgt ctgaagttct
gggaatacgc agggattaga caagttcttg 300ttctcataga gctgatatcc
tagtgtccgt ggcagggagg cagataataa actgacacat 360cactattttg
tcaggtggtg ctaagtgcca tggagacaca gtaggtgcag ggagggagaa
420taatgggaag ataccattgc aggtaggggg tgaggaatag ccttgctgga
cagggacata 480tgaacaaagg tctgagttgg gtgaggcagg atgccacaca
gacattggag gaggaaaatc 540tgagcagggg gcacagcaaa gccccaaggc
tgaggccaga tgaaggagca ggaggcaatg 600tggctggaga ggagggagca
aggggcagag tgttggtggt gaggtcaggg gcccagcagc 660ctgatccagg
ggacttgaac aggatggaag gactttgggt gcgttctgaa gaaggggaag
720ccactggaag scattaagta gaaaaaattg gaagtgagag taattatatg
tgaaagttgt 780tagagtcaca atggagtgac gatgaggcag gacaggtagt
caaggaagta agtgcagtta 840acacaatgag ccccagtatt cgcattgtaa
tccagctcat gcaagcacag ctatctcctg 900cagggaatat ttcccataga
cagcatttgc actttgattt tacctcttct caaacggacc 960ctgttctcat
gataatagta aaaaacacac ccctaggtgg agatttaaga tgctgatgaa
1020ttatgagatg tatgaacaag catgtacagc tactgcacat gtgcacccag
aggaccaccg 1080aggacatgct tactagcaac accttttctc accctcttat
gaataatcat gtaagagtcc 1140cataaaagga tttctccagc aataatcagt
gctgtccatt cagtggctca tgcctgtaac 1200ccagcacttt gggaggccga
ggtgggtgga tcacctgagg tcaggagttt gagaccagcc 1260tggtcaacat
ggtgaaacct cgtttctatt aaaaatacaa aaaaagtagc caggtgtaat
1320ggcacatgcc tgtaatccca gctacttggg aggctgaagc aggagaactg
attgaacctg 1380ggaggtggag gttgcagtga gtcatgactg tgccactgca
ctccagccaa cagagtaaga 1440ctctgttccc cctcggcccc ctgcaaaaaa
aaataataac aatgat 1486334000DNAHomo sapiens 33tttgttatgg acttatagca
attatttata caaaacataa gaattgttct gaaaaaatta 60aaaaatatat acctgcatgg
ctcataactg gaaatattat accaggaggc tttgtcactt 120ggtatcttta
tccttttact tattattttc ttttaattct acaggaagca gtaaattctt
180tatggttgga gtggatgaag aggtgccatg taatagctca gaaggcaaag
tcccttgttt 240taccagctgt ttaggcatcc atgtactcat ccttgatttg
aagggtttga gttaattcta 300tccttccaaa tcagccctta caatctcacg
tgcccacctc ttctgcaaca gtctctgggc 360ctagagggag gacgcttgca
atacaggatt ttttgcatgt tcccagtggc tccaccccat 420tctcccagtg
cacatgcagg cccttagtct gaacccacgc tacattgatt tatttccctt
480actgagcatg tgttaaggga tggaattttt caccatgggc atgtttaggc
aagccccctg 540tacacaatgt cctggatggc atttggctgt cttctgcctc
tatcattccc ccatctaaaa 600gagtacatct aactgccatt agaataagga
taagaagaaa gacaaagacc catcttaact 660gctttctgct gacagagggc
actgttttgg aaagacagca gttgggtctc cctcagaggc 720ctatctaagg
gtatctggta aaagggacca tcattcgagg ctctggttgc ataactgttt
780ggagtttgag ggcctgaagg cgagaagaga caaaccaggt tattagaaga
catgtaccaa 840aatgaaatgg gggaagggta aggacagttc aaaaatcctg
aggctgctga catgcccaga 900taactggtag ctgtagttgt gcctgctaag
atttgggtgc atgggacttg gctttggtta 960gctcccgtag tttattttcc
caaaaaagaa acctctgggt tatgggcacc ctatttactc 1020ccattatctg
gcaggatttg taggataatt gttcagaact agaatactgt tccagatttt
1080tacattaccc atgccttttg tttcttctga gctgcagcca gagatcactg
gttagttcac 1140aggaataagc agggttaatt taaaatgtag gcaaaaaact
taaaaacaac taatgagtct 1200agaatttaat gacaaatgta tgataagttt
tgaaacataa tttctttctc cccagtcctc 1260atttttgtta aaaacaaatc
ataataggag tgagttgttt gtaaaataaa ctttagtctt 1320acacttggtc
tgcttatttg cacaaagtac aacaagaata attattttta cataggcttt
1380ttaaattggc tttgatggaa ctctgttcca caaggaattt cagataggac
ttcataaaaa 1440tgagcccagc catgggtttg taccctctaa tacctatgag
ttgggtgaat tgctctcttc 1500ttgaggtccc aagaatatgc ggttcctggc
cctgttagaa agtgacattc tttactcact 1560acaggttagg gaacctgtat
ggggactgtg tagacaaagt atgaggctgg tttacccaag 1620gggcttttat
tggctctgca agttgagctt gattccttaa agggaaacat acccttccag
1680tcaaagttac agttactggt tggtaaagtt aaagttacag ctactggttg
ctaaagcaac 1740cagtttctcc aattgcatcc tgttgcaaaa gaaagtggat
tcttactgca ctgatgcaaa 1800taaccgtatt gccctaagtt aagaatactc
acagatagtt tccaaattct agaggaagca 1860ggcagagaga aaaaaaagtg
ctaaattttg ttcataggag tctgcattac tcaattatta 1920aagattgtgt
atagctcaaa aaaaaagatc agcactgttt taagctaaag tttaaaaaag
1980attacttcaa ttttctattr gttcagtctg ttcagttaac tcttgttctg
cttgatattt 2040gtgaacattt cagctcttca tgagtcctgt acgtttttcc
attattccaa tgtcacaatc 2100tccaaagtta tcagaaacct gcatttgaga
gcacctgtta cgtttctata gctgattata 2160aatcctattt gaagaagatc
aaaacaaaac aatggtctgt gaatagcaaa atgtccatgg 2220tagttacagt
caaaaacaca attgacaaag aaattttgtt atctctgtgg cttataatca
2280cctaacataa cacctttaat tgtgagtgat agcatatact tagatattag
aattttagaa 2340atcccataca gttttggagc atatattatt attcactaaa
atataaccca aagaagatta 2400aatatcattt tggcaatccc atgtacataa
atttgtcagg taatcctatt tacctctctt 2460ctggatgctc cagggatgct
aggggtcagg aaagacaacc ttgaagctga catttgattt 2520tgggaagccc
attaaatatg ttagaggttt aaaacaatgt tatgaagtag aattccagat
2580taccataaat tacttatttt gccaaaatga tgactcaaaa attttaaaac
aagccaaaaa 2640cttttactca tttagaggga agacttagat ttccaaagaa
tttgtctcct gtcttcactt 2700tcatttcctt ggcagtctat ctggaagaca
aactgaaata tttaattatc ctttactatt 2760acatgaaaat cttatacaag
ggagagaaag ccaaatttta ccctcacatt agtttactat 2820taatgtcaac
cccaattttt taatgaaacc ttatagacaa ttctatccaa tcttaaccag
2880tttgatcatg aggtaagatt cctgtaagcc ttttataacc ttttacaaat
tactaattta 2940ctaatctgct aaagagcaga ttagggcttt aagaaaacct
tgttgtgctt tcatttcaat 3000gctcagtttg tagaaaaacc atataataga
gttttggatt taatcaatgt tcacacacag 3060aatttctttt gcaagattaa
tttttagaaa cctcccacaa cttgtttaaa cctttagttt 3120atcttatcta
atttataata gtcctttaac cttaggcaaa aacttacatt tccatgcatt
3180cttataatct ttgactaata acacatttta ctgttcttac ataccttgca
tgtaaatcta 3240ttttcagtgg tctcaattac atgttataat ggtacctctt
agcacttttt aattttagtt 3300taaaacctgg taagtcgttt taattacgca
ctaggtgctg ataaagtttg attccttcca 3360gcataattaa gggtgtggtt
aattccatat gtccctgtgc cttaccaagt tgtaaagcag 3420gcagattgaa
cagttttcaa aggcaaaaga agccgtttac aaccttaaaa catttagcca
3480cctagtgcct gacttgcata atttagacca gctatttaca ttttaagaac
atttgcattt 3540tatcaattat ctttaagact acttttattt ctcagagatt
aaagtcacaa gaactaaaag 3600gcattatagc ttttatcttt cctccaaaaa
tatttgatct tagtgctgat ttttctttaa 3660gccaattaat tagagctctt
ttttataact acacagatgg agaagaagat tgagtgttat 3720aagatttttc
atttgcccat ctcctaattg gattcttggt ctctgggtgg gaccctttaa
3780gagcagggct aagaaagcat gcagtttatt ttcttttttt ctttttcttt
tctttttttt 3840tgagaaagag tttcactctt gttgcccagg ctggagtgca
atggtgcgat ctcagctcac 3900tgcaacctct gcctcccagg ttcaagcgat
tctcttacct cagcctccca agtggctgca 3960tgcagtttct agggcctaat
aaacaggcat agctggaaaa 4000344000DNAHomo sapiens 34cagctactgg
ttgctaaagc aaccagtttc tccaattgca tcctgttgca aaagaaagtg 60gattcttact
gcactgatgc aaataaccgt attgccctaa gttaagaata ctcacagata
120gtttccaaat tctagaggaa gcaggcagag agaaaaaaaa gtgctaaatt
ttgttcatag 180gagtctgcat tactcaatta ttaaagattg tgtatagctc
aaaaaaaaag atcagcactg 240ttttaagcta aagtttaaaa aagattactt
caattttcta ttagttcagt ctgttcagtt 300aactcttgtt ctgcttgata
tttgtgaaca tttcagctct tcatgagtcc tgtacgtttt 360tccattattc
caatgtcaca atctccaaag ttatcagaaa cctgcatttg agagcacctg
420ttacgtttct atagctgatt ataaatccta tttgaagaag atcaaaacaa
aacaatggtc 480tgtgaatagc aaaatgtcca tggtagttac agtcaaaaac
acaattgaca aagaaatttt 540gttatctctg tggcttataa tcacctaaca
taacaccttt aattgtgagt gatagcatat 600acttagatat tagaatttta
gaaatcccat acagttttgg agcatatatt attattcact 660aaaatataac
ccaaagaaga ttaaatatca ttttggcaat cccatgtaca taaatttgtc
720aggtaatcct atttacctct cttctggatg ctccagggat gctaggggtc
aggaaagaca 780accttgaagc tgacatttga ttttgggaag cccattaaat
atgttagagg tttaaaacaa 840tgttatgaag tagaattcca gattaccata
aattacttat tttgccaaaa tgatgactca 900aaaattttaa aacaagccaa
aaacttttac tcatttagag ggaagactta gatttccaaa 960gaatttgtct
cctgtcttca ctttcatttc cttggcagtc tatctggaag acaaactgaa
1020atatttaatt atcctttact attacatgaa aatcttatac aagggagaga
aagccaaatt 1080ttaccctcac attagtttac tattaatgtc aaccccaatt
ttttaatgaa accttataga 1140caattctatc caatcttaac cagtttgatc
atgaggtaag attcctgtaa gccttttata 1200accttttaca aattactaat
ttactaatct gctaaagagc agattagggc tttaagaaaa 1260ccttgttgtg
ctttcatttc aatgctcagt ttgtagaaaa accatataat agagttttgg
1320atttaatcaa tgttcacaca cagaatttct tttgcaagat taatttttag
aaacctccca 1380caacttgttt aaacctttag tttatcttat ctaatttata
atagtccttt aaccttaggc 1440aaaaacttac atttccatgc attcttataa
tctttgacta ataacacatt ttactgttct 1500tacatacctt gcatgtaaat
ctattttcag tggtctcaat tacatgttat aatggtacct 1560cttagcactt
tttaatttta gtttaaaacc tggtaagtcg ttttaattac gcactaggtg
1620ctgataaagt ttgattcctt ccagcataat taagggtgtg gttaattcca
tatgtccctg 1680tgccttacca agttgtaaag caggcagatt gaacagtttt
caaaggcaaa agaagccgtt 1740tacaacctta aaacatttag ccacctagtg
cctgacttgc ataatttaga ccagctattt 1800acattttaag aacatttgca
ttttatcaat tatctttaag actactttta tttctcagag 1860attaaagtca
caagaactaa aaggcattat agcttttatc tttcctccaa aaatatttga
1920tcttagtgct gatttttctt taagccaatt aattagagct cttttttata
actacacaga 1980tggagaagaa gattgagtgw tataagattt ttcatttgcc
catctcctaa ttggattctt 2040ggtctctggg tgggaccctt taagagcagg
gctaagaaag catgcagttt attttctttt 2100tttctttttc ttttcttttt
ttttgagaaa gagtttcact cttgttgccc aggctggagt 2160gcaatggtgc
gatctcagct cactgcaacc tctgcctccc aggttcaagc gattctctta
2220cctcagcctc ccaagtggct gcatgcagtt tctagggcct aataaacagg
catagctgga 2280aaacaaaaac ggattttgag agcgatctat ttgcctctaa
ttcctggggt tccatgagga 2340aaacagaggt ttctcccaaa atggaatcca
tggtgccttt tctgttttta ccaagcagcc 2400ctatgccatc agaaattatc
ttagggcctc tcatgtgcgc attaacactg gcaagacaag 2460gtggagaaaa
gtaattcagt caactgagaa aaaaatcttt ttccagcaaa acaagatcca
2520agaagagaaa aacataaagg cctttcaaat atacgtatag cttggatatc
cacttttaat 2580taagctgagc tctctttaag aaagtccttt taaatcccac
attacctgac ttcagccatg 2640ccaagcagcc aatatttctg gctttggaag
tttatcaaaa gaacctcaag gttcaaccaa 2700caagcctcaa ttaagacacg
cgaagcacac cagattggct acaccttaag accagcctca 2760taaaaccttt
ttcactaatg gaaactttac agggaatatc aacagtgatc cttatcattc
2820ttttcaccag tttacacagg gagagagagg ccaaaagtct gactggttaa
aaaactttta 2880tccttttgct ggcatgtcat gcttctgggt tcccttcccc
tgagctcaat tctaagccaa 2940ccagtttaag gtttgggaaa ttaacttttc
tcagtttgga ggatgcatcc tatgggaatg 3000tcctttagta cagggacaca
gtcacccatc tgtgaagaga ggacaaagga ggaaaaagta 3060aaaaaagatt
tttttcaaag gctccccagg ggttcaggat gcatttgaaa gggggacaga
3120ttgaagatga atggctactc atctagaaag aggggagcca gacatccctg
gttcctttct 3180ctttctagga aatagccagg gtatgtgagg gaaagaagga
acaagcatcc attttccttc 3240ttccgtcctt atgtccccaa gtcctgacaa
cctcgacagg gtgccaccca tgggtgccaa 3300tacggttctc acccatggta
acaggggacc tagtggatgg gattatccac tgttacccac 3360aaactgtctt
tccccctgct ctcaatagcc ttcaagtgcc ctagacctca tttaggccat
3420tgatactagt atgaccttta tccatgaaac aagaggcttg gcttaattgt
caggaattag 3480tcatgctcac ctatactgtg ctttttaatt tttgttgttg
tctgcctctg gatccctccg 3540atgcagttat ctttcctagg gcttctacat
gaagcttgga attgagtttg ggacaaaaga 3600actgcctcag taggtgggtg
catggactca tcaatcccca ggtgtccctc accagtctgg 3660ctgctgccgc
cttatcataa gctgaaggct aaggtgcaac tgtgaaatta ggtccttctc
3720aaacaaggga gggaaaatgg tgtcctgtga attagggtcc tggtctaata
agatgccttc 3780caaaaggaag aaaacttctg gcacagagaa gacccctcta
cccgcagggc tgtgttatta 3840ggttggtgcg aaagcaattg tggtgcccat
cattctaagt aatgacaaaa accacaacta 3900ctttcacacc agcctactaa
ctcatgactt ggtggacaaa agaaaataac aacaacaaca 3960acagcttaaa
tgcagggctg tgtttactgc tgacaaggtg 4000351191DNAHomo sapiens
35tgctagattt tgcaattgat tgcaaaatca gttttgcaat cagttgcaag tttcttgacc
60cattcactgg attgtgattg tgttacaaga ccaagtcaag attatttgac ctcatagcac
120tttactcttt aacagctctc tccttgaaat attaccttcc cgcactattc
atgaacatat 180cagcccacag atttcctcct acctctttgg ctattccttc
tcagtctcct tttaagattt 240ttcttactca ggcatctttg ggtgaaagtc
cctcaatatc tggtcttact caaaactgcc 300tctcactcac tactctctcc
ctaggcaatc ctatcaatgt ccactgtact gtatgcatga 360aatgactcac
aaatttttgt ctctaataaa gactttactt tgagtcttgg atctgaagag
420atatgtcccc tggatctctt aaaagcatat taagcttaac atattcaaaa
ccaaactcat 480aatctctatt accttgcatc ccaccaaact ggtctttttc
atcaaacccc atcaaaaaga 540tctcagcaat tcatctaatt atgcatgcaa
gaaacttaga ggtcatcttt gacatgtcct 600cttcaccatt atatccgatc
tatcacctgg tcctgccaat gttgcttact aaatgtccct 660ccaggaataa
attttctcta gtccttttca taagccaaat tcggtctcct gtagactatt
720attagtaacc tgctacttca cttatctgca tccaacctgt tccccaaaat
atagtcaaaa 780tgatcttttc tatacacaag
tctgatcata tggctcctra ataaaattat gtttttctgg 840aggaagtcac
aactccttaa aaaattcttg tacctgccta cctttccagt cccatctcat
900tatggactcc ttcctgcatg ctcttcttca atatattggt tatctttcag
tcccttgagt 960ttgctatgcc agagggcctt tgcaaatgct ggtcccttgc
ttgaaatgct ctattctttg 1020cctcaagtga tcctcctacc tcggcctccc
aaagtgctgg gattacaggc atggagccaa 1080cacacctggc cttcacatct
atttttaatc caagtaattc tagggtcaaa taatactgaa 1140atctcgctaa
gtatcaaacg ctgcttttaa ctgaagaaag tttactttgt t 119136844DNAHomo
sapiens 36atttcctcaa cagaaaattc ctgtaatcag tattttcatg aacttaaccc
tcgtgtttgg 60ggaaggacta ggcactatga caaattctgc tgtctaaaaa tactttttta
ggggctgggc 120atggtggctc acacccataa tcccagcact ttgggaggcc
aaagggggca gatcacctga 180ggtcaggagt ttgaaaccag cctggccaat
atgatgaaac cccgtctcta ctaaaaatac 240aaaaattagc caagggtggt
ggcacacact tgtaatccta gctactcggg aggcagaggc 300cggagaatcg
cttgaacccg ggatgcagag gttgcagtga gccaagatcg tgccactgca
360ctccagcctg ggtgacaaag cgagaccctg tcacacacaa acacacacac
acacacacac 420acacaaggtg acaaattgat ggagtggagg ctctgcagtc
agatatagca aatttgaacc 480ctgacttgga taatacagat ygcgagattg
gagcaatgac taaagcctct acatcttgat 540gttctggact agaaaattag
gataataaaa gctatctcct agagttgttc tgacaattag 600accaaaagag
ataatgatgt agagacctca gcaaagcaca aggcctagtc actagccgtg
660ctccgggagg gctgtccaaa agcaggaaga acaagggcaa agaaactcca
tggaactcac 720tttcccacca gggagtgaac cgcggcgtca tgctccattc
tgagtagctc ccagccgagg 780ccgccctcac cctcccgtaa taaggttcct
gtatgtctga ggtttcactg gtaaggtcac 840aaga 84437801DNAHomo sapiens
37aaggtttccc aaaatattta ttgaaagact tgaaatctag ctttctagac acataataag
60gaagatagac ggtatctata ctcggtaatc tacatggtga cagcagtttc attccatcac
120aattaaagca gaaccacaac atatattgag tataatttga tgttttaaaa
ttattattta 180tttataataa gtcttgaact tagctgtaat gacagacttc
tcttttaaaa taatatctca 240ttgtttatcc tattctaaac gcaagggata
taacagtatt atagcccatg aactggatac 300accaaagtga aagttttcaa
aattataaat ttgtcttgtg ctgttgaaaa tcccttagag 360acaggaatgg
attcaggtat tctggggtct gaaatttata yaatcttggt ccatttaatg
420tttctataac agaacacctg aggctaggta attgataagg aaaagaggtg
tacttagcca 480atgttctgca gcctgggaag ttacaagaaa tgtgctgcca
gcatccactt ggcttctggt 540gagagctttt catgctgcat gagaacatgc
tagagaaggt caatggggaa aacagatcgt 600gtgaagaggc caaactcaag
gggcatcctg gctttacaac aaccactctc atagaaacat 660ttccatgaca
aattcagtct tgcaagagtg agaactcact caactgcagc aataatggta
720ccaagccatt catgagtgct ccatccccat gacccaaaca cctcctacga
ggccctactt 780ccaacaccac cacactaagg a 80138801DNAHomo sapiens
38atattaagct tttcttttct gtttgttttt gttttgttta gtttttaatc ctgtcttaga
60agaacttatc tttattctca aaattaaatg taattttttt agtgacaaag aagaaaggaa
120acctcattac tcaatccttc tggccaagag tgtcttgctt gtggcgcctt
cctcatctct 180atataggagg atcccatgaa tgatggttta ttgggaactg
ctggggtcga ccccatacag 240agaactcagc ttgaagctgg aagcacacag
tgggtagcag gagaaggacc ggtgttggta 300ggtgcctaca gagactatag
agctagacaa agccctccaa actggcccct cctgctcact 360gcctctcctg
agtagaaatc tggtgaccta aggctcagtg yggtcaacag aaagctgcct
420tcttcacttg aggctaagtc ttcatatatg tttaaggttg tctttctagt
gaggagatac 480atatcagaga acatttgtac aattccccat gaaaattgct
ccaaagttga taacaatata 540gtcggtgctt ctagttatat gcaagtactc
agtgataaat ggattaaaaa atattcagaa 600atgtattggg gggtggagga
gaataagagg cagagcaaga gctagagaat tggtttcctt 660gcttccctgt
atgctcagaa aacattgatt tgagcataga cgcagagact gaaaaaaaaa
720tttactttga tctctgtttt tgaattctta ttatttatat tttgcttact
accttttttg 780ccttttgtcc ttttgtggag a 80139701DNAHomo sapiens
39atttgagggc aagcaagggg tctgtgtgct ggagaagagt gaggaaggtg agaattaggg
60agtgaggcct gggagattat gaggaaagga aacagatcat acagcgcctt ggaggccatt
120ataaagactt tggtttttac ccttatgaga tgggaagcta ttggcggttt
tagagcagga 180aagtgacatg atctgattta tgttccaagg ctcatgctgg
ccaccttgtt aagacaaaac 240tggagggagg caagcagagc ggggacacca
atgaggtaac catagtgacc atccagagga 300gaaatgatgg tggcctggaa
taggtagttc tgagaagtgt tgtattttgg aggtagatca 360atagaattta
ttggtgcatt gaatatatat gatgtgaaag aaagcgggga gacaaagata
420acctcaacgc ttttggcctg agcagctgta agactgggat tgcatttgat
cacagggcaa 480gctcagtcgg gctcaaaact stttgctcct tcctggctgg
aacttcgtgt gggcctaaga 540tgtttaactg gaatttcatc tggcagactt
aaacattgtg ttcttctttt aaaagctcaa 600ataacaaata ttccaaaatg
taaagcaaaa aaaggattta ttgaaatcat gtgacaatat 660atccctaaca
ccatgaagaa gatgacaatt atgatttcca t 701
* * * * *