Methods for Identifying Risk of Low Bmd and Treatments Thereof

Information

  • Patent Application
  • 20070292849
  • Publication Number
    20070292849
  • Date Filed
    December 29, 2005
    18 years ago
  • Date Published
    December 20, 2007
    16 years ago
Abstract
Provided herein are methods for identifying a risk of low BMD in a subject, reagents and kits for carrying out the methods, methods for identifying candidate therapeutics for treating low BMD-related disorders, such as osteoporosis, and therapeutic and preventative methods applicable to osteoporosis. These embodiments are based upon an analysis of polymorphic variations in nucleotide sequences within the human genome.
Description
FIELD OF THE INVENTION

The invention relates to genetic methods for identifying susceptibility to low bone mineral density (BMD) and/or bone damage generally associated with human diseases, and in particular to osteoporosis, and treatments that specifically target the disease.


BACKGROUND

Osteoporosis is a common disease characterized by low bone mineral density (BMD), deterioration of bone micro-architecture and increased risk of bone damage, such as fracture. Common types of osteoporosis include postmenopausal and senile osteoporosis, which generally occur later in life, e.g., 70+ years.


Osteoporosis is a major public health problem which affects quality of life and increases costs to health care providers. It is estimated that 44 million Americans and 100 million people worldwide are at risk for osteoporosis. In the United States today, 10 million individuals are estimated to already have the disease and almost 34 million more, or 55% of the people 50 years of age and older, have low bone mass, which puts them at increased risk of developing osteoporosis and related fractures. Of the 10 million Americans estimated to have osteoporosis, eight million are women and 2 million are men. These numbers are growing as the elderly population increases. It is estimated that by the middle of the next century the number of osteoporosis sufferers will double in the West, but may increase six-fold in Asia and South America. The estimated national direct expenditures (e.g., hospitals and nursing homes) for osteoporotic and associated fractures was $17 billion in 2001 ($47 million each day)—and the cost is rising (See National Osteoporosis Foundation; http://www.nof.org/osteoporosis/stats.htm).


Fracture is the most serious endpoint of osteoporosis, particularly fracture of the hip which affects up to 1.7 million people worldwide each year. One in two women and one in four men over age 50 will have an osteoporosis-related fracture in their lifetime. It is estimated that by the year 2050, the number of hip fractures worldwide will increase to over 6 million, as life expectancy and age of the population increase (See Spangler et al. “The Genetic Component of Osteoporosis Mini-review”; http:www.csa.com.osteointro.html).


Peak bone mass is mainly genetically determined, though dietary factors and physical activity can have positive effects. Peak bone mass occurs when skeletal growth ceases, after which time bone loss starts. In contrast to the positive balance that occurs during growth, in osteoporosis, the resorbed cavity is not completely refilled by bone and BMD decreases. Based on studies of family histories, twin studies, and racial factors, some attribute 50-60% of total bone variation (e.g., Bone Mineral Density to genetic effects and suggest there may be a predisposition for osteoporosis.


Osteoporosis can be considered a complex genetic trait with variants of several genes underlying the genetic determination of the variability of the phenotype. Low BMD is an important risk factor for fractures, the clinically most relevant feature of osteoporosis. Segregation analysis in families has shown that BMD is under polygenic control. In addition, biochemical markers of bone turnover have shown to have strong genetic components. Several candidate genes have been analyzed in relation to BMD, but the most widely studied gene in this respect, the vitamin D receptor (VDR) gene, explains only a small part of the genetic effect on BMD. Numerous studies, focusing on the BsmI allele of the vitamin D receptor gene have concluded that absence of the restriction site correlates with low bone mineral density.


SUMMARY

It has been discovered that certain polymorphic variations in human genomic DNA are associated with the occurrence of low bone mineral density (BMD) and/or bone damage generally associated with human diseases, and in particular to osteoporosis. In particular, polymorphic variants in loci containing CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1/TNIP1 regions in human genomic DNA have been associated with risk of low BMD.


Thus, featured herein are methods for identifying a subject at risk of low bone mineral density (BMD) and/or bone fracture, which indicates bone damage and related conditions such as osteoporosis in a subject. The methods comprise detecting the presence or absence of one or more of the polymorphic variations described herein in a human nucleic acid sample. In an embodiment, two or more polymorphic variations are detected and in some embodiments, 3 or more, or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more polymorphic variants are detected.


Also featured are nucleic acids that include one or more polymorphic variations associated with occurrence of low BMD, as well as polypeptides encoded by these nucleic acids. In addition, provided are methods for identifying candidate therapeutic molecules for osteoporosis and other low BMD-related disorders, as well as methods for treating osteoporosis in a subject by identifying a subject at risk of low BMD and treating the subject with a suitable prophylactic, treatment or therapeutic molecule.


Also provided are compositions comprising a cell from a subject suffering from low BMD or at risk of low BMD, and a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1/TNIP1 nucleic acid, with a RNAi, siRNA, antisense DNA or RNA, or ribozyme nucleic acid designed from a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence, or a nucleic acid that hybridizes to such a nucleotide sequence under stringent conditions. In an embodiment, the RNAi, siRNA, antisense DNA or RNA, or ribozyme nucleic acid is designed from a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence that includes one or more low BMD associated polymorphic variations, and in some instances, specifically interacts with such a nucleotide sequence. Further, provided are arrays of nucleic acids bound to a solid surface, in which one or more nucleic acid molecules of the array have a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence, or a fragment or substantially identical nucleic acid thereof, or a complementary nucleic acid of the foregoing. Featured also are compositions comprising a cell from a subject having low BMD or at risk of low BMD and/or a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 polypeptide, with an antibody that specifically binds to the polypeptide. In an embodiment, the antibody specifically binds to an epitope in the polypeptide that includes a non-synonymous amino acid modification associated with low BMD (e.g., results in an amino acid substitution in the encoded polypeptide associated with low BMD). In an embodiment, the antibody specifically binds to an epitope comprising an arginine corresponding to position 120 in a PROL4 polypeptide (SEQ ID NO: 12).




BRIEF DESCRIPTION OF THE DRAWINGS


FIGS. 1-4 show the position of each SNP in the chromosome on the x-axis, while the y-axis provides the negative logarithm of the p-value comparing the estimated allele frequency in the cases to that of the control group. Also shown in the figures are exons and introns of the genes in approximate chromosomal positions. More specifically, FIG. 1 shows proximal SNPs in a CETP region in genomic DNA. FIG. 2 shows proximal SNPs in a PROW region in genomic DNA. FIG. 3 shows proximal SNPs in a GRID2 region in genomic DNA. FIG. 4 shows proximal SNPs in a PDE4D region in genomic DNA. FIG. 5 shows proximal SNPs in a GPX3/TNIP1 region in genomic DNA.




DETAILED DESCRIPTION

It has been discovered that polymorphic variants described in a CETP, PROL4, GRID2, PDE4D and GPX3/TNIP1 loci in human genomic DNA are associated with occurrence of low BMD in subjects. Thus, detecting genetic determinants in and around this locus associated with an increased risk of low BMD occurrence can lead to early identification of a risk of low BMD, or its associated disorders such as osteoporosis, and early application of preventative and treatment measures. Associating the polymorphic variants with low BMD also has provided new targets for diagnosing low BMD, for prognosing osteoporosis, and methods for screening molecules useful in osteoporosis treatments and osteoporosis preventatives.


Cholestery ester transfer protein (CETP) transfers cholesteryl esters between lipoproteins. The transfer of insoluble cholesteryl esters among lipoprotein particles (HDL to LDL) by CETP is a step in normal cholesterol homeostasis. The lipoprotein phenotype of CETP deficiency, which is characterized by increased levels of HDL and decreased levels of low density lipoprotein (LDL), appears to have antiatherogenic potential. Bone mineral density is reduced by atherogenic diets (increased LDL/HDL ratios), possibly as a result of a shift in the balance of bone marrow stromal cells away from osteoblasts and towards adipocytes, which could result in reduced bone synthesis during remodeling. Lipoproteins may directly regulate bone density via the LRP5, the low-density lipoprotein receptor related protein 5. LRP5 was cloned from an osteoblast cDNA library (Dong, et al.: Biochem Biophys Res Commun. 1998 Oct. 29; 251(3):784-90) and mouse knockouts show a reduced BMD phenotype (Kato et. al.: J Cell Biol. 2002 Apr. 15; 157(2):303-14). A G171V mutation in LRP5 resulted in increased numbers of osteoblasts, increased AP activity, and increased trabecular number and thickness in mice (Babij et al.: J Bone Miner Res. 2003 June; 18(6): 960-74). The human G171V mutation was found to have the same phenotype, presumably by increasing WNT signaling in osteoblasts (Mao et. al.: Mol Cell. 2001 April; 7(4):801-9). Overall, there is evidence that lipoprotein profiles play a role in osteoblast differentiation. Provided is a method for treating osteoporosis or low bone mineral density by modulating a CETP function in a subject suffering from osteoporosis or low bone mineral density. CETP inhibitors and methods of making them are described in U.S. Pat. No. 6,586,613 (Substituted tetrahydronaphthaline and analogous compounds); U.S. Pat. No. 6,562,976 (4-phenyltetrahydrochinoline utilized as an inhibitor of the cholesterol ester transfer protein); U.S. Pat. No. 6,387,929 (4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein); U.S. Pat. No. 6,291,477 (Tetrahydroquinolines, processes for their preparation, pharmaceutical compositions containing them, and their use to prevent or treat hyperlipoproteinaemia); U.S. Pat. No. 6,218,431 (Substituted biphenyls); U.S. Pat. No. 6,207,671 (Cycloalkano-pyridines); U.S. Pat. No. 6,127,383 (2-aryl-substituted pyridines); U.S. Pat. No. 6,121,330 (5-Hydroxyalkyl substituted phenyls and their use in medicaments for the treatment of arteriosclerosis and hyperlipoproteinaemia); U.S. Pat. No. 6,069,148 (Cycloalkano-pyridines); U.S. Pat. No. 6,063,788 (Bicyclic-fused pyridines); U.S. Pat. No. 5,932,587 (Heterocyclic-fused pyridines); U.S. Pat. No. 5,925,645 (2-aryl-substituted pyridines); U.S. Pat. No. 6,753,346 (CETP activity inhibitor); U.S. Pat. No. 6,706,881 (Methods for preparing CETP inhibitors); U.S. Pat. No. 6,689,897 (Intermediates of CETP inhibitors); U.S. Pat. No. 6,600,045 (Methods for preparing CETP inhibitors); U.S. Pat. No. 6,573,383 (Preparation of anhydrous CETP inhibitor); U.S. Pat. No. 6,555,113 (Modulation of cholesteryl ester transfer protein (CETP) activity); U.S. Pat. No. 6,426,365 (CETP activity inhibitors); U.S. Pat. No. 6,410,022 (Modulation of cholesteryl ester transfer protein (CETP) activity); U.S. Pat. No. 6,410,020 (Monoclonal antibody reactive to human CETP and assay method for human CETP); U.S. Pat. No. 6,140,474 (Monoclonal antibody reactive with human-origin CETP and method of quantifying human-origin CETP); U.S. Pat. No. 5,948,435 (Methods of regulating CETP genes, enzymes and other compound, and pharmaceutical composition therefor); U.S. Pat. No. 5,519,001 (CETP inhibitor polypeptide antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments); and U.S. Pat. No. 5,512,548 (CETP inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments).


PROL4, also known as Lacrimal proline rich protein (LPRP) is a member of the proline-rich secreted protein family and contains a conserved acidic N-terminal region. It has 45.5% amino acid homology to a salivary Parotid acidic protein (PRH1). PRH1 and related proline-rich (salivary) proteins act as potent inhibitors of hydroxyapatite crystal growth and bind calcium with a strength that suggests that they are important in maintaining the concentration of ionic calcium in saliva. The N-terminal region of salivary proline-rich proteins, which is also the region of strongest homology to PROL4, mediates this binding. It is expected that PROL4 plays a role in maintaining calcium levels during bone remodeling, and that a loss of function of PROL4 facilitates bone loss. Provided is a method of treating low BMD or osteoporosis by increasing expression of PROL4 or otherwise increasing levels of active PROL4 in a patient suffering from low BMD or osteoporosis.


Human glutamate receptor delta-2 (GRID2) is a member of the family of ionotropic glutamate receptors that are excitatory neurotransmitter receptors in mammalian brain. A point mutation in mouse GRID2, associated with the phenotype named “lurcher” in the heterozygous state, leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. Glutamate receptors have been detected in osteoblasts and osteoclasts and may regulate bone resorption. Provided is a method of treating low bone mineral density or osteoporosis by modulating GRID2 function in a patient suffering from low BMD or osteoporosis.


PDE4D encodes cyclic AMP-dependent phosphodiesterase 4D. Phosphodiesterases are a superfamily of enzymes involved in degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Manganiello V C, et al.: Arch Biochem Biophys 1995, 322(1):1-13; and Beavo J A: Physiol Rev 1995, 75(4):725-748). cAMP and cGMP are important second messengers participating in the response of various cells to hormones. In osteoblasts, cAMP produced in response to parathyroid hormone or prostaglandins regulates osteoblastic differentiation (Farndale R W, et al. Biochem J 1988, 252(1):263-268; Kumegawa M, et al. Calcif Tissue Int 1984, 36(1):72-76; Ishizuya T, et al. J Clin Invest 1997, 99(12):2961-2970; and Partridge N C, et al. J Cell Biochem 1994, 55(3):321-327), which leads to increases in cancellous bone volume as indicated by experiments in animal models (Jee W S, et al. Bone 1987, 8(3):171-178; High W B: et al. Bone 1987, 8(6):363-373; Reeve J: et al. J Bone Miner Res 1996, 11(4):440-445; and Finkelstein J S, et al. N Engl J Med 1994, 331(24): 1618-1623). Intracellular levels of cAMP are regulated by G protein-coupled adenylyl cyclase (Casperson G F, Bourne H R: Annu Rev Pharmacol Toxicol 1987, 27:371-384), and degradation is mediated by the phosphodiesterases. The phosphodiesterase superfamily consists of seven families, PDE1-7, distinguished by substrate specificity, chromatographic behavior during purification, and affinity for biochemical activators and inhibitors. Of these, the PDE4 family is specific for cAMP and is selectively inhibited by rolipram. Four PDE4 genes, 4A, 4B, 4C, and 4D, have been cloned from rat and humans, all of which are predicted to have multiple protein products due to alternate spicing of RNAs. PDE4 inhibitors have been shown to increase bone formation in normal mice (Kinoshita T, et al. Bone 2000, 27(6):811-817) and to ameliorate loss of bone mass in animal models of osteopenia (Miyamoto K, et al. Biochem Pharmacol 1997, 54(5):613-617; and Waki Y, et al. Jpn J Pharmacol 1999, 79(4):477-483). PDE4A and PDE4D are expressed in two common mouse osteoblastic cell lines, ST2 and MC3T3-E1, that represent different stages in the osteoblast differentiation pathway (Wakabayashi S, et al. J Bone Miner Res 2002, 17(2):249-256). PDE4 inhibition with rolipram increased BMP2-induced alkaline phosphatase activity, a marker of early osteoblast differentiation in ST2 cells. Furthermore, rolipram increased the expression of alkalic phosphatase, osteopontin, collagen type I and osteocalcin in the same osteoblast precursor cells (Wakabayashi S, et al. J Bone Miner Res 2002, 17(2):249-256).


Provided herein is a method for treating osteoporosis or low bone mineral density by modulating a PDE4 function in a human suffering from osteoporosis or low bone mineral density. Modulation of PDE4D by PDE4D inhibitors may increase bone formation and treat an osteoporotic condition. PDE4D inhibitors and methods of making them are described in the following U.S. Pat. Nos. 6,218,400 (Treatment method using a cGMP-Specific PDE inhibitor), 5,891,896 (Tri-substituted phenyl derivatives useful as PDE IV inhibitors), 5,849,770 (Tri-substituted phenyl derivatives useful as PDE IV inhibitors), 5,712,298 (Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors), 5,491,147 (Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment). Also provided is a method of treating osteoporosis by decreasing expression of PDE4D or otherwise decreasing levels of active PDE4D in a subject suffering from low BMD. Provided also is a method of targeting pertinent information or administering preventative or therapeutic treatments to a subject based on a subject's PDE4D genotype.


SNP rs869975 is contained within the GPX3 gene, and the TNIP3 gene may not be ruled out due to linkage disequilibrium; therefore the GPX3/TNIP3 region is considered associated with low BMD. The GPX3 gene encodes the Plasma glutathione peroxidase 3 precursor. Glutathione peroxidase catalyzes the reduction of hydrogen peroxide, organic hydroperoxide, and lipid peroxides by reduced glutathione and functions in the protection of cells against oxidative damage. This enzyme, found mainly in the cytosol of mammalian cells, is unusual in its content of a selenocysteine residue in its active site that is encoded by a TGA opal codon. Selenium deficiency causes bone loss and might contribute to lower BMD. Osteoblasts produce glutathione peroxidase, possibly as a defense against hydrogen peroxide produced by osteoclasts during bone remodeling and thus may contribute to lower BMD. Provided is a method for treating osteoporosis or low bone mineral density by modulating a GPX function in a human suffering from osteoporosis or low bone mineral density.


In the TNIP1/NAF1/ABIN-1 pathway, NAF1 was identified by a yeast two-hybrid screen as an interacting protein to the HIV protein, Nef. Subsequently, it was found to be an A20-binding protein that is critical for the A20-mediated negative feedback regulation of NF-kappa B activation in response to tumor necrosis factor (TNF). As TNF is a critical effector of the pathogenesis of rheumatoid arthritis (RA), Gallagher et. al. (FEBS Lett. 2003 Sep. 11; 551(1-3):8-12), tested TNF-alpha-modulated gene expression in cultured primary human synoviocytes in vitro. Genes upregulated included TNIP1 and implicate TNIP1 as a potential modulator of TNF-alpha bioactivity in RA. The differentiation and functions of osteoclasts are stimulated and regulated by osteoblast/stromal cell derived factors, such as receptor activator of NFKB ligand (RANKL). Provided is a method for treating osteoporosis or low bone mineral density by modulating a TINIP function in a human suffering from osteoporosis or low bone mineral density.


Low BMD and Sample Selection


The present invention is applicable to any disease in which low BMD and/or bone fracture is a factor, and is therefore particularly concerned with diseases such as osteoporosis. Low BMD is defined by the World Health Organization as 2.5 standard deviations below the age-matched mean of bone mineral density for a given population. Bone damage may be defined as any form of structural damage such as fractures or chips of the bone, and degradation or deterioration of the bone other than normal wear and tear resulting from low bone mineral density or another cause. Such low BMD and/or bone damage is associated with osteoporosis.


Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures, especially of the hip, spine and wrist. In general, there are two types of osteoporosis: primary and secondary. Approximately 90% of all osteoporosis cases is idiopathic “primary osteoporosis”. Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women. “Secondary osteoporosis” is the result of an identifiable disease process or agent.


For some osteoporotic individuals, the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.


The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of “bone remodeling”. Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called “basic multicellular units” or “BMUs”. BMUs primarily consist of “osteoclasts”, “osteoblasts”, and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an “activated” BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by an osteoblast.


Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in osteoporotics, there is an increase in the number of BMUs that are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.


Preferred methods for the treatment of osteoporosis include an initial diagnostic step to determine the presence of the disorder. Initial diagnostic steps include determination of bone mass and rate of bone remodeling. The rate of bone remodeling can be determined by the measurement of biochemical markers. See, for example, Hui et al., “The Contribution of Bone Loss to Postmenopausal Osteoporosis” Osteoporosis Int. 30 (1990). Diagnosis of those at risk of developing osteoporosis also allows more effective preventive measures. Part of diagnosis includes specialized tests called bone density tests that measure bone density in various sites of the body. Such methods include the measurement of the radiodensity of skeletal radiographs, quantitative computerized tomography, single energy photon absorptiometry, and dual-energy photon absorptiometry. Diagnostic techniques among those useful herein are described in W. A. Peck et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation. A bone density test can detect the presence of low BMD before a fracture occurs, predict your chances of fracturing in the future, determine rate of bone loss, and monitor response to treatment.


Based in part upon selection criteria set forth above, individuals having low BMD can be selected for genetic studies. Also, individuals having a family history of low BMD or diagnosed with osteoporosis often are selected for genetic studies. Other selection criteria can include: a tissue or fluid sample derived from an individual characterized as Caucasian; sample derived from an individual of Caucasian paternal and maternal descent, case samples derived from individuals diagnosed with osteoporosis; control samples derived from individuals with normal or high BMD levels and no family history of osteoporosis; and sufficient genomic DNA for all allelotyping and genotyping reactions performed during the study. Phenotype information may included pre- or post-menopausal, familial predisposition, country or origin of mother and father, diagnosis with osteoporosis (date of primary diagnosis, age of individual as of primary diagnosis, osteoporosis-related fracture), biochemical measurements of markers of bone resorption (bone-specific alkaline phosphatase, urinary C-telopeptide of type I collagen, serum osteocalcin), current medication status (thyroid medication, hormone replacement therapy, steroid usage, bisphosphonates and cytotoxic agents for rheumatic diseases). Samples that meet the inclusion criteria and do not meet the exclusion criteria may be added to appropriate pools based on gender and disease status.


Polymorphic Variants Associated with Low BMD


A genetic analysis provided herein linked low BMD with polymorphic variant nucleic acid sequences in the human genome. As used herein, the term “polymorphic site” refers to a region in a nucleic acid at which two or more alternative nucleotide sequences are observed in a significant number of nucleic acid samples from a population of individuals. A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. A polymorphic site is often one nucleotide in length, which is referred to herein as a “single nucleotide polymorphism” or a “SNP.”


Where there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a “polymorphic variant” or “nucleic acid variant.” Where two polymorphic variants exist, for example, the polymorphic variant represented in a minority of samples from a population is sometimes referred to as a “minor allele” and the polymorphic variant that is more prevalently represented is sometimes referred to as a “major allele.” Many organisms possess a copy of each chromosome (e.g., humans), and those individuals who possess two major alleles or two minor alleles are often referred to as being “homozygous” with respect to the polymorphism, and those individuals who possess one major allele and one minor allele are normally referred to as being “heterozygous” with respect to the polymorphism. Individuals who are homozygous with respect to one allele are sometimes predisposed to a different phenotype as compared to individuals who are heterozygous or homozygous with respect to another allele.


In genetic analysis that associate polymorphic variants with low BMD, samples from individuals having low BMD and individuals not having low BMD often are allelotyped and/or genotyped. The term “allelotype” as used herein refers to a process for determining the allele frequency for a polymorphic variant in pooled DNA samples from cases and controls. By pooling DNA from each group, an allele frequency for each SNP in each group is calculated. These allele frequencies are then compared to one another. The term “genotyped” as used herein refers to a process for determining a genotype of one or more individuals, where a “genotype” is a representation of one or more polymorphic variants in a population.


A genotype or polymorphic variant may be expressed in terms of a “haplotype,” which as used herein refers to two or more polymorphic variants occurring within genomic DNA in a group of individuals within a population. For example, two SNPs may exist within a gene where each SNP position includes a cytosine variation and an adenine variation. Certain individuals in a population may carry one allele (heterozygous) or two alleles (homozygous) having the gene with a cytosine at each SNP position. As the two cytosines corresponding to each SNP in the gene travel together on one or both alleles in these individuals, the individuals can be characterized as having a cytosine/cytosine haplotype with respect to the two SNPs in the gene.


As used herein, the term “phenotype” refers to a trait which can be compared between individuals, such as presence or absence of a condition, a visually observable difference in appearance between individuals, metabolic variations, physiological variations, variations in the function of biological molecules, and the like. An example of a phenotype is occurrence of low BMD or clinically diagnosed osteoporosis.


Researchers sometimes report a polymorphic variant in a database without determining whether the variant is represented in a significant fraction of a population. Because a subset of these reported polymorphic variants are not represented in a statistically significant portion of the population, some of them are sequencing errors and/or not biologically relevant. Thus, it is often not known whether a reported polymorphic variant is statistically significant or biologically relevant until the presence of the variant is detected in a population of individuals and the frequency of the variant is determined. Methods for detecting a polymorphic variant in a population are described herein, specifically in Example 2. A polymorphic variant is statistically significant and often biologically relevant if it is represented in 5% or more of a population, sometimes 10% or more, 15% or more, or 20% or more of a population, and often 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more of a population.


A polymorphic variant may be detected on either or both strands of a double-stranded nucleic acid. Also, a polymorphic variant may be located within an intron or exon of a gene or within a portion of a regulatory region such as a promoter, a 5′ untranslated region (UTR), a 3′ UTR, and in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or a polypeptide. Polymorphic variations may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.


It was determined that polymorphic variations associated with an increased risk of low BMD existed in CETP, PROL4, GRID2, PDE4D and GPX3 nucleotide sequences. In the CETP locus, polymorphic variants at positions selected from the group consisting of rs7500979, rs2217332, rs8044804, rs2270835, rs2133783, rs247609, rs952440, rs881598, rs2291955, rs2518054, rs866038, rs1436425, rs173537, rs247611, rs166017, rs173538, rs193694, rs7205692, rs8048746, rs247618, rs183130, rs6499863, rs4783961, rs3816117, rs711752, rs708272, rs1864163, rs4369653, rs1864165, rs891141, rs891143, rs7205804, rs5885, rs1532625, rs1532624, rs289712, rs7499892, rs5883, rs289714, rs158480, rs289717, rs4344729, rs289718, rs289719, rs2033254, rs4784744, rs291044, rs8053613, rs5881, rs5880, rs7198026, rs5882, rs8045701, rs289741, rs1801706, rs289742, rs289743, rs289746, rs172337, rs289747, rs1566439, rs7205459, rs289749, rs289751, rs8059220, rs8058353, rs289735, rs289737, rs291042, rs1875236, rs821466, rs821465, rs4275846, rs289707, rs821463, rs289706, rs1167741, rs2052880, rs1167742, rs1183256, rs1651665, rs1651666, rs4784751, rs1651667, rs8052091, rs1684574, rs1684575, rs1672865, rs821470, rs1549669, rs291040 and rs289754 were tested for association with low BMD. Polymorphic variants at the following positions were associated with low BMD: rs166017, rs193694, rs7205804, rs1801706, rs7205459 and rs821465. At these positions in SEQ ID NO:1, a thymine at position 14328, a thymine at position 14996, a guanine at position 37336, a guanine at position 50109, a thymine at position 57618, and a guanine at position 68805 were associated with low BMD.


In the PROL4 locus, polymorphic variants at positions selected from the group consisting of rs523051, rs693620, rs2588349, rs2588350, rs619381, rs3759252, rs3759251, rs2418107, rs7303054, rs1838345, rs620878, rs2537817, rs1548803, rs667123, rs1838346, rs2159903, rs3944035, rs3741845, rs2110096, rs759055, rs589377, rs7960194, rs7978242, rs601051, rs4262797, rs2215714, rs1373434, rs2215715, rs612456, rs612808, rs689118, rs597468, rs592864, rs640372, rs7966559, rs654834, rs4763216, rs668521, rs669503, rs3906864, rs3906863, rs7957888, rs9300230, rs7306214, rs763839, rs2418105, rs666841, rs3851578, rs7138797, rs7295252, rs2418106, rs7299578, rs621112, rs3863320, rs1373432, rs1047699, rs1063193, rs2232959, rs2227296, rs1548804, rs2232958, rs2232957, rs2232956, rs1972571, rs3759250, rs3759249, rs1541525, rs2098248, rs2900550, rs7302130, rs4763583, rs4360778, rs1607695, rs1607694, rs2192139, rs7978300, rs7397871, rs4763217, rs2159900, rs10772370, rs7398682, rs2900551, rs2900552, rs2418214, rs2418215, rs965243, rs1117548, rs1520225, rs1520226, rs1520227, rs971919, rs2159901, rs2159902, rs2110099, rs7314847, rs7296003, rs4281556, rs4763219, rs3851579, rs3851580, rs1049119, rs2298866, rs2298865, rs2298864, rs2298863, rs3180393, rs2070837, rs7956204, rs2418216, rs3741844, rs4262798, rs2418217, rs2418218, rs7137492, rs2110100, rs1013312, rs4579993, rs1013313, rs7397106, rs2215716, rs2192140, rs4763589, rs1468697, rs2070837, rs3180393 and rs2298865 were tested for association with low BMD. Polymorphic variants at the following positions were associated with an increased risk of low BMD: rs2588350, rs619381, rs620878, rs759055, rs4262797, rs612808, rs3906863, rs7957888, rs763839, rs2418105, rs666841, rs3851578, rs7299578, rs621112, rs1047699, rs1548804, rs2232956, rs1520227 and rs2215716. At these positions in SEQ ID NO:2, a cytosine at position 2424, a cytosine at position 3625, a guanine at position 7097, an adenine at position 15688, a guanine at position 22861, a cytosine at position 24138, a cytosine at position 32459, an adenine at position 35151, a guanine at position 36930, an adenine at position 37490, a cytosine at position 38432, an adenine at position 38688, a guanine at position 42665, an adenine at position 43038, a cytosine at position 49075, an adenine at position 50773, an adenine at position 52107, a cytosine at position 75246, and a guanine at position 93715 were associated with risk of low BMD.


In the GRID2 locus, polymorphic variants at positions selected from the group consisting of rs1433661, rs1485009, rs7681947, rs1816432, rs1485018, rs1485017, rs7438397, rs6834311, rs1368717, rs1017391, rs2870701, rs7679839, rs1385404, rs1368716, rs4693316, rs1905707, rs1905708, rs1905709, rs3912442, rs2082553, rs6831638, rs5860329, rs2870702, rs2870703, rs1948016, rs6835836, rs1994253, rs1905710, rs1485019, rs978191, rs1385405, rs7694361, rs1905711, rs1905734, rs1485012, rs1485013, rs4692981, rs7670552, rs7670932, rs7688091, rs7440540, rs2171000, rs2870704, rs7655758, rs7661436, rs7662289, rs7667044, rs7691929, rs5860330, rs901013, rs901012, rs901011, rs1948018, rs2870705, rs1948017, rs1905733, rs1385408, rs1385409, rs1385410, rs1485026, rs1485027, rs2904483, rs1385406, rs1905732, rs2046418, rs2200377, rs1905731, rs1905730, rs975713, rs6820985, rs7670441, rs6810794, rs7676623, rs1154861, rs1032125, rs1485022, rs1485024, rs3913651, rs4693319, rs1872383, rs2200376, rs7668090, rs7692930, rs967096, rs6822249, rs6532405, rs1017897, rs7672674, rs7694568, rs2904484, rs7340830, rs1485033, rs2870706, rs1905729, rs4693320, rs6848749, rs6532406, rs6532407, rs1905728, rs6819866, rs1905727, rs7674069, rs1905724, rs1905723, rs1485020 and rs6814101 were tested for association with low BMD. Polymorphic variants at the following positions were associated with an increased risk of low BMD: rs1433661, rs7679839, rs1368716, rs1905707, rs1905708, rs1994253, rs1485019, rs1905734, rs1485012, rs7670552, rs7691929, rs1948018, rs1948017, rs1485024, rs7694568, rs4693320, rs6848749, rs6532406, rs6532407 and rs6819866. At these positions in SEQ ID NO:3, a thymine at position 206, a guanine at position 8612, an adenine at position 9285, a thymine at position 11866, a guanine at position 11958, a cytosine at position 28773, a thymine at position 29876, a cytosine at position 35588, a guanine at position 37663, a thymine at position 39375, a cytosine at position 43705, an adenine at position 48962, a cytosine at position 49110, an adenine at position 65050, a cytosine at position 78331, a thymine at position 85405, a guanine at position 86441, an adenine at position 86967, a cytosine at position 87121, and an adenine at position 90969 were associated with risk of low BMD.


In the PDE4D locus, polymorphic variants at positions selected from the group consisting of rs6886495, rs6450498, rs1472456, rs4700315, rs4700316, rs7714708, rs7710479, rs2968013, rs2968014, rs2968015, rs1391648, rs2055297, rs2055296, rs3989138, rs4700317, rs2036220, rs7727206, rs7723432, rs1546221, rs4479801, rs4395595, rs4395596, rs4699932, rs2936201, rs7356672, rs2936200, rs1909296, rs7703131, rs7445308, rs3087748, rs4321723, rs2968016, rs5868151, rs1874858, rs1874857, rs7712922, rs4631140, rs4469166, rs1078369, rs1078368, rs2968006, rs2968005, rs2936190, rs2409613, rs4415048, rs2968004, rs2968003, rs2968002, rs2936191, rs1498610, rs6874662, rs3060393, rs7729722, rs7733884, rs7714489, rs7735570, rs2936193, rs2291851, rs2291852, rs1498602, rs1995166, rs1498603, rs1498604, rs1498605, rs1948651, rs4699934, rs4700319, rs2279737, rs7720361, rs7706419, rs1006431, rs1353747, rs1498606, rs1353748, rs1553113, rs2968012, rs2968011, rs1498608, rs2936189, rs1498609, rs2968019, rs6891238, rs2968010, rs2968009, rs2936203, rs1498601, rs1498600, rs1498599, rs2936202, rs7730070, rs6450501, rs6450502, rs6889456, rs6894618, rs7706044, rs7707541, rs7712076, rs6892860, rs6867053, rs7737269, rs6864156, rs950447, rs2936196, rs7719347, rs1391649, rs1391650, rs1391651, rs1353749, rs10682149, rs5868153, rs1363882, rs2409626, rs2968018, rs954740, rs986067, rs6869400, and rs5010782 were tested for association with low BMD. Polymorphic variants at the following positions were associated with an increased risk of low BMD: rs7714708, rs1498602, rs4699934, rs1006431, rs1353747, rs1498608, rs1498609, rs2968010, rs2936202 and rs1391649. At these positions in SEQ ID NO:4, an adenine at position 1599, a cytosine at position 39626, a thymine at position 40356, a thymine at position 43555, a thymine at position 44066, a thymine at position 49652, a cytosine at position 51103, an adenine at position 57173, a guanine at position 63980, and an adenine at position 82591 were associated with risk of low BMD.


In the GPX3/TNIP1 locus, polymorphic variants at positions selected from the group consisting of rs1478398, rs1478397, rs1160114, rs1160113, rs1382323, rs1160112, rs7709870, rs7710643, rs7730467, rs6579829, rs6579830, rs6579831, rs6896232, rs1351131, rs1038074, rs1478396, rs6880512, rs4958858, rs4958431, rs4958432, rs6898463, rs4958859, rs4130064, rs4130065, rs4133119, rs4958860, rs4958861, rs4437356, rs4958868, rs1478400, rs6889375, rs1600159, rs6875892, rs4608909, rs2345000, rs4516840, rs2054440, rs707141, rs707142, rs841236, rs707143, rs70144, rs6869405, rs707145, rs707146, rs707148, rs707150, rs5872184, rs3763015, rs2042235, rs3763013, rs2042236, rs1946234, rs1946235, rs1946236, rs8177402, rs8177403, rs8177404, rs8177405, rs8177406, rs8177407, rs8177408, rs8177409, rs6888961, rs8177410, rs8177411, rs8177412, rs8177413, rs870407, rs870406, rs6873202, rs8177414, rs8177415, rs3805435, rs8177416, rs3792799, rs3792798, rs3828599, rs8177417, rs3792797, rs8177418, rs8177419, rs8177420, rs8177421, rs4958872, rs3792796, rs8177422, rs8177423, rs4958434, rs8177424, rs8177425, rs8177426, rs8177427, rs8177429, rs6889737, rs3792795, rs8177430, rs8177431, rs4958873, rs8177432, rs8177433, rs8177434, rs8177435, rs3763011, rs8177436, rs8177437, rs4958874, rs8177439, rs8177440, rs8177441, rs8177442, rs8177443, rs869975, rs869976, rs8177444, rs8177445, rs7721469, rs8177446, rs7704191, rs8177447, rs11548, rs2230303, rs7722386, rs8177448, rs8177449, rs2070593, rs8177450, rs8177451, rs8177452, rs8177453, rs8177454, rs3763010, rs8177455, rs8177456, rs736775, rs2277940, rs8177458, rs8177834, rs3924, rs2233312, rs2233311, rs2233310, rs2233309, rs4958875, rs2233308, rs2233307, rs2233306, rs2233305, rs2233304, rs2233303, rs2233302, rs2287719, rs2287720, rs7727034, rs7727250, rs7709800, rs3840312, rs2287721, rs6875293, rs3805434, rs2080982, rs2080983, rs2287722, rs2233301, rs2233300, rs4958876, rs2233299, rs2233298, rs2287723, rs2161359, rs7734456, rs4292439, rs4958878, rs6862024, rs3834819, rs2233297, rs2233296, rs2233295, rs2233294, rs7713028, rs7713223, rs7713567, rs888989, rs2233293, rs3749657, rs2233292, rs2112635, rs871269, rs3792794, rs6579837, rs3805433, rs5872186, rs2233291, rs2233290, rs2233289, rs4958435, rs4958880, rs1422673, rs2042234, rs3805432, rs3805431, rs2233288, rs2233287, rs3815720, rs3792792, rs3792791, rs2303018, rs3792790, rs4958436, rs2233286, rs2233285, rs7732451, rs2233284, rs1422674, rs3792789, rs4562032, rs6865077, rs1559126, rs3792788, rs1559127, rs3792786, rs6880110, rs6861227, rs3805430, rs1862364, rs4958881, rs3792785, rs6869605, rs6870205, rs4246047, rs4958882, rs3792784, rs3792783 and rs5872188 were tested for association with low BMD. Polymorphic variants at the following positions were associated with an increased risk of low BMD: rs1478398, rs1160114, rs1160113, rs1160112, rs4958858, rs4958431, rs6898463, rs4958859, rs4958860, rs4608909, rs707144, rs2042235, rs3763013, rs2042236, rs8177404, rs8177426, rs8177427, rs8177429, rs3792795, rs4958873, rs8177437, rs869975, rs8177447, rs11548, rs2277940, rs8177834, rs2233311, rs2233302, rs7727034, rs7727250, rs3805434, rs7734456, rs7713028, rs7713223, rs888989, rs3792794, rs4958880, rs1422673, rs3805432 and rs4958436. At these positions in SEQ ID NO:5, an adenine at position 231, a cytosine at position 582, a guanine at position 589, an adenine at position 1066, a thymine at position 5621, a guanine at position 5735, a cytosine at position 6658, a cytosine at position 7901, a thymine at position 15803, a cytosine at position 25599, a thymine at position 31203, a thymine at position 41624, a guanine at position 41671, an adenine at position 41825, a cytosine at position 43294, an adenine at position 46650, an adenine at position 46721, a guanine at position 46808, a guanine at position 47512, an adenine at position 47806, a guanine at position 49097, a guanine at position 50082, a thymine at position 51166, a cytosine at position 51493, a thymine at position 53187, an adenine at position 53699, a thymine at position 53929, a cytosine at position 58808, a cytosine at position 59187, a cytosine at position 59361, a cytosine at position 64049, a guanine at position 70882, an adenine at position 74131, a cytosine at position 74406, a cytosine at position 74740, a guanine at position 78432, a cytosine at position 82187, a cytosine at position 82698, an adenine at position 83214 and a thymine at position 86539 were associated with risk of low BMD.


Based in part upon analyses summarized in FIGS. 1-5, regions with significant association have been identified in loci associated with low BMD. Any polymorphic variants associated with low BMD in a region of significant association can be utilized for embodiments described herein. The following table reports such regions, where “begin” and “end” designate the boundaries of the region according to chromosome positions within the genomic sequence provided in SEQ ID Nos:1-5. The locus, the chromosome on which the locus resides and an incident polymorphism in the locus also are noted.

TABLE 1COMBINED ASSOCIATION RANGESIncident SNPLocusChromosomeBeginEndSizers1801706CETP16q21143286880554477rs1047699PROL412p1324249371591291rs1948017GRID24q222069096990763rs1498608PDE4D5q1215998259180992rs869975GPX3/TNIP15q232318653986308


Additional Polymorphic Variants Associated with Low BMD


Also provided is a method for identifying polymorphic variants proximal to an incident, founder polymorphic variant associated with low BMD. Thus, featured herein are methods for identifying a polymorphic variation associated with low BMD that is proximal to an incident polymorphic variation associated with low BMD, which comprises identifying a polymorphic variant proximal to the incident polymorphic variant associated with low BMD, where the incident polymorphic variant is in a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence. The nucleotide sequence often comprises a polynucleotide sequence selected from the group consisting of (a) a polynucleotide sequence of SEQ ID NO's:1-5; (b) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence encoded by a polynucleotide sequence of SEQ ID NO's:1-5; and (c) a polynucleotide sequence that encodes a polypeptide having an amino acid sequence that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-5 or a polynucleotide sequence 90% or more identical to the polynucleotide sequence of SEQ ID NO's:1-5. The presence or absence of an association of the proximal polymorphic variant with low BMD then is determined using a known association method, such as a method described in the Examples hereafter. In an embodiment, the incident polymorphic variant is a polymorphic variant associated with low BMD described herein. In another embodiment, the proximal polymorphic variant identified sometimes is a publicly disclosed polymorphic variant, which for example, sometimes is published in a publicly available database. In other embodiments, the polymorphic variant identified is not publicly disclosed and is discovered using a known method, including, but not limited to, sequencing a region surrounding the incident polymorphic variant in a group of nucleic samples. Thus, multiple polymorphic variants proximal to an incident polymorphic variant are associated with low BMD using this method.


The proximal polymorphic variant often is identified in a region surrounding the incident polymorphic variant. In certain embodiments, this surrounding region is about 50 kb flanking the first polymorphic variant (e.g. about 50 kb 5′ of the first polymorphic variant and about 50 kb 3′ of the first polymorphic variant), and the region sometimes is composed of shorter flanking sequences, such as flanking sequences of about 40 kb, about 30 kb, about 25 kb, about 20 kb, about 15 kb, about 10 kb, about 7 kb, about 5 kb, or about 2 kb 5′ and 3′ of the incident polymorphic variant. In other embodiments, the region is composed of longer flanking sequences, such as flanking sequences of about 55 kb, about 60 kb, about 65 kb, about 70 kb, about 75 kb, about 80 kb, about 85 kb, about 90 kb, about 95 kb, or about 100 kb 5′ and 3′ of the incident polymorphic variant.


In certain embodiments, polymorphic variants associated with low BMD are identified iteratively. For example, a first proximal polymorphic variant is associated with low BMD using the methods described above and then another polymorphic variant proximal to the first proximal polymorphic variant is identified (e.g., publicly disclosed or discovered) and the presence or absence of an association of one or more other polymorphic variants proximal to the first proximal polymorphic variant with low BMD is determined.


The methods described herein are useful for identifying or discovering additional polymorphic variants that may be used to further characterize a gene, region or loci associated with a condition, a disease (e.g., osteoporosis), or a disorder. For example, allelotyping or genotyping data from the additional polymorphic variants may be used to identify a functional mutation or a region of linkage disequilibrium. In certain embodiments, polymorphic variants identified or discovered within a region comprising the first polymorphic variant associated with low BMD are genotyped using the genetic methods and sample selection techniques described herein, and it can be determined whether those polymorphic variants are in linkage disequilibrium with the first polymorphic variant. The size of the region in linkage disequilibrium with the first polymorphic variant also can be assessed using these genotyping methods. Thus, provided herein are methods for determining whether a polymorphic variant is in linkage disequilibrium with a first polymorphic variant associated with low BMD, and such information can be used in prognosis/diagnosis methods described herein.


Isolated Nucleic Acids


Featured herein are isolated CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid variants depicted in SEQ ID NO's:1-10, and substantially identical nucleic acids thereof. A nucleic acid variant may be represented on one or both strands in a double-stranded nucleic acid or on one chromosomal complement (heterozygous) or both chromosomal complements (homozygous)).


As used herein, the term “nucleic acid” includes DNA molecules (e.g., a complementary DNA (cDNA) and genomic DNA (gDNA)) and RNA molecules (e.g., mRNA, rRNA, siRNA and tRNA) and analogs of DNA or RNA, for example, by use of nucleotide analogs. The nucleic acid molecule can be single-stranded and it is often double-stranded. The term “isolated or purified nucleic acid” refers to nucleic acids that are separated from other nucleic acids present in the natural source of the nucleic acid. For example, with regard to genomic DNA, the term “isolated” includes nucleic acids which are separated from the chromosome with which the genomic DNA is naturally associated. An “isolated” nucleic acid is often free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5′ and/or 3′ ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of 5′ and/or 3′ nucleotide sequences which flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. As used herein, the term “gene” refers to a nucleotide sequence that encodes a polypeptide.


The nucleic acid often comprises a part of or all of a nucleotide sequence in SEQ ID NO's:1-5, or a substantially identical sequence thereof. Such a nucleotide sequence sometimes is a 5′ and/or 3′ sequence flanking a polymorphic variant described above that is 5-1000 nucleotides in length, or in some embodiments 5-500, 5-100, 5-75, 5-50, 5-45, 5-40, 5-35, 5-30, 5-25 or 5-20 nucleotides in length. Other embodiments are directed to methods of identifying a polymorphic variation at one or more positions in a nucleic acid (e.g., genotyping at one or more positions in the nucleic acid), such as at a position corresponding to rs1801706 in the CETP gene, rs1047699 in the PROL4 gene, rs1948017 in the GRID2 gene, rs1498608 in the PDE4D gene, or rs869975 in the GPX3 gene.


Also included herein are nucleic acid fragments. These fragments often are a nucleotide sequence identical to a nucleotide sequence of SEQ ID NO's:1-10, a nucleotide sequence substantially identical to a nucleotide sequence of SEQ ID NO's:1-10, or a nucleotide sequence that is complementary to the foregoing. The nucleic acid fragment may be identical, substantially identical or homologous to a nucleotide sequence in an exon or an intron in a nucleotide sequence of SEQ ID NO's:1-5, and may encode a domain or part of a domain of a polypeptide. Sometimes, the fragment will comprises one or more of the polymorphic variations described herein as being associated with low BMD. The nucleic acid fragment is often 50, 100, or 200 or fewer base pairs in length, and is sometimes about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 2000, 3000, 4000, 5000, 10000, 15000, or 20000 base pairs in length. A nucleic acid fragment that is complementary to a nucleotide sequence identical or substantially identical to a nucleotide sequence in SEQ ID NO's:1-5 and hybridizes to such a nucleotide sequence under stringent conditions is often referred to as a “probe.” Nucleic acid fragments often include one or more polymorphic sites, or sometimes have an end that is adjacent to a polymorphic site as described hereafter. CETP nucleic acid fragments sometimes encode the mature protein from positions 182 to 1609 of the mRNA sequence (SEQ ID NO: 6), for example.


An example of a nucleic acid fragment is an oligonucleotide. As used herein, the term “oligonucleotide” refers to a nucleic acid comprising about 8 to about 50 covalently linked nucleotides, often comprising from about 8 to about 35 nucleotides, and more often from about 10 to about 25 nucleotides. The backbone and nucleotides within an oligonucleotide may be the same as those of naturally occurring nucleic acids, or analogs or derivatives of naturally occurring nucleic acids, provided that oligonucleotides having such analogs or derivatives retain the ability to hybridize specifically to a nucleic acid comprising a targeted polymorphism. Oligonucleotides described herein may be used as hybridization probes or as components of prognostic or diagnostic assays, for example, as described herein.


Oligonucleotides are typically synthesized using standard methods and equipment, such as the ABI™3900 High Throughput DNA Synthesizer and the EXPEDITE™ 8909 Nucleic Acid Synthesizer, both of which are available from Applied Biosystems (Foster City, Calif.). Analogs and derivatives are exemplified in U.S. Pat. Nos. 4,469,863; 5,536,821; 5,541,306; 5,637,683; 5,637,684; 5,700,922; 5,717,083; 5,719,262; 5,739,308; 5,773,601; 5,886,165; 5,929,226; 5,977,296; 6,140,482; WO 00/56746; WO 01/14398, and related publications. Methods for synthesizing oligonucleotides comprising such analogs or derivatives are disclosed, for example, in the patent publications cited above and in U.S. Pat. Nos. 5,614,622; 5,739,314; 5,955,599; 5,962,674; 6,117,992; in WO 00/75372; and in related publications.


Oligonucleotides may also be linked to a second moiety. The second moiety may be an additional nucleotide sequence such as a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), and others. Alternatively, the second moiety may be a non-nucleotide moiety such as a moiety which facilitates linkage to a solid support or a label to facilitate detection of the oligonucleotide. Such labels include, without limitation, a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, and the like. The second moiety may be attached to any position of the oligonucleotide, provided the oligonucleotide can hybridize to the nucleic acid comprising the polymorphism.


Uses of Nucleic Acid Sequence


Nucleic acid coding sequences (e.g., SEQ ID NO: 7-12) may be used for diagnostic purposes for detection and control of polypeptide expression. Also, included herein are oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide. Antisense techniques and RNA interference techniques are known in the art and are described herein.


Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. For example, hammerhead motif ribozyme molecules may be engineered that specifically and efficiently catalyze endonucleolytic cleavage of RNA sequences corresponding to or complementary to CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequences. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences, GUA, GUU and GUC. Once identified, short RNA sequences of between fifteen (15) and twenty (20) ribonucleotides corresponding to the region of the target gene containing the cleavage site may be evaluated for predicted structural features such as secondary structure that may render the oligonucleotide sequence unsuitable. The suitability of candidate targets may also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using ribonuclease protection assays.


Antisense RNA and DNA molecules, siRNA and ribozymes may be prepared by any method known in the art for the synthesis of RNA molecules. These include techniques for chemically synthesizing oligodeoxyribonucleotides well known in the art such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.


DNA encoding a polypeptide also may have a number of uses for the diagnosis of diseases, including low BMD, resulting from aberrant expression of a target gene described herein. For example, the nucleic acid sequence may be used in hybridization assays of biopsies or autopsies to diagnose abnormalities of expression or function (e.g., Southern or Northern blot analysis, in situ hybridization assays).


In addition, the expression of a polypeptide during embryonic development may also be determined using nucleic acid encoding the polypeptide. As addressed, infra, production of functionally impaired polypeptide is the cause of various disease states, such as osteoporosis. In situ hybridizations using polypeptide as a probe may be employed to predict problems related to low BMD. Further, as indicated, infra, administration of human active polypeptide, recombinantly produced as described herein, may be used to treat disease states related to functionally impaired polypeptide. Alternatively, gene therapy approaches may be employed to remedy deficiencies of functional polypeptide or to replace or compete with dysfunctional polypeptide.


Expression Vectors, Host Cells, and Genetically Engineered Cells


Provided herein are nucleic acid vectors, often expression vectors, which contain a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or a substantially identical sequence thereof. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid, or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors may include replication defective retroviruses, adenoviruses and adeno-associated viruses for example.


A vector can include a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence in a form suitable for expression of an encoded target polypeptide or target nucleic acid in a host cell. A “target polypeptide” is a polypeptide encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or a substantially identical nucleotide sequence thereof. The recombinant expression vector typically includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. The term “regulatory sequence” includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences. The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, and the like. Expression vectors can be introduced into host cells to produce target polypeptides, including fusion polypeptides.


Recombinant expression vectors can be designed for expression of target polypeptides in prokaryotic or eukaryotic cells. For example, target polypeptides can be expressed in E. coli, insect cells (e.g., using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.


Expression of polypeptides in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion polypeptides. Fusion vectors add a number of amino acids to a polypeptide encoded therein, usually to the amino terminus of the recombinant polypeptide. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant polypeptide; 2) to increase the solubility of the recombinant polypeptide; and 3) to aid in the purification of the recombinant polypeptide by acting as a ligand in affinity purification. Often, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety subsequent to purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith & Johnson, Gene 67: 31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.


Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for target polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector is used to infect bone marrow cells that are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed (e.g., six (6) weeks).


Expressing the polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide is often used to maximize recombinant polypeptide expression (Gottesman, S., Gene Expression Technology: Methods in Enzymology, Academic Press, San Diego, Calif. 185: 119-128 (1990)). Another strategy is to alter the nucleotide sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., Nucleic Acids Res. 20: 2111-2118 (1992)). Such alteration of nucleotide sequences can be carried out by standard DNA synthesis techniques.


When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. Recombinant mammalian expression vectors are often capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Non-limiting examples of suitable tissue-specific promoters include an albumin promoter (liver-specific; Pinkert et al., Genes Dev. 1: 268-277 (1987)), lymphoid-specific promoters (Calame & Eaton, Adv. Immunol. 43: 235-275 (1988)), promoters of T cell receptors (Winoto & Baltimore, EMBO J. 8: 729-733 (1989)) promoters of immunoglobulins (Banerji et al., Cell 33: 729-740 (1983); Queen & Baltimore, Cell 33: 741-948 (1983)), neuron-specific promoters (e.g., the neurofilament promoter; Byrne & Ruddle, Proc. Natl. Acad. Sci. USA 86: 5473-5477 (1989)), pancreas-specific promoters (Edlund et al., Science 230: 912-916 (1985)), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (Kessel & Gruss, Science 249: 374-379 (1990)) and the α-fetopolypeptide promoter (Campes & Tilghman, Genes Dev. 3: 537-546 (1989)).


A CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid may also be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid cloned in the antisense orientation can be chosen for directing constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types. Antisense expression vectors can be in the form of a recombinant plasmid, phagemid or attenuated virus. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub et al., Antisense RNA as a molecular tool for genetic analysis, Reviews—Trends in Genetics, Vol. 1(1) (1986).


Also provided herein are host cells that include a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence within a recombinant expression vector or a fragment of such a nucleotide sequence which facilitate homologous recombination into a specific site of the host cell genome. The terms “host cell” and “recombinant host cell” are used interchangeably herein. Such terms refer not only to the particular subject cell but rather also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, a target polypeptide can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.


Vectors can be introduced into host cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transduction/infection, DEAE-dextran-mediated transfection, lipofection, or electroporation.


A host cell provided herein can be used to produce (i.e., express) a target polypeptide or a substantially identical polypeptide thereof. Accordingly, further provided are methods for producing a target polypeptide using host cells described herein. In one embodiment, the method includes culturing host cells into which a recombinant expression vector encoding a target polypeptide has been introduced in a suitable medium such that a target polypeptide is produced. In another embodiment, the method further includes isolating a target polypeptide from the medium or the host cell.


Also provided are cells or purified preparations of cells which include a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 transgene, or which otherwise misexpress target polypeptide. Cell preparations can consist of human or non-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. In preferred embodiments, the cell or cells include a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 transgene (e.g., a heterologous form of a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 gene, such as a human gene expressed in non-human cells). The transgene can be misexpressed, e.g., overexpressed or underexpressed. In other preferred embodiments, the cell or cells include a gene which misexpress an endogenous target polypeptide (e.g., expression of a gene is disrupted, also known as a knockout). Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed alleles or for use in drug screening. Also provided are human cells (e.g., a hematopoietic stem cells) transformed with a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid.


Also provided are cells or a purified preparation thereof (e.g., human cells) in which an endogenous CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene corresponding to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence. The expression characteristics of an endogenous gene within a cell (e.g., a cell line or microorganism) can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the corresponding endogenous gene. For example, an endogenous corresponding gene (e.g., a gene which is “transcriptionally silent,” not normally expressed, or expressed only at very low levels) may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published on May 16, 1991.


Transyenic Animals


Non-human transgenic animals that express a heterologous target polypeptide (e.g., expressed from a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid or substantially identical sequence thereof) can be generated. Such animals are useful for studying the function and/or activity of a target polypeptide and for identifying and/or evaluating modulators of the activity of CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acids and encoded polypeptides. As used herein, a “transgenic animal” is a non-human animal such as a mammal (e.g., a non-human primate such as chimpanzee, baboon, or macaque; an ungulate such as an equine, bovine, or caprine; or a rodent such as a rat, a mouse, or an Israeli sand rat), a bird (e.g., a chicken or a turkey), an amphibian (e.g., a frog, salamander, or newt), or an insect (e.g., Drosophila melanogaster), in which one or more of the cells of the animal includes a transgene. A transgene is exogenous DNA or a rearrangement (e.g., a deletion of endogenous chromosomal DNA) that is often integrated into or occurs in the genome of cells in a transgenic animal. A transgene can direct expression of an encoded gene product in one or more cell types or tissues of the transgenic animal, and other transgenes can reduce expression (e.g., a knockout). Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal (e.g., an embryonic cell of the animal) prior to development of the animal.


Intronic sequences and polyadenylation signals can also be included in the transgene to increase expression efficiency of the transgene. One or more tissue-specific regulatory sequences can be operably linked to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence in its genome and/or expression of encoded mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence can further be bred to other transgenic animals carrying other transgenes.


Target polypeptides can be expressed in transgenic animals or plants by introducing, for example, a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid into the genome of an animal that encodes the target polypeptide. In preferred embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Also included is a population of cells from a transgenic animal.


Target Polypeptides


Also featured herein are isolated target polypeptides, which are encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence (e.g., SEQ ID NO's:1-10) or a substantially identical nucleotide sequence thereof, such as the polypeptides having amino acid sequences in SEQ ID NO's:11-15. The term “polypeptide” as used herein includes proteins and peptides. An “isolated” or “purified” polypeptide or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. In one embodiment, the language “substantially free” means preparation of a target polypeptide having less than about 30%, 20%, 10% and more preferably 5% (by dry weight), of non-target polypeptide (also referred to herein as a “contaminating protein”), or of chemical precursors or non-target chemicals. When the target polypeptide or a biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, specifically, where culture medium represents less than about 20%, sometimes less than about 10%, and often less than about 5% of the volume of the polypeptide preparation. Isolated or purified target polypeptide preparations are sometimes 0.01 milligrams or more or 0.1 milligrams or more, and often 1.0 milligrams or more and 10 milligrams or more in dry weight.


Further included herein are target polypeptide fragments. The polypeptide fragment may be a domain or part of a domain of a target polypeptide. In addition, the polypeptide fragment may be a full-length polypeptide or a mature polypeptide (i.e., the polypeptide minus the signal peptide). For example, a fragment sometimes is a CTEP mature protein that corresponds to amino acid positions 18493 of SEQ ID NO:11. The polypeptide fragment may have increased, decreased or unexpected biological activity. The polypeptide fragment is often 50 or fewer, 100 or fewer, or 200 or fewer amino acids in length, and is sometimes 300, 400, 500, 600, 700, or 900 or fewer amino acids in length.


Substantially identical target polypeptides may depart from the amino acid sequences of target polypeptides in different manners. For example, conservative amino acid modifications may be introduced at one or more positions in the amino acid sequences of target polypeptides. A “conservative amino acid substitution” is one in which the amino acid is replaced by another amino acid having a similar structure and/or chemical function. Families of amino acid residues having similar structures and functions are well known. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Also, essential and non-essential amino acids may be replaced. A “non-essential” amino acid is one that can be altered without abolishing or substantially altering the biological function of a target polypeptide, whereas altering an “essential” amino acid abolishes or substantially alters the biological function of a target polypeptide. Amino acids that are conserved among target polypeptides are typically essential amino acids.


Also, target polypeptides may exist as chimeric or fusion polypeptides. As used herein, a target “chimeric polypeptide” or target “fusion polypeptide” includes a target polypeptide linked to a non-target polypeptide. A “non-target polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a polypeptide which is not substantially identical to the target polypeptide, which includes, for example, a polypeptide that is different from the target polypeptide and derived from the same or a different organism. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire target polypeptide or a fragment thereof. The non-target polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.


Fusion polypeptides can include a moiety having high affinity for a ligand. For example, the fusion polypeptide can be a GST-target fusion polypeptide in which the target sequences are fused to the C-terminus of the GST sequences, or a polyhistidine-target fusion polypeptide in which the target polypeptide is fused at the N- or C-terminus to a string of histidine residues. Such fusion polypeptides can facilitate purification of recombinant target polypeptide. Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide), and a nucleotide sequence in SEQ ID NO's:1-10, or a substantially identical nucleotide sequence thereof, can be cloned into an expression vector such that the fusion moiety is linked in-frame to the target polypeptide. Further, the fusion polypeptide can be a target polypeptide containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression, secretion, cellular internalization, and cellular localization of a target polypeptide can be increased through use of a heterologous signal sequence. Fusion polypeptides can also include all or a part of a serum polypeptide (e.g., an IgG constant region or human serum albumin).


Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these target polypeptides can be used to affect the bioavailability of a substrate of the target polypeptide and may effectively increase target polypeptide biological activity in a cell. Target fusion polypeptides may be useful therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a target polypeptide; (ii) mis-regulation of the gene encoding the target polypeptide; and (iii) aberrant post-translational modification of a target polypeptide. Also, target polypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify target polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a target polypeptide with a substrate.


In addition, polypeptides can be chemically synthesized using techniques known in the art (See, e.g., Creighton, 1983 Proteins. New York, N.Y.: W. H. Freeman and Company, and Hunkapiller et al., (1984) Nature July 12-18; 310(5973):105-11). For example, a relative short fragment can be synthesized by use of a peptide synthesizer. Furthermore, if desired, non-classical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the fragment sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoroamino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).


Polypeptides and polypeptide fragments sometimes are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; and the like. Additional post-translational modifications include, for example, N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide.


Also provided are chemically modified derivatives of polypeptides that can provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see e.g., U.S. Pat. No. 4,179,337. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.


The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).


The polymers should be attached to the polypeptide with consideration of effects on functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art (e.g., EP 0 401 384 (coupling PEG to G-CSF) and Malik et al. (1992) Exp Hematol. September; 20(8):1028-35 (pegylation of GM-CSF using tresyl chloride)). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. For therapeutic purposes, the attachment sometimes is at an amino group, such as attachment at the N-terminus or lysine group.


Proteins can be chemically modified at the N-terminus. Using polyethylene glycol as an illustration of such a composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, and the like), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus may be accomplished by reductive alkylation, which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.


Substantially Identical Nucleic Acids and Polypeptides


Nucleotide sequences and polypeptide sequences that are substantially identical to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence and the target polypeptide sequences encoded by those nucleotide sequences, respectively, are included herein. The term “substantially identical” as used herein refers to two or more nucleic acids or polypeptides sharing one or more identical nucleotide sequences or polypeptide sequences, respectively. Included are nucleotide sequences or polypeptide sequences that are 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more (each often within a 1%, 2%, 3% or 4% variability) identical to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or the encoded target polypeptide amino acid sequences. One test for determining whether two nucleic acids are substantially identical is to determine the percent of identical nucleotide sequences or polypeptide sequences shared between the nucleic acids or polypeptides.


Calculations of sequence identity are often performed as follows. Sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The length of a reference sequence aligned for comparison purposes is sometimes 30% or more, 40% or more, 50% or more, often 60% or more, and more often 70% or more, 80% or more, 90% or more, or 100% of the length of the reference sequence. The nucleotides or amino acids at corresponding nucleotide or polypeptide positions, respectively, are then compared among the two sequences. When a position in the first sequence is occupied by the same nucleotide or amino acid as the corresponding position in the second sequence, the nucleotides or amino acids are deemed to be identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, introduced for optimal alignment of the two sequences.


Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers & Miller, CABIOS 4: 11-17 (1989), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. Also, percent identity between two amino acid sequences can be determined using the Needleman & Wunsch, J. Mol. Biol. 48: 444-453 (1970) algorithm which has been incorporated into the GAP program in the GCG software package (available at the http address www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http address www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A set of parameters often used is a Blossum 62 scoring matrix with a gap open penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.


Another manner for determining if two nucleic acids are substantially identical is to assess whether a polynucleotide homologous to one nucleic acid will hybridize to the other nucleic acid under stringent conditions. As use herein, the term “stringent conditions” refers to conditions for hybridization and washing. Stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 6.3.1-6.3.6 (1989). Aqueous and non-aqueous methods are described in that reference and either can be used. An example of stringent hybridization conditions is hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50° C. Another example of stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 55° C. A further example of stringent hybridization conditions is hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 60° C. Often, stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C. More often, stringency conditions are 0.5M sodium phosphate, 7% SDS at 65° C., followed by one or more washes at 0.2×SSC, 1% SDS at 65° C.


An example of a substantially identical nucleotide sequence to a nucleotide sequence in SEQ ID NO's:1-10 is one that has a different nucleotide sequence but still encodes the same polypeptide sequence encoded by the nucleotide sequence in SEQ ID NO's:1-10. Another example is a nucleotide sequence that encodes a polypeptide having a polypeptide sequence that is more than 70% or more identical to, sometimes more than 75% or more, 80% or more, or 85% or more identical to, and often more than 90% or more and 95% or more identical to a polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO's:1-10. As used herein, “SEQ ID NO's:1-10” typically refers to one or more sequences in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, and/or 10. Many of the embodiments described herein are applicable to (a) a nucleotide sequence of SEQ ID NO's:1-10; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO's:1-10; (d) a fragment of a nucleotide sequence of (a), (b), or (c); and/or a nucleotide sequence complementary to the nucleotide sequences of (a), (b), (c) and/or (d), where nucleotide sequences of (b) and (c), fragments of (b) and (c) and nucleotide sequences complementary to (b) and (c) are examples of substantially identical nucleotide sequences. Examples of substantially identical nucleotide sequences include nucleotide sequences from subjects that differ by naturally occurring genetic variance, which sometimes is referred to as background genetic variance (e.g. nucleotide sequences differing by natural genetic variance sometimes are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one another).


Nucleotide sequences in SEQ ID NO's:1-10 and amino acid sequences of encoded polypeptides can be used as “query sequences” to perform a search against public databases to identify other family members or related sequences, for example. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al., J. Mol. Biol. 215: 403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to nucleotide sequences in SEQ ID NO's:1-10. BLAST polypeptide searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to polypeptides encoded by the nucleotide sequences of SEQ ID NO's:1-10. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17): 3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see the http address www.ncbi.nlm.nih.gov).


A nucleic acid that is substantially identical to a nucleotide sequence in SEQ ID NO's:1-10 may include polymorphic sites at positions equivalent to those described herein when the sequences are aligned. For example, using the alignment procedures described herein, SNPs in a sequence substantially identical to a sequence in SEQ ID NO's:1-10 can be identified at nucleotide positions that match with or correspond to (i.e., align) nucleotides at SNP positions in each nucleotide sequence in SEQ ID NO's:1-10. Also, where a polymorphic variation results in an insertion or deletion, insertion or deletion of a nucleotide sequence from a reference sequence can change the relative positions of other polymorphic sites in the nucleotide sequence.


Substantially identical nucleotide and polypeptide sequences include those that are naturally occurring, such as allelic variants (same locus), splice variants, homologs (different locus), and orthologs (different organism) or can be non-naturally occurring. Non-naturally occurring variants can be generated by mutagenesis techniques, including those applied to polynucleotides, cells, or organisms. The variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions (as compared in the encoded product). Orthologs, homologs, allelic variants, and splice variants can be identified using methods known in the art. These variants normally comprise a nucleotide sequence encoding a polypeptide that is 50% or more, about 55% or more, often about 70-75% or more or about 80-85% or more, and sometimes about 90-95% or more identical to the amino acid sequences of target polypeptides or a fragment thereof. Such nucleic acid molecules can readily be identified as being able to hybridize under stringent conditions to a nucleotide sequence in SEQ ID NO's:1-10 or a fragment of this sequence. Nucleic acid molecules corresponding to orthologs, homologs, and allelic variants of a nucleotide sequence in SEQ ID NO's:1-10 can further be identified by mapping the sequence to the same chromosome or locus as the nucleotide sequence in SEQ ID NO's:1-10.


Also, substantially identical nucleotide sequences may include codons that are altered with respect to the naturally occurring sequence for enhancing expression of a target polypeptide in a particular expression system. For example, the nucleic acid can be one in which one or more codons are altered, and often 10% or more or 20% or more of the codons are altered for optimized expression in bacteria (e.g., E. coli), yeast (e.g., S. cervesiae), human (e.g., 293 cells), insect, or rodent (e.g., hamster) cells.


Methods for Identifying Subjects at Risk of Osteoporosis and Risk of Osteoporosis in a Subject


Methods for prognosing and diagnosing low BMD and its related disorders (e.g., osteoporosis) are included herein. These methods include detecting the presence or absence of one or more polymorphic variations in a nucleotide sequence associated with low BMD, such as variants in or around the loci set forth herein, or a substantially identical sequence thereof, in a sample from a subject, where the presence of a polymorphic variant described herein is indicative of a risk of low BMD or one or more low BMD related disorders (e.g., osteoporosis). Determining a risk of osteoporosis refers to determining whether an individual is at an increased risk of osteoporosis (e.g., intermediate risk or higher risk).


Thus, featured herein is a method for identifying a subject who is at risk of osteoporosis, which comprises detecting low BMD-associated aberration in a nucleic acid sample from the subject. An embodiment is a method for detecting a risk of osteoporosis in a subject, which comprises detecting the presence or absence of a polymorphic variation associated with low BMD at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of: (a) a nucleotide sequence of SEQ ID NO's:1-10; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO's:1-10; and (d) a fragment of a nucleotide sequence of (a), (b), or (c) comprising the polymorphic site; whereby the presence of the polymorphic variation is indicative of a predisposition to osteoporosis in the subject. In certain embodiments, polymorphic variants at the positions described herein are detected for determining a risk of osteoporosis, and polymorphic variants at positions in linkage disequilibrium with these positions are detected for determining a risk of osteoporosis. As used herein, “SEQ ID NO's:1-10” refers to individual sequences in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12.


Results from prognostic tests may be combined with other test results to diagnose osteoporosis. For example, prognostic results may be gathered, an initial diagnostic test may be ordered based on a determined predisposition to low BMD, and the results of the analysis may be utilized to diagnose osteoporosis. Also osteoporosis diagnostic methods can be developed from studies used to generate prognostic/diagnostic methods in which populations are stratified into subpopulations having different progressions of osteoporosis. In another embodiment, prognostic results may be gathered; a patient's risk factors for developing osteoporosis analyzed (e.g., age, race, family history, age of menopause); and an initial diagnostic test may be ordered based on a determined predisposition to low BMD.


Risk factors believed to be associated with low BMD include personal history of fracture after age 50; current low bone mass; history of fracture in a 1° relative; being female; being thin and/or having a small frame; low body weight; advanced age; a family history of osteoporosis; estrogen deficiency, especially as a result of menopause which is early or surgically induced; abnormal absence of menstrual periods (amenorrhea); anorexia nervosa; low lifetime calcium intake; use of certain medications, such as corticosteroids and anticonvulsants; low testosterone levels in men; an inactive lifestyle; current cigarette smoking; excessive use of alcohol; being Caucasian or Asian, although African Americans and Hispanic Americans are at significant risk as well. (See National Osteoporosis Foundation; http://www.nof.org/osteoporosis/stats.htm). In an alternative embodiment, the results from predisposition analyses described herein may be combined with other test results indicative of osteoporosis, which were previously, concurrently, or subsequently gathered with respect to the predisposition testing. In these embodiments, the combination of the prognostic test results with other test results can be probative of osteoporosis, and the combination can be utilized as an osteoporosis diagnostic. The results of any test indicative of osteoporosis known in the art may be combined with the methods described herein. Examples of such tests are bone density tests that measure bone density in various sites of the body. Such methods include the measurement of the radiodensity of skeletal radiographs, quantitative computerized tomography, single energy photon absorptiometry, and dual-energy photon absorptiometry. Diagnostic techniques among those useful herein are described in W. A. Peck et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation (incorporated by reference herein).


Risk of low BMD sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. The risk sometimes is expressed as a relative risk with respect to a population average risk of low BMD, and sometimes is expressed as a relative risk with respect to the lowest risk group. Such relative risk assessments often are based upon penetrance values determined by statistical methods and are particularly useful to clinicians and insurance companies for assessing risk of osteoporosis (e.g., a clinician can target appropriate detection, prevention and therapeutic regimens to a patient after determining the patient's risk of osteoporosis, and an insurance company can fine tune actuarial tables based upon population genotype assessments of osteoporosis risk). Risk of osteoporosis sometimes is expressed as an odds ratio, which is the odds of a particular person having a genotype has or will develop osteoporosis with respect to another genotype group (e.g., the most disease protective genotype or population average). The risk often is based upon the presence or absence of one or more polymorphic variants described herein, and also may be based in part upon phenotypic traits of the individual being tested. In an embodiment, two or more polymorphic variations are detected in a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 locus. In certain embodiments, 3 or more, or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more polymorphic variants are detected in the sample. Methods for calculating risk based upon patient data are well known (see, e.g., Agresti, Categorical Data Analysis, 2nd Ed. 2002. Wiley). Allelotyping and genotyping analyses may be carried out in populations other than those exemplified herein to enhance the predictive power of the prognostic method.


The nucleic acid sample typically is isolated from a biological sample obtained from a subject. For example, nucleic acid can be isolated from blood, saliva, sputum, urine, cell scrapings, and biopsy tissue. The nucleic acid sample can be isolated from a biological sample using standard techniques, such as the technique described in Example 2. As used herein, the term “subject” refers primarily to humans but also refers to other mammals such as dogs, cats, and ungulates (e.g., cattle, sheep, and swine). Subjects also include avians (e.g., chickens and turkeys), reptiles, and fish (e.g., salmon), as embodiments described herein can be adapted to nucleic acid samples isolated from any of these organisms. The nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.


The presence or absence of a polymorphic variant is determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic acid sample from a subject having a copy of each chromosome is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample. For example, primer extension methods, ligase sequence determination methods (e.g., U.S. Pat. Nos. 5,679,524 and 5,952,174, and WO 01/27326), mismatch sequence determination methods (e.g., U.S. Pat. Nos. 5,851,770; 5,958,692; 6,110,684; and 6,183,958), microarray sequence determination methods, restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499), PCR-based assays (e.g., TAQMAN® PCR System (Applied Biosystems)), and nucleotide sequencing methods may be used.


Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PCR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation. One oligonucleotide primer is complementary to a region 3′ of the polymorphism and the other is complementary to a region 5′ of the polymorphism. A PCR primer pair may be used in methods disclosed in U.S. Pat. Nos. 4,683,195; 4,683,202, 4,965,188; 5,656,493; 5,998,143; 6,140,054; WO 01/27327; and WO 01/27329 for example. PCR primer pairs may also be used in any commercially available machines that perform PCR, such as any of the GENEAMP® Systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence using knowledge available in the art.


Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. As used herein, the term “adjacent” refers to the 3′ end of the extension oligonucleotide being often 1 nucleotide from the 5′ end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5′ end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid. The extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present. Oligonucleotide extension methods are disclosed, for example, in U.S. Pat. Nos. 4,656,127; 4,851,331; 5,679,524; 5,834,189; 5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981,186; 6,004,744; 6,013,431; 6,017,702; 6,046,005; 6,087,095; 6,210,891; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos. 5,547,835; 5,605,798; 5,691,141; 5,849,542; 5,869,242; 5,928,906; 6,043,031; and 6,194,144, and a method often utilized is described herein in Example 2.


A microarray can be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A microarray may include any oligonucleotides described herein, and methods for making and using oligonucleotide microarrays suitable for diagnostic use are disclosed in U.S. Pat. Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940; 5,849,483; 6,018,041; 6,045,996; 6,136,541; 6,142,681; 6,156,501; 6,197,506; 6,223,127; 6,225,625; 6,229,911; 6,239,273; WO 00/52625; WO 01/25485; and WO 01/29259. The microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions. The oligonucleotides may also be linked to the solid support directly or by a spacer molecule. A microarray may comprise one or more oligonucleotides complementary to a polymorphic site set forth herein.


A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit often comprises one or more pairs of oligonucleotide primers useful for amplifying a fragment of a nucleotide sequence of SEQ ID NO's:1-10 or a substantially identical sequence thereof, where the fragment includes a polymorphic site. The kit sometimes comprises a polymerizing agent, for example, a thermostable nucleic acid polymerase such as one disclosed in U.S. Pat. No. 4,889,818 or 6,077,664. Also, the kit often comprises an elongation oligonucleotide that hybridizes to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it also often comprises chain elongating nucleotides, such as dATP, dTTP, dGTP, dCTP, and dITP, including analogs of dATP, dTTP, dGTP, dCTP and dITP, provided that such analogs are substrates for a thermostable nucleic acid polymerase and can be incorporated into a nucleic acid chain elongated from the extension oligonucleotide. Along with chain elongating nucleotides would be one or more chain terminating nucleotides such as ddATP, ddTTP, ddGTP, ddCTP, and the like. In an embodiment, the kit comprises one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides. Kits optionally include buffers, vials, microtiter plates, and instructions for use.


An individual identified as being at risk of osteoporosis may be heterozygous or homozygous with respect to the allele associated with low BMD. A subject homozygous for an allele associated with low BMD is at a comparatively high risk of osteoporosis, a subject heterozygous for an allele associated with low BMD is at a comparatively intermediate risk of osteoporosis, and a subject homozygous for an allele associated with normal or high BMD levels (i.e., a decreased risk of low BMD) is at a comparatively low risk of osteoporosis. A genotype may be assessed for a complementary strand, such that the complementary nucleotide at a particular position is detected.


Also featured are methods for determining risk of osteoporosis and/or identifying a subject at risk of osteoporosis by contacting a polypeptide or protein encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence from a subject with an antibody that specifically binds to an epitope associated with increased risk of osteoporosis in the polypeptide. In an embodiment, the antibody specifically binds to an epitope comprising an arginine at position 120 in a PROL4 polypeptide.


Applications of Prognostic and Diagnostic Results to Pharmacogenomic Methods


Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype as a particular treatment regimen may exert a differential effect depending upon the subject's genotype. For example, based upon the outcome of a prognostic test described herein, a clinician or physician may target pertinent information and preventative or therapeutic treatments to a subject who would be benefited by the information or treatment and avoid directing such information and treatments to a subject who would not be benefited (e.g., the treatment has no therapeutic effect and/or the subject experiences adverse side effects).


The following is an example of a pharmacogenomic embodiment. A particular treatment regimen can exert a differential effect depending upon the subject's genotype. Where a candidate therapeutic exhibits a significant interaction with a major allele and a comparatively weak interaction with a minor allele (e.g., an order of magnitude or greater difference in the interaction), such a therapeutic typically would not be administered to a subject genotyped as being homozygous for the minor allele, and sometimes not administered to a subject genotyped as being heterozygous for the minor allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a major allele but is comparatively toxic when administered to subjects heterozygous or homozygous for a minor allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the minor allele.


The methods described herein are applicable to pharmacogenomic methods for preventing, alleviating or treating low BMD conditions such as osteoporosis. For example, a nucleic acid sample from an individual may be subjected to a prognostic test described herein. Where one or more polymorphic variations associated with low BMD are identified in a subject, information for preventing or treating osteoporosis and/or one or more osteoporosis treatment regimens then may be prescribed to that subject.


In certain embodiments, a treatment or preventative regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing osteoporosis assessed by the methods described herein. Thus, provided are methods for identifying a subject predisposed to osteoporosis and then prescribing a therapeutic or preventative regimen to individuals identified as having a predisposition. Thus, certain embodiments are directed to a method for increasing BMD levels or otherwise treating osteoporosis in a subject, which comprises: detecting the presence or absence of a polymorphic variant associated with low BMD in a nucleotide sequence in a nucleic acid sample from a subject, where the nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of: (a) a nucleotide sequence of SEQ ID NO's:1-10; (b) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10; (c) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO's:1-10; and (d) a fragment of a polynucleotide sequence of (a), (b), or (c); and prescribing or administering a treatment regimen to a subject from whom the sample originated where the presence of a polymorphic variation associated with low BMD is detected in the nucleotide sequence. In these methods, predisposition results may be utilized in combination with other test results to diagnose low BMD associated conditions, such as osteoporosis.


Certain preventative treatments often are prescribed to subjects having a predisposition to osteoporosis and where the subject is diagnosed with low BMD or is diagnosed as having symptoms indicative of early stage osteoporosis. Established diagnostic techniques use x-ray and ultrasonography to measure skeletal parameters of bone size, volume and mineral density to predict fracture risk and to assess response to therapy. Such measurements give a “static” value which can be compared to normal values to aid diagnosis of low bone mass and fracture risk (Schott, Cornier et al. 1998). The World Health Organization defines osteoporosis as a bone mineral density level more than 2.5 standard deviations below the young normal mean. The various techniques used to measure bone mineral density include, a) Dual energy X-ray absorptiometry (DXA)—used to measure bone mass at the lumbar spine and hip, but it can also be applied to measuring total skeletal bone mass, soft-tissue composition and other regional bone measurements. DXA is considered the “gold standard” for BMD measurement; b) high-resolution quantitative computed tomography QCT)—highly sensitive, accurate and specific spinal measurements. This technique is more costly, not widely available and involves higher radiation doses than other techniques; c) single-energy x-ray absorptiometry (SXA)—provides accurate radius BMD measurements; d) quantitative ultrasound QUS)—new and promising technique which may have applications in both BMD measurement and assessment or architectural deterioration of bone tissue. Recent studies suggest QUS of calcaneus bone predicts hip fracture as well as DXA (Hans, Dargent-Molina et al. 1996).


An alternative method to predict fracture independently of bone mass is to measure bone turnover. High turnover (bone resorption and formation) is associated with rapid bone loss and is likely to contribute to micro-architectural deterioration (Ross and Knowlton 1998). This is a “dynamic” measurement which is assessed with biochemical markers in urine or serum and can be used effectively in therapy monitoring in preference to BNO measurements. When used in combination with bone mass assessment, biomarkers can provide more accurate fracture predictions over bone mass measurement alone. Osteoporosis-related biomarkers for bone resorption include deoxypyridinoline crosslinks, and osteoporosis-related biomarkers for bone formation include bone alkaline phosphatase and osteocalcin. Some of these biomarkers have been developed for use in diagnostic kits. The current challenge is to reduce the variability of the measurements and improve their reliability and applicability.


The treatment sometimes is preventative (e.g., is prescribed or administered to reduce the probability that a low BMD associated condition arises or progresses), sometimes is therapeutic, and sometimes delays, alleviates or halts the progression of a low BMD associated condition. Any known preventative or therapeutic treatment for alleviating or preventing the occurrence of a low BMD associated disorder is prescribed and/or administered. Preventative treatment for osteoporosis is most effective at the time when bone loss is increasing and before the bones have become fragile and prone to fracturing. Strategies for the prevention of this disease include development of bone density in early adulthood (i.e., building strong bones during childhood and adolescence), and minimization of bone loss in later life. Changes in lifestyle, nutrition and hormonal factors have been shown to affect bone loss. Specifically, a balanced diet rich in calcium and vitamin D, weight-bearing exercise, a healthy lifestyle with no smoking or excessive alcohol intake, and bone density testing and medication when appropriate are known to help reduce the risk of osteoporosis.


As therapeutic approaches for low BMD continue to evolve and improve, the goal of treatments for low BMD related disorders is to intervene even before clinical signs (e.g., impaired glucose tolerance, or IGT) first manifest. Thus, genetic markers associated with susceptibility to low BMD prove useful for early diagnosis, prevention and treatment of low BMD.


As osteoporosis preventative and treatment information can be specifically targeted to subjects in need thereof (e.g., those at risk of low BMD or those that have early stages of osteoporosis), provided herein is a method for preventing or reducing the risk of developing osteoporosis in a subject, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with low BMD at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying a subject with a predisposition to osteoporosis, whereby the presence of the polymorphic variation is indicative of a predisposition to osteoporosis in the subject; and (c) if such a predisposition is identified, providing the subject with information about methods or products to prevent osteoporosis or to delay the onset of osteoporosis. Also provided is a method of targeting information or advertising to a subpopulation of a human population based on the subpopulation being genetically predisposed to a disease or condition, which comprises: (a) detecting the presence or absence of a polymorphic variation associated with low BMD at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) identifying the subpopulation of subjects in which the polymorphic variation is associated with low BMD; and (c) providing information only to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition.


Pharmacogenomics methods also may be used to analyze and predict a response to a osteoporosis treatment or a drug. For example, if pharmacogenomics analysis indicates a likelihood that an individual will respond positively to a osteoporosis treatment with a particular drug, the drug may be administered to the individual. Conversely, if the analysis indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects. The response to a therapeutic treatment can be predicted in a background study in which subjects in any of the following populations are genotyped: a population that responds favorably to a treatment regimen, a population that does not respond significantly to a treatment regimen, and a population that responds adversely to a treatment regiment (e.g., exhibits one or more side effects). These populations are provided as examples and other populations and subpopulations may be analyzed. Based upon the results of these analyses, a subject is genotyped to predict whether he or she will respond favorably to a treatment regimen, not respond significantly to a treatment regimen, or respond adversely to a treatment regimen.


The tests described herein also are applicable to clinical drug trials. One or more polymorphic variants indicative of response to an agent for treating osteoporosis or to side effects to an agent for treating osteoporosis may be identified using the methods described herein. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as a result of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems.


Thus, another embodiment is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of: (a) obtaining a nucleic acid sample from an individual; (b) determining the identity of a polymorphic variation which is associated with a positive response to the treatment or the drug, or at least one polymorphic variation which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and (c) including the individual in the clinical trial if the nucleic acid sample contains said polymorphic variation associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said polymorphic variation associated with a negative response to the treatment or the drug. In addition, the methods described herein for selecting an individual for inclusion in a clinical trial of a treatment or drug encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination. The polymorphic variation may be in a sequence selected individually or in any combination from the group consisting of (i) a nucleotide sequence of SEQ ID NO's:1-10; (ii) a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10; (iii) a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10, or a nucleotide sequence about 90% or more identical to a nucleotide sequence of SEQ ID NO's:1-10; and (iv) a fragment of a polynucleotide sequence of (i), (ii), or (iii) comprising the polymorphic site. The including step (c) optionally comprises administering the drug or the treatment to the individual if the nucleic acid sample contains the polymorphic variation associated with a positive response to the treatment or the drug and the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug.


Also provided herein is a method of partnering between a diagnostic/prognostic testing provider and a provider of a consumable product, which comprises: (a) the diagnostic/prognostic testing provider detects the presence or absence of a polymorphic variation associated with low BMD at a polymorphic site in a nucleotide sequence in a nucleic acid sample from a subject; (b) the diagnostic/prognostic testing provider identifies the subpopulation of subjects in which the polymorphic variation is associated with low BMD; (c) the diagnostic/prognostic testing provider forwards information to the subpopulation of subjects about a particular product which may be obtained and consumed or applied by the subject to help prevent or delay onset of the disease or condition; and (d) the provider of a consumable product forwards to the diagnostic test provider a fee every time the diagnostic/prognostic test provider forwards information to the subject as set forth in step (c) above.


Compositions Comprising Osteoporosis-Directed Molecules


Featured herein is a composition comprising a cell from a subject having low BMD or at risk of osteoporosis and one or more molecules specifically directed and targeted to a nucleic acid comprising a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or amino acid sequence. Such directed molecules include, but are not limited to, a compound that binds to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or amino acid sequence referenced herein; a nucleic acid that hybridizes to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid under conditions of high stringency; a RNAi or siRNA molecule having a strand complementary to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence; an antisense nucleic acid complementary to an RNA encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence; a ribozyme that hybridizes to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence; a nucleic acid aptamer that specifically binds a polypeptide encoded by CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence; and an antibody that specifically binds to a polypeptide encoded by CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or binds to a nucleic acid having such a nucleotide sequence. In specific embodiments, the osteoporosis directed molecule interacts with a nucleic acid or polypeptide variant associated with osteoporosis, such as variants referenced herein. In other embodiments, the osteoporosis directed molecule interacts with a polypeptide involved in a signal pathway of a polypeptide encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence, or a nucleic acid comprising such a nucleotide sequence.


Compositions sometimes include an adjuvant known to stimulate an immune response, and in certain embodiments, an adjuvant that stimulates a T-cell lymphocyte response. Adjuvants are known, including but not limited to an aluminum adjuvant (e.g., aluminum hydroxide); a cytokine adjuvant or adjuvant that stimulates a cytokine response (e.g., interleukin (IL)-12 and/or γ-interferon cytokines); a Freund-type mineral oil adjuvant emulsion (e.g., Freund's complete or incomplete adjuvant); a synthetic lipoid compound; a copolymer adjuvant (e.g., TitreMax); a saponin; Quil A; a liposome; an oil-in-water emulsion (e.g., an emulsion stabilized by Tween 80 and pluronic polyoxyethlene/polyoxypropylene block copolymer (Syntex Adjuvant Formulation); TitreMax; detoxified endotoxin (MPL) and mycobacterial cell wall components (TDW, CWS) in 2% squalene (Ribi Adjuvant System)); a muramyl dipeptide; an immune-stimulating complex (ISCOM, e.g., an Ag-modified saponin/cholesterol micelle that forms stable cage-like structure); an aqueous phase adjuvant that does not have a depot effect (e.g., Gerbu adjuvant); a carbohydrate polymer (e.g., AdjuPrime); L-tyrosine; a manide-oleate compound (e.g., Montanide); an ethylene-vinyl acetate copolymer (e.g., Elvax 40W1,2); or lipid A, for example. Such compositions are useful for generating an immune response against a osteoporosis directed molecule (e.g., an HLA-binding subsequence within a polypeptide encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence). In such methods, a peptide having an amino acid subsequence of a polypeptide encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence is delivered to a subject, where the subsequence binds to an HLA molecule and induces a CTL lymphocyte response. The peptide sometimes is delivered to the subject as an isolated peptide or as a minigene in a plasmid that encodes the peptide. Methods for identifying HLA-binding subsequences in such polypeptides are known (see e.g., publication WO02/20616 and PCT application US98/01373 for methods of identifying such sequences).


The cell may be in a group of cells cultured in vitro or in a tissue maintained in vitro or present in an animal in vivo (e.g., a rat, mouse, ape or human). In certain embodiments, a composition comprises a component from a cell such as a nucleic acid molecule (e.g., genomic DNA), a protein mixture or isolated protein, for example. The aforementioned compositions have utility in diagnostic, prognostic and pharmacogenomic methods described previously and in osteoporosis therapeutics described hereafter. Certain osteoporosis directed molecules are described in greater detail below.


Compounds


Compounds can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive (see, e.g., Zuckermann et al., J. Med. Chem. 37: 2678-85 (1994)); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; “one-bead one-compound” library methods; and synthetic library methods using affinity chromatography selection. Biological library and peptoid library approaches are typically limited to peptide libraries, while the other approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, Anticancer Drug Des. 12: 145, (1997)). Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al., Proc. Natl. Acad. Sci. U.S.A. 90: 6909 (1993); Erb et al., Proc. Natl. Acad. Sci. USA 91: 11422 (1994); Zuckermann et al., J. Med. Chem. 37: 2678 (1994); Cho et al., Science 261: 1303 (1993); Carrell et al., Angew. Chem. Int. Ed. Engl. 33: 2059 (1994); Carell et al., Angew. Chem. Int. Ed. Engl. 33: 2061 (1994); and in Gallop et al., J. Med. Chem. 37: 1233 (1994).


Libraries of compounds may be presented in solution (e.g., Houghten, Biotechniques 13: 412-421 (1992)), or on beads (Lam, Nature 354: 82-84 (1991)), chips (Fodor, Nature 364: 555-556 (1993)), bacteria or spores (Ladner, U.S. Pat. No. 5,223,409), plasmids (Cull et al., Proc. Natl. Acad. Sci. USA 89: 1865-1869 (1992)) or on phage (Scott and Smith, Science 249: 386-390 (1990); Devlin, Science 249: 404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. 87: 6378-6382 (1990); Felici, J. Mol. Biol. 222: 301-310 (1991); Ladner supra.).


A compound sometimes alters expression and sometimes alters activity of a polypeptide target and may be a small molecule. Small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.


Antisense Nucleic Acid Molecules, Ribozymes, RNAi, siRNA and Modified Nucleic Acid Molecules


An “antisense” nucleic acid refers to a nucleotide sequence complementary to a “sense” nucleic acid encoding a polypeptide, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire coding strand (e.g., SEQ ID NO: 7-13), or to a portion thereof or a substantially identical sequence thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence (e.g., 5′ and 3′ untranslated regions in SEQ ID NO's:1-5).


An antisense nucleic acid can be designed such that it is complementary to the entire coding region of an mRNA encoded by a nucleotide sequence (e.g., SEQ ID NO's:1-10), and often the antisense nucleic acid is an oligonucleotide antisense to only a portion of a coding or noncoding region of the mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of the mRNA, e.g., between the −10 and +10 regions of the target gene nucleotide sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length. The antisense nucleic acids, which include the ribozymes described hereafter, can be designed to target a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence, often a variant associated with low BMD, or a substantially identical sequence thereof. Among the variants, minor alleles and major alleles can be targeted, and those associated with a higher risk of osteoporosis are often designed, tested, and administered to subjects.


An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).


When utilized as therapeutics, antisense nucleic acids typically are administered to a subject (e.g., by direct injection at a tissue site) or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide and thereby inhibit expression of the polypeptide, for example, by inhibiting transcription and/or translation. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then are administered systemically. For systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. Antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. Sufficient intracellular concentrations of antisense molecules are achieved by incorporating a strong promoter, such as a pol II or pol III promoter, in the vector construct.


Antisense nucleic acid molecules sometimes are *-anomeric nucleic acid molecules. An *-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual *-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids. Res. 15: 6625-6641 (1987)). Antisense nucleic acid molecules can also comprise a 2′-o-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15: 6131-6148 (1987)) or a chimeric RNA-DNA analogue (Inoue et al., FEBS Lett. 215: 327-330 (1987)). Antisense nucleic acids sometimes are composed of DNA or PNA or any other nucleic acid derivatives described previously.


In another embodiment, an antisense nucleic acid is a ribozyme. A ribozyme having specificity for a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence can include one or more sequences complementary to such a nucleotide sequence, and a sequence having a known catalytic region responsible for mRNA cleavage (see e.g., U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach, Nature 334: 585-591 (1988)). For example, a derivative of a Tetrahymena L-19 IVS RNA is sometimes utilized in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA (see e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742). Also, target mRNA sequences can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules (see e.g., Bartel & Szostak, Science 261: 1411-1418(1993)).


Osteoporosis directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or a substantially identical sequence thereof, especially one that includes a regulatory region that controls expression of a polypeptide. Gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a nucleotide sequence referenced herein or a substantially identical sequence (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells (see e.g., Helene, Anticancer Drug Des. 6(6): 569-84 (1991); Helene et al., Ann. N.Y. Acad. Sci. 660: 27-36 (1992); and Maher, Bioassays 14(12): 807-15 (1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a so-called “switchback” nucleic acid molecule. Switchback molecules are synthesized in an alternating 5′-3′, 3′-5′ manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.


Osteoporosis directed molecules include RNAi and siRNA nucleic acids. Gene expression may be inhibited by the introduction of double-stranded RNA (dsRNA), which induces potent and specific gene silencing, a phenomenon called RNA interference or RNAi. See, e.g., Fire et al., U.S. Pat. No. 6,506,559; Tuschl et al. PCT International Publication No. WO 01/75164; Kay et al. PCT International Publication No. WO 03/010180A1; or Bosher J M, Labouesse, Nat Cell Biol 2000 February; 2(2):E31-6. This process has been improved by decreasing the size of the double-stranded RNA to 20-24 base pairs (to create small-interfering RNAs or siRNAs) that “switched off” genes in mammalian cells without initiating an acute phase response, i.e., a host defense mechanism that often results in cell death (see, e.g., Caplen et al. Proc Natl Acad Sci USA. 2001 Aug. 14; 98(17):9742-7 and Elbashir et al. Methods 2002 February; 26(2): 199-213). There is increasing evidence of post-transcriptional gene silencing by RNA interference (RNAi) for inhibiting targeted expression in mammalian cells at the mRNA level, in human cells. There is additional evidence of effective methods for inhibiting the proliferation and migration of tumor cells in human patients, and for inhibiting metastatic cancer development (see, e.g., U.S. Patent Application No. US2001000993183; Caplen et al. Proc Natl Acad Sci USA; and Abdeffahmani et al. Mol Cell Biol 2001 November 21(21):7256-67).


An “siRNA” or “RNAi” refers to a nucleic acid that forms a double stranded RNA and has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is delivered to or expressed in the same cell as the gene or target gene. “siRNA” refers to short double-stranded RNA formed by the complementary strands. Complementary portions of the siRNA that hybridize to form the double stranded molecule often have substantial or complete identity to the target molecule sequence. In one embodiment, an siRNA refers to a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA.


When designing the siRNA molecules, the targeted region often is selected from a given DNA sequence beginning 50 to 100 nucleotides downstream of the start codon. See, e.g., Elbashir et al., Methods 26:199-213 (2002). Initially, 5′ or 3′ UTRs and regions nearby the start codon were avoided assuming that UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. Sometimes regions of the target 23 nucleotides in length conforming to the sequence motif AA(N19)TT (N, an nucleotide), and regions with approximately 30% to 70% G/C-content (often about 50% G/C-content) often are selected. If no suitable sequences are found, the search often is extended using the motif NA(N21). The sequence of the sense siRNA sometimes corresponds to (N19) TT or N21 (position 3 to 23 of the 23-nt motif), respectively. In the latter case, the 3′ end of the sense siRNA often is converted to TT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3′ overhangs. The antisense siRNA is synthesized as the complement to position 1 to 21 of the 23-nt motif. Because position 1 of the 23-nt motif is not recognized sequence-specifically by the antisense siRNA, the 3′-most nucleotide residue of the antisense siRNA can be chosen deliberately. However, the penultimate nucleotide of the antisense siRNA (complementary to position 2 of the 23-nt motif) often is complementary to the targeted sequence. For simplifying chemical synthesis, TT often is utilized. siRNAs corresponding to the target motif NAR(N17)YNN, where R is purine (A,G) and Y is pyrimidine (C,U), often are selected. Respective 21 nucleotide sense and antisense siRNAs often begin with a purine nucleotide and can also be expressed from pol III expression vectors without a change in targeting site. Expression of RNAs from pol III promoters often is efficient when the first transcribed nucleotide is a purine.


The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof. Often, the siRNA is about 15 to about 50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15-50 nucleotides in length, and the double stranded siRNA is about 15-50 base pairs in length, sometimes about 20-30 nucleotides in length or about 20-25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. The siRNA sometimes is about 21 nucleotides in length. Methods of using siRNA are well known in the art, and specific siRNA molecules may be purchased from a number of companies including Dharmacon Research, Inc. An siRNA molecule sometimes is of a different chemical composition as compared to native RNA that imparts increased stability in cells (e.g., decreased susceptibility to degradation), and sometimes includes one or more modifications in siSTABLE RNA described at the http address www.dharmacon.com.


Antisense, ribozyme, RNAi and siRNA nucleic acids can be altered to form modified nucleic acid molecules. The nucleic acids can be altered at base moieties, sugar moieties or phosphate backbone moieties to improve stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of nucleic acid molecules can be modified to generate peptide nucleic acids (see Hyrup et al., Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)). As used herein, the terms “peptide nucleic acid” or “PNA” refers to a nucleic acid mimic such as a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can allow for specific hybridization to DNA and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described, for example, in Hyrup et al., (1996) supra and Perry-O'Keefe et al., Proc. Natl. Acad. Sci. 93: 14670-675 (1996).


PNA nucleic acids can be used in prognostic, diagnostic, and therapeutic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, for example, inducing transcription or translation arrest or inhibiting replication. PNA nucleic acid molecules can also be used in the analysis of single base pair mutations in a gene, (e.g., by PNA-directed PCR clamping); as “artificial restriction enzymes” when used in combination with other enzymes, (e.g., S1 nucleases (Hyrup (1996) supra)); or as probes or primers for DNA sequencing or hybridization (Hyrup et al., (1996) supra; Perry-O'Keefe supra).


In other embodiments, oligonucleotides may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across cell membranes (see e.g., Letsinger et al., Proc. Natl. Acad. Sci. USA 86: 6553-6556 (1989); Lemaitre et al., Proc. Natl. Acad. Sci. USA 84: 648-652 (1987); PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (See, e.g., Krol et al., Bio-Techniques 6: 958-976 (1988)) or intercalating agents. (See, e.g., Zon, Pharm. Res. 5: 539-549 (1988)). To this end, the oligonucleotide may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).


Also included herein are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence or a substantially identical sequence thereof, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantifying the presence of the nucleic acid in a sample. Molecular beacon nucleic acids are described, for example, in Lizardi et al., U.S. Pat. No. 5,854,033; Nazarenko et al., U.S. Pat. No. 5,866,336, and Livak et al., U.S. Pat. No. 5,876,930.


Antibody


The term “antibody” as used herein refers to an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab′)2 fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody sometimes is a polyclonal, monoclonal, recombinant (e.g., a chimeric or humanized), fully human, non-human (e.g., murine), or a single chain antibody. An antibody may have effector function and can fix complement, and is sometimes coupled to a toxin or imaging agent.


Antibodies


A full-length polypeptide or antigenic peptide fragment encoded by a nucleotide sequence referenced herein can be used as an immunogen or can be used to identify antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. An antigenic peptide often includes at least 8 amino acid residues of the amino acid sequences encoded by a nucleotide sequence referenced herein, or substantially identical sequence thereof, and encompasses an epitope. Antigenic peptides sometimes include 10 or more amino acids, 15 or more amino acids, 20 or more amino acids, or 30 or more amino acids. Hydrophilic and hydrophobic fragments of polypeptides sometimes are used as immunogens.


Epitopes encompassed by the antigenic peptide are regions located on the surface of the polypeptide (e.g., hydrophilic regions) as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human polypeptide sequence can be used to indicate the regions that have a particularly high probability of being localized to the surface of the polypeptide and are thus likely to constitute surface residues useful for targeting antibody production. The antibody may bind an epitope on any domain or region on polypeptides described herein.


Also, chimeric, humanized, and completely human antibodies are useful for applications which include repeated administration to subjects. Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al International Application No. PCT/US86/02269; Akira, et al European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al European Patent Application 173,494; Neuberger et al PCT International Publication No. WO 86/01533; Cabilly et al U.S. Pat. No. 4,816,567; Cabilly et al European Patent Application 125,023; Better et al., Science 240: 1041-1043 (1988); Liu et al., Proc. Natl. Acad. Sci. USA 84: 3439-3443 (1987); Liu et al., J. Immunol. 139: 3521-3526 (1987); Sun et al., Proc. Natl. Acad. Sci. USA 84: 214-218 (1987); Nishimura et al., Canc. Res. 47: 999-1005 (1987); Wood et al., Nature 314: 446-449 (1985); and Shaw et al., J. Natl. Cancer Inst. 80: 1553-1559 (1988); Morrison, S. L., Science 229:1202-1207(1985); Oi et al., BioTechniques 4: 214(1986); Winter U.S. Pat. No. 5,225,539; Jones et al., Nature 321: 552-525 (1986); Verhoeyan et al., Science 239: 1534; and Beidler et al., J. Immunol. 141: 4053-4060 (1988).


Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar, Int. Rev. Immunol. 13: 65-93 (1995); and U.S. Pat. Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Fremont, Calif.) and Medarex, Inc. (Princeton, N.J.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above. Completely human antibodies that recognize a selected epitope also can be generated using a technique referred to as “guided selection.” In this approach a selected non-human monoclonal antibody (e.g., a murine antibody) is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described for example by Jespers et al., Bio/Technology 12: 899-903 (1994).


An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al., Ann. N Y Acad. Sci. 880: 263-80 (1999); and Reiter, Clin. Cancer Res. 2: 245-52 (1996)). Single chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.


Antibodies also may be selected or modified so that they exhibit reduced or no ability to bind an Fc receptor. For example, an antibody may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor (e.g., it has a mutagenized or deleted Fc receptor binding region).


Also, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, l dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).


Antibody conjugates can be used for modifying a given biological response. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, γ-interferon, α-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor “G-CSF”), or other growth factors. Also, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, for example.


An antibody (e.g., monoclonal antibody) can be used to isolate target polypeptides by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, an antibody can be used to detect a target polypeptide (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance (i.e., antibody labeling). Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125I, 131I, 35S or 3H. Also, an antibody can be utilized as a test molecule for determining whether it can treat osteoporosis, and as a therapeutic for administration to a subject for treating osteoporosis.


An antibody can be made by immunizing with a purified antigen, or a fragment thereof, e.g., a fragment described herein, a membrane associated antigen, tissues, e.g., crude tissue preparations, whole cells, preferably living cells, lysed cells, or cell fractions.


Included herein are antibodies which bind only a native polypeptide, only denatured or otherwise non-native polypeptide, or which bind both, as well as those having linear or conformational epitopes. Conformational epitopes sometimes can be identified by selecting antibodies that bind to native but not denatured polypeptide. Also featured are antibodies that specifically bind to a polypeptide variant associated with low BMD.


Methods for Identifying Candidate Therapeutics for Treating Osteoporosis


Current treatment for osteoporosis can help stop further bone loss and fractures, but there is still a clear need for specific anabolic agents that considerably increase bone formation in people who have already suffered substantial bone loss. There are no such drugs currently approved. Known osteoporosis treatments include bone-active phosphonates (See, e.g., U.S. Pat. No. 6,329,354), bisphosphonates, e.g., alendronate (Fosamax®) and risedronate (Actonel®); calcitonin (Niacalcin®); estrogen and hormone therapy, e.g., estrogens (Climara®, Estrace®, Estraderm®, Estratab®, Ogen®, Ortho-Est®, Vivelle®, Premarin®, and others) and estrogens and progestins (brand names, such as Activella™, FemHrt®, Premphase®, Prempro®, and others); parathyroid hormone, e.g., teriparatide {PTH 1-34} (Forteo®); as well as, estrogen and estrogen receptor modulators (SERMs), e.g., raloxifene HCl (Evista®), sodium fluoride and vitamin D metabolites. Any of the above therapeutics may be administered alone or in combination (e.g., bone-active phosphonates and estrogen and hormone therapy). Current therapeutic approaches were largely developed in the absence of defined molecular targets or even a solid understanding of disease pathogenesis. Therefore, provided are methods of identifying candidate therapeutics that target biochemical pathways related to the development of osteoporosis.


Thus, featured herein are methods for identifying a candidate therapeutic for treating osteoporosis. The methods comprise contacting a test molecule with a target molecule in a system. A “target molecule” as used herein refers to a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid, a substantially identical nucleic acid thereof, or a fragment thereof, and an encoded polypeptide of the foregoing. The methods also comprise determining the presence or absence of an interaction between the test molecule and the target molecule, where the presence of an interaction between the test molecule and the nucleic acid or polypeptide identifies the test molecule as a candidate osteoporosis therapeutic. The interaction between the test molecule and the target molecule may be quantified.


Test molecules and candidate therapeutics include, but are not limited to, compounds, antisense nucleic acids, siRNA molecules, ribozymes, polypeptides or proteins encoded by a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleotide sequence, or a substantially identical sequence or fragment thereof, and immunotherapeutics (e.g., antibodies and HLA-presented polypeptide fragments). A test molecule or candidate therapeutic may act as a modulator of target molecule concentration or target molecule function in a system. A “modulator” may agonize (i.e., up-regulates) or antagonize (i.e., down-regulates) a target molecule concentration partially or completely in a system by affecting such cellular functions as DNA replication and/or DNA processing (e.g. DNA methylation or DNA repair), RNA transcription and/or RNA processing (e.g., removal of intronic sequences and/or translocation of spliced mRNA from the nucleus), polypeptide production (e.g., translation of the polypeptide from mRNA), and/or polypeptide post-translational modification (e.g., glycosylation, phosphorylation, and proteolysis of pro-polypeptides). A modulator may also agonize or antagonize a biological function of a target molecule partially or completely, where the function may include adopting a certain structural conformation, interacting with one or more binding partners, ligand binding, catalysis (e.g., phosphorylation, dephosphorylation, hydrolysis, methylation, and isomerization), and an effect upon a cellular event (e.g., effecting progression of osteoporosis). In certain embodiments, a candidate therapeutic increases BMD.


As used herein, the term “system” refers to a cell free in vitro environment and a cell-based environment such as a collection of cells, a tissue, an organ, or an organism. A system is “contacted” with a test molecule in a variety of manners, including adding molecules in solution and allowing them to interact with one another by diffusion, cell injection, and any administration routes in an animal. As used herein, the term “interaction” refers to an effect of a test molecule on test molecule, where the effect sometimes is binding between the test molecule and the target molecule, and sometimes is an observable change in cells, tissue, or organism.


There are many standard methods for detecting the presence or absence of interaction between a test molecule and a target molecule. For example, titrametric, acidimetric, radiometric, NMR, monolayer, polarographic, spectrophotometric, fluorescent, and ESR assays probative of a target molecule interaction may be utilized.


Test molecule/target molecule interactions can be detected and/or quantified using assays known in the art. For example, an interaction can be determined by labeling the test molecule and/or the target molecule, where the label is covalently or non-covalently attached to the test molecule or target molecule. The label is sometimes a radioactive molecule such as 125I, 131I, 35S or 3H, which can be detected by direct counting of radioemission or by scintillation counting. Also, enzymatic labels such as horseradish peroxidase, alkaline phosphatase, or luciferase may be utilized where the enzymatic label can be detected by determining conversion of an appropriate substrate to product. In addition, presence or absence of an interaction can be determined without labeling. For example, a microphysiometer (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indication of an interaction between a test molecule and target molecule (McConnell, H. M. et al., Science 257: 1906-1912 (1992)).


In cell-based systems, cells typically include a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid, an encoded polypeptide, or substantially identical nucleic acid or polypeptide thereof, and are often of mammalian origin, although the cell can be of any origin. Whole cells, cell homogenates, and cell fractions (e.g., cell membrane fractions) can be subjected to analysis. Where interactions between a test molecule with a target polypeptide are monitored, soluble and/or membrane bound forms of the polypeptide may be utilized. Where membrane-bound forms of the polypeptide are used, it may be desirable to utilize a solubilizing agent. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)n, 3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS), 3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate (CHAPSO), or N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate.


An interaction between a test molecule and target molecule also can be detected by monitoring fluorescence energy transfer (FET) (see, e.g., Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos et al. U.S. Pat. No. 4,868,103). A fluorophore label on a first, “donor” molecule is selected such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, “acceptor” molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the “donor” polypeptide molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the “acceptor” molecule label may be differentiated from that of the “donor”. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the “acceptor” molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g. using a fluorimeter).


In another embodiment, determining the presence or absence of an interaction between a test molecule and a target molecule can be effected by monitoring surface plasmon resonance (see, e.g., Sjolander & Urbaniczk, Anal. Chem. 63: 2338-2345 (1991) and Szabo et al., Curr. Opin. Struct. Biol. 5: 699-705 (1995)). “Surface plasmon resonance” or “biomolecular interaction analysis (BIA)” can be utilized to detect biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.


In another embodiment, the target molecule or test molecules are anchored to a solid phase, facilitating the detection of target molecule/test molecule complexes and separation of the complexes from free, uncomplexed molecules. The target molecule or test molecule is immobilized to the solid support. In an embodiment, the target molecule is anchored to a solid surface, and the test molecule, which is not anchored, can be labeled, either directly or indirectly, with detectable labels discussed herein.


It may be desirable to immobilize a target molecule, an anti-target molecule antibody, and/or test molecules to facilitate separation of target molecule/test molecule complexes from uncomplexed forms, as well as to accommodate automation of the assay. The attachment between a test molecule and/or target molecule and the solid support may be covalent or non-covalent (see, e.g., U.S. Pat. No. 6,022,688 for non-covalent attachments). The solid support may be one or more surfaces of the system, such as one or more surfaces in each well of a microtiter plate, a surface of a silicon wafer, a surface of a bead (see, e.g., Lam, Nature 354: 82-84 (1991)) that is optionally linked to another solid support, or a channel in a microfluidic device, for example. Types of solid supports, linker molecules for covalent and non-covalent attachments to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are well known (see, e.g., U.S. Pat. Nos. 6,261,776; 5,900,481; 6,133,436; and 6,022,688; and WIPO publication WO 01/18234).


In an embodiment, target molecule may be immobilized to surfaces via biotin and streptavidin. For example, biotinylated target polypeptide can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In another embodiment, a target polypeptide can be prepared as a fusion polypeptide. For example, glutathione-S-transferase/target polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivitized microtiter plates, which are then combined with a test molecule under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, or the matrix is immobilized in the case of beads, and complex formation is determined directly or indirectly as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of target molecule binding or activity is determined using standard techniques.


In an embodiment, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that a significant percentage of complexes formed will remain immobilized to the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of manners. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface, e.g., by adding a labeled antibody specific for the immobilized component, where the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody.


In another embodiment, an assay is performed utilizing antibodies that specifically bind target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule. Such antibodies can be derivitized to a solid support, and unbound target molecule may be immobilized by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.


Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by any of a number of standard techniques, including but not limited to: differential centrifugation (see, e.g., Rivas, G., and Minton, Trends Biochem Sci August; 18(8): 284-7 (1993)); chromatography (gel filtration chromatography, ion-exchange chromatography); electrophoresis (see, e.g., Ausubel et al., eds. Current Protocols in Molecular Biology, J. Wiley: New York (1999)); and immunoprecipitation (see, e.g., Ausubel et al., eds., supra). Media and chromatographic techniques are known to one skilled in the art (see, e.g., Heegaard, J Mol. Recognit. Winter; 11(1-6): 141-8 (1998); Hage & Tweed, J. Chromatogr. B Biomed. Sci. Appl. October 10; 699 (1-2): 499-525 (1997)). Further, fluorescence energy transfer may also be conveniently utilized, as described herein, to detect binding without further purification of the complex from solution.


In another embodiment, modulators of target molecule expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of target mRNA or target polypeptide is evaluated relative to the level of expression of target mRNA or target polypeptide in the absence of the candidate compound. When expression of target mRNA or target polypeptide is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as an agonist of target mRNA or target polypeptide expression. Alternatively, when expression of target mRNA or target polypeptide is less (e.g., less with statistical significance) in the presence of the candidate compound than in its absence, the candidate compound is identified as an antagonist or inhibitor of target mRNA or target polypeptide expression. The level of target mRNA or target polypeptide expression can be determined by methods described herein.


In another embodiment, binding partners that interact with a target molecule are detected. The target molecules can interact with one or more cellular or extracellular macromolecules, such as polypeptides in vivo, and these interacting molecules are referred to herein as “binding partners.” Binding partners can agonize or antagonize target molecule biological activity. Also, test molecules that agonize or antagonize interactions between target molecules and binding partners can be useful as therapeutic molecules as they can up-regulate or down-regulated target molecule activity in vivo and thereby treat osteoporosis.


Binding partners of target molecules can be identified by methods known in the art. For example, binding partners may be identified by lysing cells and analyzing cell lysates by electrophoretic techniques. Alternatively, a two-hybrid assay or three-hybrid assay can be utilized (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J. Biol. Chem. 268: 12046-12054 (1993); Bartel et al., Biotechniques 14: 920-924 (1993); Iwabuchi et al., Oncogene 8: 1693-1696 (1993); and Brent WO94/10300). A two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. The assay often utilizes two different DNA constructs. In one construct, a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid (sometimes referred to as the “bait”) is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In another construct, a DNA sequence from a library of DNA sequences that encodes a potential binding partner (sometimes referred to as the “prey”) is fused to a gene that encodes an activation domain of the known transcription factor. Sometimes, a CETP, PROL4, GRID2, PDE4D or GPX3/TNIP1 nucleic acid can be fused to the activation domain. If the “bait” and the “prey” molecules interact in vivo, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to identify the potential binding partner.


In an embodiment for identifying test molecules that antagonize or agonize complex formation between target molecules and binding partners, a reaction mixture containing the target molecule and the binding partner is prepared, under conditions and for a time sufficient to allow complex formation. The reaction mixture often is provided in the presence or absence of the test molecule. The test molecule can be included initially in the reaction mixture, or can be added at a time subsequent to the addition of the target molecule and its binding partner. Control reaction mixtures are incubated without the test molecule or with a placebo. Formation of any complexes between the target molecule and the binding partner then is detected. Decreased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule antagonizes target molecule/binding partner complex formation. Alternatively, increased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule agonizes target molecule/binding partner complex formation. In another embodiment, complex formation of target molecule/binding partner can be compared to complex formation of mutant target molecule/binding partner (e.g., amino acid modifications in a target polypeptide). Such a comparison can be important in those cases where it is desirable to identify test molecules that modulate interactions of mutant but not non-mutated target gene products.


The assays can be conducted in a heterogeneous or homogeneous format. In heterogeneous assays, target molecule and/or the binding partner are immobilized to a solid phase, and complexes are detected on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the molecules being tested. For example, test compounds that agonize target molecule/binding partner interactions can be identified by conducting the reaction in the presence of the test molecule in a competition format. Alternatively, test molecules that agonize preformed complexes, e.g., molecules with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed.


In a heterogeneous assay embodiment, the target molecule or the binding partner is anchored onto a solid surface (e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored molecule can be immobilized by non-covalent or covalent attachments. Alternatively, an immobilized antibody specific for the molecule to be anchored can be used to anchor the molecule to the solid surface. The partner of the immobilized species is exposed to the coated surface with or without the test molecule. After the reaction is complete, unreacted components are removed (e.g., by washing) such that a significant portion of any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface is indicative of complex. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored to the surface; e.g., by using a labeled antibody specific for the initially non-immobilized, species. Depending upon the order of addition of reaction components, test compounds that inhibit complex formation or that disrupt preformed complexes can be detected.


In another embodiment, the reaction can be conducted in a liquid phase in the presence or absence of test molecule, where the reaction products are separated from unreacted components, and the complexes are detected (e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes). Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.


In an alternate embodiment, a homogeneous assay can be utilized. For example, a preformed complex of the target gene product and the interactive cellular or extracellular binding partner product is prepared. One or both of the target molecule or binding partner is labeled, and the signal generated by the label(s) is quenched upon complex formation (e.g., U.S. Pat. No. 4,109,496 that utilizes this approach for immunoassays). Addition of a test molecule that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target molecule/binding partner complexes can be identified.


Candidate therapeutics for treating osteoporosis are identified from a group of test molecules that interact with a target molecule. Test molecules are normally ranked according to the degree with which they modulate (e.g. agonize or antagonize) a function associated with the target molecule (e.g., DNA replication and/or processing, RNA transcription and/or processing, polypeptide production and/or processing, and/or biological function/activity), and then top ranking modulators are selected. Also, pharmacogenomic information described herein can determine the rank of a modulator. The top 10% of ranked test molecules often are selected for further testing as candidate therapeutics, and sometimes the top 15%, 20%, or 25% of ranked test molecules are selected for further testing as candidate therapeutics. Candidate therapeutics typically are formulated for administration to a subject.


Therapeutic Formulations


Formulations and pharmaceutical compositions typically include in combination with a pharmaceutically acceptable carrier one or more target molecule modulators. The modulator often is a test molecule identified as having an interaction with a target molecule by a screening method described above. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner. Also, formulations may comprise a target polypeptide or fragment thereof in combination with a pharmaceutically acceptable carrier.


As used herein, the term “pharmaceutically acceptable carrier” includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.


A pharmaceutical composition typically is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.


Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.


Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.


Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.


For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.


Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. Molecules can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.


In one embodiment, active molecules are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.


It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.


Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Molecules which exhibit high therapeutic indices are preferred. While molecules that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.


The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such molecules lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any molecules used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.


As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, sometimes about 0.01 to 25 mg/kg body weight, often about 0.1 to 20 mg/kg body weight, and more often about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, sometimes between 2 to 8 weeks, often between about 3 to 7 weeks, and more often for about 4, 5, or 6 weeks. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.


With regard to polypeptide formulations, featured herein is a method for treating osteoporosis in a subject, which comprises contacting one or more cells in the subject with a first polypeptide, where the subject comprises a second polypeptide having one or more polymorphic variations associated with low BMD, and where the first polypeptide comprises fewer polymorphic variations associated with low BMD than the second polypeptide. The first and second polypeptides are encoded by a nucleic acid which comprises a nucleotide sequence in SEQ ID NO's:1-10; a nucleotide sequence which encodes a polypeptide consisting of an amino acid sequence encoded by a nucleotide sequence referenced in SEQ ID NO's:1-10; a nucleotide sequence which encodes a polypeptide that is 90% or more identical to an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO's:1-10 and a nucleotide sequence 90% or more identical to a nucleotide sequence in SEQ ID NO's:1-10. The subject often is a human.


For antibodies, a dosage of 0.1 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg) is often utilized. If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is often appropriate. Generally, partially human antibodies and fully human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g., into the brain). A method for lipidation of antibodies is described by Cruikshank et al., J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193 (1997).


Antibody conjugates can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, .alpha.-interferon, .beta.-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.


For compounds, exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight, for example, about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid described herein, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.


With regard to nucleic acid formulations, gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (see e.g., Chen et al., (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). Pharmaceutical preparations of gene therapy vectors can include a gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells (e.g., retroviral vectors) the pharmaceutical preparation can include one or more cells which produce the gene delivery system. Examples of gene delivery vectors are described herein.


Therapeutic Methods


A therapeutic formulation described above can be administered to a subject in need of a therapeutic for inducing a desired biological response. Therapeutic formulations can be administered by any of the paths described herein. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from pharmacogenomic analyses described herein.


As used herein, the term “treatment” is defined as the application or administration of a therapeutic formulation to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect osteoporosis, symptoms of osteoporosis or a predisposition towards osteoporosis. A therapeutic formulation includes, but is not limited to, small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides. Administration of a therapeutic formulation can occur prior to the manifestation of symptoms characteristic of low BMD, such that osteoporosis is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.


As discussed, successful treatment of osteoporosis can be brought about by techniques that serve to agonize target molecule expression or function, or alternatively, antagonize target molecule expression or function. These techniques include administration of modulators that include, but are not limited to, small organic or inorganic molecules; antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab′)2 and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.


Further, antisense and ribozyme molecules that inhibit expression of the target gene can also be used to reduce the level of target gene expression, thus effectively reducing the level of target gene activity. Still further, triple helix molecules can be utilized in reducing the level of target gene activity. Antisense, ribozyme and triple helix molecules are discussed above. It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extracellular polypeptide, it can be preferable to co-administer normal target gene polypeptide into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.


Another method by which nucleic acid molecules may be utilized in treating or preventing osteoporosis is use of aptamer molecules specific for target molecules. Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to ligands (see, e.g., Osborne, et al., Curr. Opin. Chem. Biol. 1(1): 5-9 (1997); and Patel, D. J., Curr. Opin. Chem. Biol. June; 1(1): 32-46 (1997)).


Yet another method of utilizing nucleic acid molecules for osteoporosis treatment is gene therapy, which can also be referred to as allele therapy. Provided herein is a gene therapy method for treating osteoporosis in a subject, which comprises contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with low BMD (e.g., the second nucleic acid has a nucleotide sequence in SEQ ID NO's:1-10). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with low BMD than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human. Allele therapy methods often are utilized in conjunction with a method of first determining whether a subject has genomic DNA that includes polymorphic variants associated with low BMD.


In another allele therapy embodiment, provided herein is a method which comprises contacting one or more cells in the subject or from the subject with a polypeptide encoded by a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject comprises a second nucleotide sequence having one or more polymorphic variations associated with low BMD (e.g., the second nucleic acid has a nucleotide sequence in SEQ ID NO's:1-10). The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer polymorphic variations associated with low BMD than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human.


For antibody-based therapies, antibodies can be generated that are both specific for target molecules and that reduce target molecule activity. Such antibodies may be administered in instances where antagonizing a target molecule function is appropriate for the treatment of osteoporosis.


In circumstances where stimulating antibody production in an animal or a human subject by injection with a target molecule is harmful to the subject, it is possible to generate an immune response against the target molecule by use of anti-idiotypic antibodies (see, e.g., Herlyn, Ann. Med.; 31(1): 66-78 (1999); and Bhattacharya-Chatterjee & Foon, Cancer Treat. Res.; 94: 51-68 (1998)). Introducing an anti-idiotypic antibody to a mammal or human subject often stimulates production of anti-anti-idiotypic antibodies, which typically are specific to the target molecule. Vaccines directed to osteoporosis also may be generated in this fashion.


In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies may be preferred. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells. Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen is preferred. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used. Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (see, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA 90: 7889-7893 (1993)).


Modulators can be administered to a patient at therapeutically effective doses to treat osteoporosis. A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of osteoporosis. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Modulators that exhibit large therapeutic indices are preferred. While modulators that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such molecules to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.


Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.


Another example of effective dose determination for an individual is the ability to directly assay levels of “free” and “bound” compound in the serum of the test subject. Such assays may utilize antibody mimics and/or “biosensors” that have been created through molecular imprinting techniques. Molecules that modulate target molecule activity are used as a template, or “imprinting molecule”, to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated “negative image” of the compound and is able to selectively rebind the molecule under biological assay conditions. A detailed review of this technique can be seen in Ansell et al., Current Opinion in Biotechnology 7: 89-94 (1996) and in Shea, Trends in Polymer Science 2: 166-173 (1994). Such “imprinted” affinity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrixes in this way can be seen in Vlatakis, et al., Nature 361: 645-647 (1993). Through the use of isotope-labeling, the “free” concentration of compound which modulates target molecule expression or activity readily can be monitored and used in calculations of IC50. Such “imprinted” affinity matrixes can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes readily can be assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual IC50. An example of such a “biosensor” is discussed in Kriz et al., Analytical Chemistry 67: 2142-2144 (1995).


The examples set forth below are intended to illustrate but not limit the invention.


EXAMPLES

In the following studies a group of subjects were selected according to specific parameters relating to low BMD. Nucleic acid samples obtained from individuals in the study group were subjected to genetic analysis, which identified associations between low BMD and certain polymorphic variants in CETP, PROL4, GRID2, PDE4D and GPX3 (herein referred to as “target genes”, “target nucleotides”, “target polypeptides” or simply “targets”). Methods are described for producing CETP, PROL4, GRID2, PDE4D and GPX3 polypeptides and polypeptide variants in vitro or in vivo. CETP, PROL4, GRID2, PDE4D and GPX3 nucleic acids or polypeptides and variants thereof are utilized for screening test molecules for those that interact with CETP, PROL4, GRID2, PDE4D and GPX3 molecules. Test molecules identified as being interactors with target polypeptides can be screened further as osteoporosis therapeutics.


Example 1
Samples and Pooling Strategies

Sample Selection


Blood samples were collected from individuals with low BMD, which were referred to as case samples. Also, blood samples were collected from individuals with high BMD (i.e., not diagnosed with osteoporosis or any form of osteoporosis-related disease); these samples served as gender and age-matched controls. All of the samples were of Caucasian (English) descent A database was created that listed all phenotypic trait information gathered from individuals for each case and control sample. Genomic DNA was extracted from each of the blood samples for genetic analyses.


DNA Extraction from Blood Samples


Six to ten milliliters of whole blood was transferred to a 50 ml tube containing 27 ml of red cell lysis solution (RCL). The tube was inverted until the contents were mixed. Each tube was incubated for 10 minutes at room temperature and inverted once during the incubation. The tubes were then centrifuged for 20 minutes at 3000×g and the supernatant was carefully poured off. 100-200 μl of residual liquid was left in the tube and was pipetted repeatedly to resuspend the pellet in the residual supernatant White cell lysis solution (WCL) was added to the tube and pipetted repeatedly until completely mixed. While no incubation was normally required, the solution was incubated at 37° C. or room temperature if cell clumps were visible after mixing until the solution was homogeneous. 2 ml of protein precipitation was added to the cell lysate. The mixtures were vortexed vigorously at high speed for 20 sec to mix the protein precipitation solution uniformly with the cell lysate, and then centrifuged for 10 minutes at 3000×g. The supernatant containing the DNA was then poured into a clean 15 ml tube, which contained 7 ml of 100% isopropanol. The samples were mixed by inverting the tubes gently until white threads of DNA were visible. Samples were centrifuged for 3 minutes at 2000×g and the DNA was visible as a small white pellet. The supernatant was decanted and 5 ml of 70% ethanol was added to each tube. Each tube was inverted several times to wash the DNA pellet, and then centrifuged for 1 minute at 2000×g. The ethanol was decanted and each tube was drained on clean absorbent paper. The DNA was dried in the tube by inversion for 10 minutes, and then 1000 μl of 1×TE was added. The size of each sample was estimated, and less TE buffer was added during the following DNA hydration step if the sample was smaller. The DNA was allowed to rehydrate overnight at room temperature, and DNA samples were stored at 2-8° C.


DNA was quantified by placing samples on a hematology mixer for at least 1 hour. DNA was serially diluted (typically 1:80, 1:160, 1:320, and 1:640 dilutions) so that it would be within the measurable range of standards. 125 μl of diluted DNA was transferred to a clear U-bottom microtitre plate, and 125 μl of 1×TE buffer was transferred into each well using a multichannel pipette. The DNA and 1×TE were mixed by repeated pipetting at least 15 times, and then the plates were sealed. 50 μl of diluted DNA was added to wells A5-H12 of a black flat bottom microtitre plate. Standards were inverted six times to mix them, and then 50 μl of 1×TE buffer was pipetted into well A1, 1000 ng/ml of standard was pipetted into well A2, 500 ng/ml of standard was pipetted into well A3, and 250 ng/ml of standard was pipetted into well A4. PicoGreen (Molecular Probes, Eugene, Oreg.) was thawed and freshly diluted 1:200 according to the number of plates that were being measured. PicoGreen was vortexed and then 50 μl was pipetted into all wells of the black plate with the diluted DNA. DNA and PicoGreen were mixed by pipetting repeatedly at least 10 times with the multichannel pipette. The plate was placed into a Fluoroskan Ascent Machine (microplate fluorometer produced by Labsystems) and the samples were allowed to incubate for 3 minutes before the machine was run using filter pairs 485 nm excitation and 538 nm emission wavelengths. Samples having measured DNA concentrations of greater than 450 ng/l were re-measured for conformation. Samples having measured DNA concentrations of 20 ng/μl or less were re-measured for confirmation.


Pooling Strategies


Samples were placed into one of two groups based on BMD levels. The two groups were made up of individuals with low BMD levels and individuals with high BMD levels. A select set of samples from each group were utilized to generate pools, and one pool was created for each group. Each individual sample in a pool was represented by an equal amount of genomic DNA. For example, where 25 ng of genomic DNA was utilized in each PCR reaction and there were 200 individuals in each pool, each individual would provide 125 pg of genomic DNA. Inclusion or exclusion of samples for a pool was based upon the following criteria: the sample was derived from an individual of Caucasian paternal and maternal descent; the database included relevant phenotype information for the individual; case samples were derived from individuals with low BMD; control samples were derived from individuals with normal or high BMD and no history of osteoporosis or osteoporosis-related diseases; and sufficient genomic DNA was extracted from each blood sample for all allelotyping and genotyping reactions performed during the study. Phenotype information included pre- or post-menopausal, familial predisposition, country or origin of mother and father, diagnosis with osteoporosis (date of primary diagnosis, age of individual as of primary diagnosis, osteoporosis-related fracture), biochemical measurements of markers of bone resorption (bone-specific alkaline Phosphatase, Urinary C-telopeptide of type I collagen, serum osteocalcin), current medication status (thyroid medication, hormone replacement therapy, steroid usage, bisphosphonates and cytotoxic agents for rheumatic diseases). Samples that met the inclusion criteria and did not meet the exclusion criteria were added to appropriate pools based on gender and disease status.


The selection process yielded the pools set forth in Table 2, which were used in the studies that follow. The average (mean) T-score in the High group is 1.56, and in the Low group −2.1 which means that on average individuals in the high BMD pool are 1.56 standard deviations above the average BMD in young females, whereas individuals in the low BMD pool are on average 2.1 standard deviations below the normal young value.

TABLE 2Female High BMDFemale Low BMDPool size321319(Number)Mean T-score1.56−2.10(BMD leveles adjusted forage and BMI)Mean Age52.952.4(ex: years)


Example 2
Association of Polymorphic Variants with Low BMD

A whole-genome screen was performed to identify particular SNPs associated with low BMD. As described in Example 1, two groups of samples were utilized, which included samples from female individuals having low BMD (osteoporosis cases), and samples from female individuals having high BMD levels (controls). The initial screen of each pool was performed in an allelotyping study, in which certain samples in each group were pooled. By pooling DNA from each group, an allele frequency for each SNP in each group was calculated. These allele frequencies were then compared to one another. Particular SNPs were considered as being associated with low BMD when allele frequency differences calculated between case and control pools were statistically significant. SNP disease association results obtained from the allelotyping study were then validated by genotyping each associated SNP across all samples from each pool. The results of the genotyping were then analyzed, allele frequencies for each group were calculated from the individual genotyping results, and a p-value was calculated to determine whether the case and control groups had statistically significantly differences in allele frequencies for a particular SNP. When the genotyping results agreed with the original allelotyping results, the SNP disease association was considered validated at the genetic level.


SNP Panel Used for Genetic Analyses


A whole-genome SNP screen began with an initial screen of approximately 25,000 SNPs over each set of disease and control samples using a pooling approach. The pools studied in the screen are described in Example 1. The SNPs analyzed in this study were part of a set of 25,488 SNPs confirmed as being statistically polymorphic as each is characterized as having a minor allele frequency of greater than 10%. The SNPs in the set reside in genes or in close proximity to genes, and many reside in gene exons. Specifically, SNPs in the set are located in exons, introns, and within 5,000 base-pairs upstream of a transcription start site of a gene. In addition, SNPs were selected according to the following criteria: they are located in ESTs; they are located in Locuslink or Ensemb1 genes; and they are located in Genomatix promoter predictions. SNPs in the set were also selected on the basis of even spacing across the genome, as depicted in Table 3. An additional 3088 SNPs were included with these 25,488 SNPs and these additional SNPs had been chosen on the basis of gene location, with preference to non-synonymous coding SNPs located in disease candidate genes.

TABLE 3General StatisticsSpacing StatisticsTotal # of SNPs25,488Median 37,058 bp# of Exonic SNPs>4,335 (17%)Minimum* 1,000 bp# SNPs with20,776 (81%)Maximum*3,000,000 bp  refSNP IDGene Coverage>10,000Mean122,412 bpChromosomeAllStd Deviation373,325 pbCoverage
*Excludes outliers


Allelotyping and Genotyping Results


The genetic studies summarized above and described in more detail below identified allelic variants associated with low BMD. The allelic variants identified from the SNP panel described in Table 3 are summarized below in Table 4.

TABLE 4LowPositionBMDSNPChromosomein SEQContigContigSequenceSequenceAllelicAssoc.ReferenceChromosomePositionID NosIdentificationPositionIdentificationLocusPositionVariabilityAllelers180170616q215706882350109NT_01049810631861NM_000078CETPUTRAGGrs104769912p131114388649075NT_0097143758682NM_007244PROL4Exon:CTCR120Qrs19480174q229463636549110NT_01635418829520NM_001510GRID2IntronCTCrs14986085q125989558049652NT_0067138937426NM_006203PDE4DIntronATTrs8699755q2315047523350082NT_02928911569308NM_002084GPX3IntronAGG


Table 4 includes information pertaining to the incident polymorphic variant associated with low BMD identified herein. Public information pertaining to the polymorphism and the genomic sequence that includes the polymorphism are indicated. The genomic sequences identified in Table 4 may be accessed at the http address www.ncbi.nih.gov/entrez/query.fcgi, for example, by using the publicly available SNP reference number (e.g., rs1801706). The chromosome position refers to the position of the SNP within NCBI's Genome Build 34, which may be accessed at the following http address: www.ncbi.nlm.nih.gov/mapview/map_search.cgi?chr=hum_chr.inf&query=. The “Contig Position” provided in Table 4 corresponds to a nucleotide position set forth in the contig sequence, and designates the polymorphic site corresponding to the SNP reference number. The sequence containing the polymorphisms also may be referenced by the “Sequence Identification” set forth in Table 4. The “Sequence Identification” corresponds to cDNA sequence that encodes associated target polypeptides (e.g., CETP) of the invention. The position of the SNP within the cDNA sequence is provided in the “Sequence Position” column of Table 4. Also, the allelic variation at the polymorphic site and the allelic variant identified as associated with low BMD is specified in Table 4. All nucleotide sequences referenced and accessed by the parameters set forth in Table 4 are incorporated herein by reference.


Assay for Verifying, Allelotyping, and Genotyping SNPs


A MassARRAY® system (Sequenom, Inc.) was utilized to perform SNP genotyping in a high-throughput fashion. This genotyping platform was complemented by a homogeneous, single-tube assay method (hME™ or homogeneous MassEXTEND™ (Sequenom, Inc.)) in which two genotyping primers anneal to and amplify a genomic target surrounding a polymorphic site of interest. A third primer (the MassEXTEND™ primer), which is complementary to the amplified target up to but not including the polymorphism, was then enzymatically extended one or a few bases through the polymorphic site and then terminated.


For each polymorphism, SpectroDESIGNER™ software (Sequenom, Inc.) was used to generate a set of PCR primers and a MassEXTEND™ primer was used to genotype the polymorphism. Table 5 shows PCR primers and Table 6 shows extension primers used for analyzing polymorphisms. The initial PCR amplification reaction was performed in a 5 A1 total volume containing 1×PCR buffer with 1.5 mM MgCl2 (Qiagen), 200 μM each of dATP, dGTP, dCTP, dTTP (Gibco-BRL), 2.5 ng of genomic DNA, 0.1 units of HotStar DNA polymerase (Qiagen), and 200 nM each of forward and reverse PCR primers specific for the polymorphic region of interest.

TABLE 5PCR PrimersReferenceForwardReverseSNP IDPCR primerPCR primerrs1801706ACGTTGGATGTTGTAGCAGACGTTGGATGTCCATCTCCGAAGGCAAGCACTACTCCTAACrs1047699GATTACCAGAGTGGTTGCTCCTGCAGGAAGCATCATCATCrs1948017GTTTAACAGCAACCATTGACCCCAAAGGTATGTTAAGAGGGrs1498608GAATCCCTGTTCATTCCTTATACCTAGGTATAACCTCGGGrs869975AACTCACTGGTGATCCTGCTGTCTCATCCACACCACTCCG


Samples were incubated at 95° C. for 15 minutes, followed by 45 cycles of 95° C. for 20 seconds, 56° C. for 30 seconds, and 72° C. for 1 minute, finishing with a 3 minute final extension at 720° C. Following amplification, shrimp alkaline phosphatase (SAP) (0.3 units in a 2 μl volume) (Amersham Pharmacia) was added to each reaction (total reaction volume was 7 μl) to remove any residual dNTPs that were not consumed in the PCR step. Samples were incubated for 20 minutes at 37° C., followed by 5 minutes at 85° C. to denature the SAP.


Once the SAP reaction was complete, a primer extension reaction was initiated by adding a polymorphism-specific MassEXTEND™ primer cocktail to each sample. Each MassEXTEND™ cocktail included a specific combination of dideoxynucleotides (ddNTPs) and deoxynucleotides (dNTPs) used to distinguish polymorphic alleles from one another. In Table 6, ddNTPs are shown and the fourth nucleotide not shown is the dNTP.

TABLE 6Extend PrimersReferenceExtendTermSNP IDProbeMixrs1801708CCTGGTGTCTCCTCCAGCACTrs1047699TGTCTTGCTGGTCTGTCCCTCACGrs1948017CAGCAACCATTGAGGGTGAATACGrs1498608CCCTAAAAACTGTTCCAGGTACGTrs869975GGGCCTCAGTAGTTCCAGCACT


The MassEXTEND™ reaction was performed in a total volume of 9 μl, with the addition of 1× ThermoSequenase buffer, 0.576 units of ThermoSequenase (Amersham Pharmacia), 600 nM MassEXTEND™ primer, 2 mM of ddATP and/or ddCTP and/or ddGTP and/or ddTTP, and 2 mM of dATP or dCTP or dGTP or dTTP. The deoxy nucleotide (dNTP) used in the assay normally was complementary to the nucleotide at the polymorphic site in the amplicon. Samples were incubated at 94° C. for 2 minutes, followed by 55 cycles of 5 seconds at 94° C., 5 seconds at 52° C., and 5 seconds at 72° C.


Following incubation, samples were desalted by adding 16 μl of water (total reaction volume was 25 μl), 3 mg of SpectroCLEAN™ sample cleaning beads (Sequenom, Inc.) and allowed to incubate for 3 minutes with rotation. Samples were then robotically dispensed using a piezoelectric dispensing device (SpectroJET™ (Sequenom, Inc.)) onto either 96-spot or 384-spot silicon chips containing a matrix that crystallized each sample (SpectroCHIP® (Sequenom, Inc.)). Subsequently, MALDI-TOF mass spectrometry (Biflex and Autoflex MALDI-TOF mass spectrometers (Bruker Daltonics) can be used) and SpectroTYPER RT™ software (Sequenom, Inc.) were used to analyze and interpret the SNP genotype for each sample.


Genetic Analysis


Variations identified in the target genes are provided in their respective genomic sequences (see SEQ ID NOs:1-4) Minor allelic frequencies for these polymorphisms was verified as being 10% or greater by determining the allelic frequencies using the extension assay described above in a group of samples isolated from 92 individuals originating from the state of Utah in the United States, Venezuela and France (Coriell cell repositories).


Genotyping results for the allelic variant set forth in Table 4 are shown for female pools in Table 7. In Table 7, “F case” and “F control” refer to female case (low BMD) and female control (high BMD) groups, and “AF” refers to allele frequency.

TABLE 7Female Genotype ResultsLow BMDSNPF AF caseF AF controlOddsAssociatedReference(low)(high)p-valueRatioAllelera1801706A = 0.15A = 0.190.007650.661GG = 0.85G = 0.81rs1047699C = 0.85C = 0.780.0005941.65CT = 0.15T = 0.22rs1948017C = 0.14C = 0.100.01881.51CT = 0.86T = 0.90rs1498608A = 0.09A = 0.120.03470.672TT = 0.91T = 0.88rs869975A = 0.05A = 0.100.0002430.441GG = 0.95G = 0.90


The single marker alleles set forth in Table 7 were considered validated, since the genotyping data were significantly associated with low BMD, and because the genotyping results agreed with the original allelotyping results. Particularly significant associations with low BMD are indicated by a calculated p-value of less than 0.05 for genotype results, which are set forth in bold text.


Odds ratio results are shown in Table 7 (and other Tables below). An odds ratio is an unbiased estimate of relative risk which can be obtained from most case-control studies. Relative risk (RR) is an estimate of the likelihood of disease in the exposed group (susceptibility allele or genotype carriers) compared to the unexposed group (not carriers). It can be calculated by the following equation:

RR=IA/Ia


IA is the incidence of disease in the A carriers and Ia is the incidence of disease in the non-carriers.


RR>1 indicates the A allele increases disease susceptibility.


RR<1 indicates the a allele increases disease susceptibility.


For example, RR=1.5 indicates that carriers of the A allele have 1.5 times the risk of disease than non-carriers, i.e., 50% more likely to get the disease.


Case-control studies do not allow the direct estimation of IA and Ia, therefore relative risk cannot be directly estimated. However, the odds ratio (OR) can be calculated using the following equation:

OR=(nDAnda)/(ndAnDa)=pDA(1−pdA)/pdA(1−pDA), or


OR=((case f)/(1−case f)/((control f)/(1−control f)), where f=susceptibility allele frequency.


An odds ratio can be interpreted in the same way a relative risk is interpreted and can be directly estimated using the data from case-control studies, i.e., case and control allele frequencies. The higher the odds ratio value, the larger the effect that particular allele has on the development of low BMD. Possessing an allele associated with a relatively high odds ratio translates to having a higher risk of developing or having low BMD.


Example 3
CETP Region Proximal SNPs

It has been discovered that a polymorphic variation (rs1801706) in a gene encoding CETP is associated with the occurrence of low BMD (see Examples 1 and 2). Ninety-one additional allelic variants proximal to rs1801706 were identified and subsequently allelotyped in low BMD case and high BMD control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 8. The chromosome positions provided in column four of Table 8 are based on Genome “Build 34” of NCBI's GenBank. The “genome letter” corresponds to the particular allele that appears in NCBI's build 34 genomic sequence of the region (chromosome 16: positions 56743155-56840953), and the “deduced iupac” corresponds to the single letter IUPAC code for the CTEP polymorphic variants as they appear in SEQ ID NO:1. Also, the “genome letter” may differ from the alleles (A1/A2) provided in Table 8 (and in subsequent Tables that provide the same information) if the genome letter is on one stand and the alleles are on the complementary strand, thus having different strand orientations (i.e., reverse vs forward).

TABLE 8Position inChromosomeAllelesGenomeDeduceddbSNPSEQ ID NO: 1ChromosomePosition(A1/A2)letteriupac75009792051656743155g/agR221733215951656744545g/agR804480426501656745600c/taR227083554961656748446c/ttY213378357821656748732g/aaR24760959081656748858c/tgR95244075521656750502g/aaR88159891911656752141t/cgR2291955101271656753077g/atY2518054103451656753295g/agR866038103991656753349t/ccY1436425120281656754978g/aaR173537133551656756305a/gtY247611136871656756637a/ggR166017143281656757278t/ccY173538147461656757696c/ttY193694149961656757946t/ccY7205692193611656762311g/aaR8048746217751656764725g/aaR247618232501656766200g/agR183130238101656766760c/tcY6499863244641656767414g/agR4783961273411656770291g/agR3816117286051656771555c/ttY711752286581656771608g/agR708272287351656771685c/tgR1864163296801656772630g/agR4369653299981656772948g/acY1864165325211656775471c/tcY891141361701656779120t/ggK891143364271656779377c/ttY7205804373361656780286g/agR5885377181656780668c/tcY1532625377481656780698a/gcY1532624379261656780876t/gcM289712387521656781702g/acY7499892390371656781987c/tcY5883398001656782750c/tcY289714398981656782848c/tgR158480406741656783624c/tgR289717418351656784785c/tgR4344729423251656785275c/tgR289718423791656785329a/gcY289719423881656785338g/atY2033254424321656785382c/ttY4784744436321656786582g/agR291044438991656786849c/tgR8053613442731656787223c/tcY5881444591656787409a/ggR5880475381656790488c/ggS7198026476921656790642c/ttY5882485391656791489g/agR8045701487491656791699c/ttY289741499211656792871a/ggR1801706501091656793059a/ggR289742502091656793159c/gcS289743502431656793193c/tgR289746526521656795602g/acY172337551951656798145c/ttY289747563851656799335a/gcY1566439571091656800059a/gtY7205459576181656800568c/ttY289749587411656801691t/cgR289751592221656802172t/cgR8059220607711656803721c/tcY8058353609621656803912g/agR289735620091656804959a/gcY289737645891656807539t/gaM291042660541656809004g/aaR1875236661431656809093c/tgR821466678221656810772a/gtY821465688051656811755c/gcS4275846700751656813025c/tgR289707703501656813300a/gtY821463712141656814164g/atY289706795491656822499c/tcY1167741827601656825710c/tcY2052880864631656829413a/cgK1167742865331656829483c/gcS1183256870191656829969a/gaR1651665889101656831860a/caM1651666889551656831905c/tcY4784751890211656831971c/tcY1651667890561656832006a/gaR8052091898631656832813g/agR1684574898791656832829t/ctY1684575900661656833016t/ggK1672865901011656833051a/gaR821470910291656833979g/aaR1549669914341656834384t/gaM291040936361656836586t/ctY289754980031656840953c/tcY


Assay for Verifying and Allelotyping SNPs


The methods used to verify and allelotype the proximal SNPs of Table 8 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 9 and Table 10, respectively.

TABLE 9dbSNPrs#Forward PCR primerReverse PCR primer7500979TTGTATATGTAGGGTCCTGCAAAATAATTCAAAACCACTG2217332ATCCAACAACAGCTTCCCAGGGTGAAATGCTGACCTGTGT8044804ATAAATACAACCCAGCCCACCATTTCATTTCCCTGCACTG2270835CATTTACCATGTAACTGCCGGGGTTGAGTATGAACAAATG2133783ACACTCATCCCTCCATTCTGTCCCGGGAATTGAAGGGAAT247609GTCACTAAACTATGTATCAGGGGTAGAGTGTAAATGACAG952440AGTCAGTGCCTGACTTTACCCATACTGAGGCATGGAACAG881598ACTGCACTCCAGCCTGGGTGATGCTCCTGGCAGCAAATATC2291955GCTAGACATGTTTTAGCAGGCCCCTTAGTTTAAAGTAAAGC2518054CTGATCATTCTTACCGGCACCTAGACAGTCAACAACTGAG866038CAAGGAACAAAGCAAGACCCGTGCCGGTAAGAATGATCAG1436425GTATTCAGAGTGGTGTGTGGGGGACATGGCAGAAATTCAG173537TCCCTGTCCTTGAACTCATCCCTCTTGGGTCTTGTAGTCG247611AGGGTCCTCCATGATTGGAGTTTCTGGACCTGACTGGGTG166017TAGATGGGCTGTTTCTACTGAGGGAAGATTCCAGTAAAGC173538TCCCAAAGTGCTGGGATTACGGGTTTCTCAAAGGGCTAAG193694TCCTTCCGTGATCTCACAACCACACCAAAAGAACTGCATG7205692TCTTAGCCTGGGACTTTCTGAAAAGCAGCTGTGACCTAAG8048746CAAGTTCTTCCTCCATCCACTTCCTCTCTCTGGGCTTATC247618TTTTCCCCCTTTTTGGGGCTGGGTTGTCACAGCAAGGTGG183130ATAAACGGGAAAGAAGAGACAGGGTGGAGAATCTACAGAA6499863GTCTTGACAGGTTTGAGGAGCATCAGACAGATCCCAACAG4783961GAAACATGAGTCGGGATGGCAGCTTTGGTATTGGAGCAGG3816117ACTAGCCCAGAGAGAGGAGTAAGAACTTGACCTTGAAGGC711752CACAAATCCCTATACCTGGCTCGCCTTCAAGGTCAAGTTC708272AACCTGGCTCAGATCTGAACGCCAGGTATAGGGATTTGTG1864163TTAGAGGGGCTGTTGGAGAGAGAGCCTGACACCTTCCCTA4369653AGTATCTTGACTTTATTTGGGAAAAAAATATATGATAAAGG1864165TAAAAGGCTAGAAGTCCACCAATTAATTCTCCCCTATAGC891141AGGCCCAGCCTGGGAAGTTTTATCAGATGGTATCCACATG891143TCGTGCCCATCCTGTTAGTGCACAAGCATGCCCTGTGTGG7205804AGGCAGCAAGCACCACAATGATGAACGGTGCCTGGTACAC5885GCAAAGAGATCAACGTCATCATGCAGACAGAAACGCACTCA1532625ACTGCTGTCTTCTGAGGCATCATCATGGCCGATTTTGTCC1532624TCTATAGACTTGCCCAACGCTACTTTGGCAAATCTCTGCC289712ATTCGGCTTCTGTCATCCTCGGGTCCAAAGCTTTTGTCAG7499892TGGCTGACTGGCCTGACCACCCCTCCATTCTGTACCACTTA5883TACTTCTGGTTCTCTGAGCGTTGAACTCGTCTCCCATCAG289714ACACACACATACCACATGCCTGATGGGAGACGAGTTCAAG158480TGAGTAGTTGGGACTATAGGACCCCTGTCTCTACAAAAAT289717CTCTGAGCCCAGAGTTGATCCATTCCCTGCTCCATTTCCC4344729GCCTGAGTTCAGAAGGGAAGGGCCGTTCTCCTGTTCTAAC289718GCCTGCCCAATATTGTGAGTTCTTCCCTTCTGAACTCAGG289719TCTTCCCTTCTGAACTCAGGGCCTGCCCAATATTGTGAGT2033254CACAACTCACAATATTGGGCCAAAGGAACAGGACTCAGAC4784744ATCACATGCCCCAAGAAACCCCGGCCCTTTCTTTCTTTTG291044AGGGCATCCCAGAACAGAACTGACTAGGTCAGGTCCCCTC8053613GAGTTCAGGGTAGGAATAGCGCTGTGCAAATTAGGACTCT5881GACCCCTGTCTTCCACAGGTATCTTGGGCATCTTGAGGCA5880TTTCTCTCCCCAGGATATCGCCAAGAGGCTTAAGAAGAGC7198026TGTTGGTGGGGAAATGTGGCACGAAGATTCTATCTAGGCA5882TCCAGGGAGGACTCACCATGTGACTGCAGGAAGCTCTGG8045701TTGATACTTAGCGGTCCTGGTAATATTCTGCAGGTAAACC289741TCTACCAGCTTGGCTCCCTCAAGGGAGGGGCAGTAGGAGA1801706GTAGCAGAAGGCAAGCACAGGGAGGAGTTGGGAGCC289742ACTGGTGAGACAATCCCTTCCCACTGGCATTAAAGTGCTG289743TGAAAAGAGGTGGACGGCACAGTCCTTCTTCTGTGGCTGG289746GAGGCTTACCAAAATGGGACAGAGCTTCTAGGCTTGGATG172337AGCTGGACTTTGAGGATGGCAAGGAGAGGAGGGACTGGAG289747GTTGTTTAGGCCAAAAAGTCCAATTACGGAAGTTACACTG1566439AAGCCCATGGCTTTTCAAGGAGATCCTGGAGCCTCATTGT7205459GCAGAGGGGAAAGATCTTGGAAGAGGGTATGTGTGTTGG289749TGAACTAAGGACCAGGCAAGGCTCACATCCTTAGATTGCC289751AAATGATATGGAATTATGCGTATCTTTCCAAATGTTTTAC8059220ACCTGCCATCATGAGTGCATTAGAGCAGGGCCTGGTGTGT8058353CCCTACAAGAAGGCTACATCAGTGACTGCAGTGAAGAAGG289735CAAGGCATGCATGCTCCTTCATCGCCAGACCCTCAAGAAC289737GCAAGGAAGACTGATTCGTGAGCCTCAAGTCACTGATGTC291042TGTCTCCCCATAACCAACACAAGAAACAGCTCCCAGTCTG1875236GAGCTGAGTGATTCTTGTCCAATATGGTCAACTTGGTGGC821466AAGGAAGGAAGTGAGGGATGGGAAAGCAAAGGAATGGCAG821465CACTGTTTACAATAGCCAAGTGGAATTACAGGCGTGAGCT4275846GCAGCTGAGCAAAGATATGGTGGACCTCTTCTATCATCAC289707CTCCTTCCTTCTGCTATCTCACCAAGATTCAGGCACTGAG821463CGTCTGCTGGGACACTGAAAGCACCTGGAAGATTTATGGG289706TTAAGTCCTTTACCAAAGGGTGAATGTGGCTTTACCAAGG1167741GCCCTATTTACGTGGATTTGGCTCTGATTGTGTCTCTGTG2052880CATCAAGACTCCATGGAGAGAGTCAAGAACCAGTCCCTAC1167742CCCTAGAAACTCCCTTATCCTGAGTGGGGTACAGATGAAC1183256AGCTCAACTCCCCCCAAGTTGAAGATAGGTGAGTTGAGGG1651665AAGTGAGAACAGGCTTCCTGTCAAGGCTTTAGCTTGTCCC1651666TCTAACCTGGAACCCCTCAGATGAAGCCTGACACTTTGGG4784751CAAAGTGTCAGGCTTCATGGAGCTGTGGGTGAGTGTCAAG1651667TCCCGACTTGTACACCTTGGAGAAAATCAGCCAAAGGCTC8052091AGTCTTGCAGTCCAGGATGTTCCCTGATGGACAGATGGC1684574TCTTGCAGTCCAGGATGCAGGGCCATTTAGTGCTTGGAGC1684575TTTCCAGTCCCTGCATGTGGAGGGGTTACCCAGAACCTT1672865AAAGGTTCTGGGTAACCCCTCAGGCCTGAAAAAGCAAAGG821470CCTCTTTCTGTAATATCTGGCTGGGCATTGCAGAACTGAA1549869CTGCAATAGTACACGTGGTGAGATGTTGCAAAGGAGGTGC291040TACACTTGCCCAAAGTCCACTCTCTCTGTCAATCATGGGC289754ACTGCTTAGGTTGGCAAAGGATGCTTCCTTCCACAGGGAC











TABLE 10








dbSNP rs#
Extend Primer
Term Mix


















7500979
TCAACCAATAGAAAAGGC
ACG






2217332
AACCTCTGGTCCTCTGGA
ACG





8044804
TAAGCCTTGGTATGATAC
ACG





2270835
GCCGTAAATTCCATTCTTC
ACG





2133783
CTGAACTTTACAGGTAACA
ACG





247609
AAACTATGTATCAGACAAAAGCAC
ACG





952440
CCTGGAAGGCAGCTGTGG
ACG





881598
CAGCCTGGGTGACAGAGC
ACT





2291955
GACTTTTCTAGGAAAGACTTA
ACG





2518054
TACCGGCACAAACAGTC
ACG





866038
CCCATCTCAAAAACAAAAAC
ACT





1436425
GGTGTGTGGCCCATGAT
ACG





173537
CATCACACCTGTCTGCCATC
ACT





247611
CTCCATGATTGGAGACTGACA
ACT





166017
CTACTGGCAGGGAACAT
ACT





173538
TTACAGGCGTAAGCCAC
ACG





193694
CTTAAAATCTACTCCCATACAT
ACT





7205692
CAAAAGAGTTAGGGGAG
ACG





8048746
CATGCCAAAATCTCGCC
ACG





247618
TTGGGGCCCCATGTAAA
ACG





183130
CTTCTGTGCAGGAGAAT
ACG





6499863
TTGAGGAGCAGTGGTCA
ACG





4783961
GGGTCCTGCCCTAGTCC
ACG





3816117
GAGGGAGATGGGCTGAG
ACG





711752
CAATGCAGCTAGGACCTTCT
ACG





708272
CTGGCTCAGATCTGAACCCTAACT
ACG





1864163
GGCTGTTGGAGAGGTTGATA
ACG





4369653
CAGGTGCTTTTACAAACAA
ACG





1864165
GTCCACCATGGCCCTCC
ACG





891141
CTGGGAAGTTTGCAGGG
ACT





891143
AGTGTGTCCACGGCTCC
ACG





7205804
CCTGTGCATCCATGGAG
ACG





5885
CATCTCTAACATCATGGC
ACG





1532625
TGAGGCATGCAGACAGAAAC
ACT





1532624
CAACGCCACACAGCTTGTGA
ACT





289712
CAGTGGATTGTGGCCCCC
ACG





7499892
AGCCCGTTGGCCTGAAC
ACG





5883
GTTCTCTGAGCGAGTCTT
ACG





289714
CATACCACATGCCATCTGGAT
ACG





158480
GGGACTATAGGTATGCAC
ACG





289717
TTCCAGCCCCCTACAAGTCACG
ACG





4344729
CAGAAGGGAAGAGGGAC
ACG





289718
TATGTGCAAGGAGAGAG
ACT





289719
CTGTGATGCCTCTCTCC
ACG





2033254
GGCAGGCCCCTGACCGGC
ACG





4784744
CCAAGAAACCACTGAAC
ACG





291044
AGTATTTAAAGGAGAGACACAC
ACG





8053613
GATGAGAAACTGAGGCC
ACG





5881
TTCCACAGGTTGTCGGC
ACT





5880
ATATCGTGACTACCGTCCAG
ACT





7198026
GAAATGTGGCCCCTTTC
ACG





5882
CAGAGCAGCTCCGAGTCC
ACT





8045701
CCTCTCCCTGCTGGTGG
ACG





289741
TGGGAGTCAGCCCAGCTC
ACT





1801706
CCTGGTGTCTCCTCCAGC
ACT





289742
GCCACAGAAGAAGGACTCC
ACT





289743
TGAGACAATCCCTTCCCCC
ACG





289746
TACCAAAATGGGACTGACCTC
ACG





172337
TTTGAGGATGGCCCCTGACACG
ACG





289747
TAGGCCAAAAAGTCTAAATTGC
ACT





1566439
CCTTAGAGAAACGGAAGGTG
ACT





7205459
ACTTTATTCCTGGATCAGA
ACG





289749
CAGGCAAGCTAATGCAA
ACT





289751
TGGAATTATGCGTTAAAGG
ACT





8059220
TGCATTCAGCTTCTCCA
ACG





8058353
CTACATCTGCCTCTCTATC
ACG





289735
GAGGGACAGAAGGGACC
ACT





289737
CTTACTTGTGTGGTTTAGAAT
ACT





291042
CCCATAACCAACACTCAGCT
ACG





1875236
GATTCTTGTCCTCTGAGAGC
ACG





821466
GAGGACAGGAGTGGAGCC
ACT





821465
ACAGAGAAAATGTGGCA
ACT





4275846
GATATGGTTTCAAAAGCCT
ACG





289707
TGCCATTCTCTAGGCCCGTC
ACT





821463
TGGGACACTGAAACCAGGG
ACG





289706
ACCAAAGGGATTGACTT
ACG





1167741
GAACTCTGAGTTACATTCC
ACG





2052880
CTTCCCTGCCTATTTTATGTC
ACT





1167742
CTTATCCCCCAACTCACCTT
ACT





1183256
TCATCTGCCCCCAGTTT
ACT





1651665
AGGGGTTCCAGGTTAGACCCTT
ACT





1651666
AGGAAGCCTGTTCTCACTTTC
ACG





4784751
TCATGGGGAAGCCCTAA
ACG





1651667
CTTGTACACCTTGGACTTGAC
ACT





8052091
CAACAGCCAGCAGCCCC
ACG





1684574
GATGCAGGAAGCAGGGCC
ACT





1684575
CACCTGTCTGTGGACTGGA
ACT





1672865
GGGTAACCCCTCAGCCCAG
ACT





821470
TCTGGATCCCCAGTGCC
ACG





1549669
TAGTACACGTGGTGTAAGGG
ACT





291040
CCAAAGTCCACCAGCCTCTACT
ACT





289754
CAAAGGATTTTAACTTCCTCTAG
ACG









Genetic Analysis


Allelotyping results are shown for female cases and controls in Table 11. The allele frequency for the A2 allele is noted in the fifth and sixth columns for control pools and case pools, respectively, where “AF” is allele frequency. Some SNPs do not have an allele frequency disclosed because of failed assays.

TABLE 11Position inLow BMDdbSNPSEQ IDChromosomeA1/A2Associatedrs#NO: 1PositionAlleleHigh AFLow AFp-ValueORAllele750097920556743155G/AG = 0.71G = 0.720.60291.07GA = 0.29A = 0.282217332159556744545G/AG = 0.85G = 0.840.53900.90AA = 0.15A = 0.168044804265056745600C/TC = 0.47C =T = 0.53T =2270835549656748446C/TC = 0.00C = 0.00T = 1.00T = 1.002133783578256748732G/AG = 0.41G = 0.440.34121.14GA = 0.59A = 0.56247609590856748858C/TC = 0.70C = 0.700.88441.02CT = 0.30T = 0.30952440755256750502G/AG = 0.31G = 0.300.84100.97AA = 0.69A = 0.70881598919156752141T/CT = 0.23T = 0.250.47031.11TC = 0.77C = 0.7522919551012756753077G/AG = 0.00G = 0.00A = 1.00A = 1.0025180541034556753295G/AG = 0.87G = 0.910.08351.47GA = 0.13A = 0.098660381039956753349T/CT = 0.49T = 0.510.58351.07TC = 0.51C = 0.4914364251202856754978G/AG = 0.39G = 0.380.76600.96AA = 0.61A = 0.621735371335556756305A/GA = 0.80A = 0.810.80111.04AG = 0.20G = 0.192476111368756756637A/GA = 0.38A = 0.390.75291.04AG = 0.62G = 0.611660171432856757278T/CT = 0.29T = 0.430.000011.80TC = 0.71C = 0.571735381474656757696C/TC = 0.68C = 0.670.57020.93TT = 0.32T = 0.331936941499656757946T/CT = 0.14T = 0.240.00152.02TC = 0.86C = 0.7672056921936156762311G/AG = 0.01G = 0.01A = 0.99A = 0.9980487462177556764725G/AG = 0.00G = 0.00A = 1.00A = 1.002476182325056766200G/AG = 0.28G = 0.290.53391.08GA = 0.72A = 0.711831302381056766760C/TC = 0.64C = 0.590.07200.80TT = 0.36T = 0.4164998632446456767414G/AG = 0.83G = 0.840.58101.09GA = 0.17A = 0.1647839612734156770291G/AG = 0.48G = 0.460.38030.90AA = 0.52A = 0.5438161172860556771555C/TC = 0.56C = 0.550.80190.97TT = 0.44T = 0.457117522865856771608G/AG = 0.59G = 0.580.68870.95AA = 0.41A = 0.427082722873556771685C/TC = 0.62C = 0.620.96291.01CT = 0.38T = 0.3818641632968056772630G/AG = 0.74G = 0.740.99381.00GA = 0.26A = 0.2643696532999856772948G/AG = 0.37G = 0.370.81630.97GA = 0.63A = 0.6318641653252156775471C/TC = 1.00C = 1.00T = 0.00T = 0.008911413617056779120T/GT = 1.00T = 1.00G = 0.00G = 0.008911433642756779377C/TC = 1.00C = 1.00T = 0.00T = 0.0072058043733656780286G/AG = 0.72G = 0.780.02121.41GA = 0.28A = 0.2258853771856780668C/TC = 1.00C = 1.00T = 0.00T = 0.0015326253774856780698A/GA = 0.60A = 0.610.63291.06AG = 0.40G = 0.3915326243792656780876T/GT = 0.64T = 0.640.98071.00TG = 0.36G = 0.362897123875256781702G/AG = 0.66G = 0.670.66441.06GA = 0.34A = 0.3374998923903756781987C/TC = 0.88C = 0.880.96321.01CT = 0.12T = 0.1258833980056782750C/TC = 0.95C = 0.960.89941.04CT = 0.05T = 0.042897143989856782848C/TC = 0.19C = 0.230.09721.28CT = 0.81T = 0.771584804067456783624C/TC = 0.59C = 0.560.33150.86TT = 0.41T = 0.442897174183556784785C/TC = 0.67C = 0.720.11481.25CT = 0.33T = 0.2843447294232556785275C/TC = 1.00C = 1.00T = 0.00T = 0.002897184237956785329A/GA =A = 0.20G =G = 0.802897194238856785338G/AG =G = 0.39A =A = 0.6120332544243256785382C/TC = 0.34C = 0.380.19471.17CT = 0.66T = 0.6247847444363256786582G/AG = 0.63G = 0.640.51131.08GA = 0.37A = 0.362910444389956786849C/TC = 0.65C = 0.650.96661.01CT = 0.35T = 0.3580536134427356787223C/TC = 1.00C = 1.00T = 0.00T = 0.0058814445956787409A/GA = 0.00A = 0.00G = 1.00G = 1.0058804753856790488C/GC = 0.09C = 0.090.93391.02CG = 0.91G = 0.9171980264769256790642C/TC = 0.00C = 0.00CT = 1.00T = 1.0058824853956791489A/GA = 0.76A = 0.800.09581.27AG = 0.24G = 0.2080457014874956791699C/TC = 0.00C = 0.00T = 1.00T = 1.002897414992156792871A/GA = 0.85A = 0.860.59741.09AG = 0.15G = 0.1418017065010956793059A/GA = 0.31A = 0.230.00250.67GG = 0.69G = 0.772897425020956793159C/GC = 0.91C = 0.920.62981.12CG = 0.09G = 0.082897435024356793193C/TC = 0.27C = 0.240.18690.84TT = 0.73T = 0.762897465265256795602G/AG = 0.72G = 0.720.89160.98GA = 0.28A = 0.281723375519556798145C/TC = 0.94C = 0.910.08860.67TT = 0.06T = 0.092897475638556799335A/GA = 0.49A = 0.540.09811.22AG = 0.51G = 0.4615664395710956800059A/GA = 0.66A = 0.650.85780.98GG = 0.34G = 0.3572054595761856800568C/TC = 0.16C = 0.100.00350.59TT = 0.84T = 0.902897495874156801691T/CT =T = 0.42C =C = 0.582897515922256802172T/CT = 0.98T = 0.94C = 0.02C = 0.0680592206077156803721C/TC = 1.00C = 1.00T = 0.00T = 0.0080583536096256803912G/AG = 0.98G = 0.95A = 0.02A = 0.052897356200956804959A/GA =A = 0.39G =G = 0.612897376458956807539T/GT =T = 0.28G =G = 0.722910426605456809004G/AG = 0.80G = 0.820.45481.12GA = 0.20A = 0.1818752366614356809093C/TC = 0.91C = 0.900.31060.80TT = 0.09T = 0.108214666782256810772A/GA = 0.77A = 0.760.67430.94GG = 0.23G = 0.248214656880556811755C/GC = 0.93C = 0.870.00410.54GG = 0.07G = 0.1342758467007556813025C/TC = 1.00C = 1.00T = 0.00T = 0.002897077035056813300A/GA = 0.44A = 0.460.61171.07AG = 0.56G = 0.548214637121456814164G/AG = 0.38G = 0.410.42811.10GA = 0.62A = 0.592897067954956822499C/TC = 0.00C = 0.00T = 1.00T = 1.0011677418276056825710C/TC = 0.45C = 0.460.76351.04CT = 0.55T = 0.5420528808646356829413A/CA = 0.67A = 0.680.83781.03AC = 0.33C = 0.3211677428653356829483C/GC = 0.70C = 0.690.73220.96GG = 0.30G = 0.3111832568701956829969A/GA = 1.00A = 1.00G = 0.00G = 0.0016516658891056831860A/CA = 0.30A = 0.350.14231.24AC = 0.70C = 0.6516516668895556831905C/TC = 0.71C = 0.670.12940.81TT = 0.29T = 0.3347847518902156831971C/TC = 0.70C = 0.730.19711.18CT = 0.30T = 0.2716516678905656832006A/GA = 0.44A = 0.470.29021.13AG = 0.56G = 0.5380520918986356832813G/AG = 1.00G = 1.00A = 0.00A = 0.0016845748987956832829T/CT = 0.01T =C = 0.99C =16845759006656833016T/GT = 0.65T = 0.670.34731.12TG = 0.35G = 0.3316728659010156833051A/GA = 0.49A = 0.500.69591.05AG = 0.51G = 0.508214709102956833979G/AG = 0.37G = 0.380.83401.03GA = 0.63A = 0.6215496699143456834384T/GT = 0.51T = 0.500.90750.99GG = 0.49G = 0.502910409363656836586T/CT = 0.76T = 0.740.40560.89CC = 0.24C = 0.262897549800356840953C/TC = 0.70C = 0.690.65080.94TT = 0.30T = 0.31


Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in FIG. 1. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in FIG. 1 can be determined by consulting Table 11. For example, the left-most X on the left graph is at position 56743155. By proceeding down the table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.


To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn very 20 kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W. M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J. M. Chambers and T. J. Hastie, Wadsworth & Brooks/Cole). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10 kb sliding window with 1 kb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10−8 were truncated at that value.


Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3′ end of each gene to show the direction of transcription.


Example 4
PROL4 Proximal SNPs

It has been discovered that a polymorphic variation (rs1047699) in a gene encoding PROL4 is associated with the occurrence of low BMD (see Examples 1 and 2). One hundred twenty-five additional allelic variants proximal to rs1047699 were identified and subsequently allelotyped in low BMD case and high BMD control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 12. The chromosome position provided in column four of Table 12 is based on Genome “Build 34” of NCBI's GenBank.

TABLE 12Position inSEQ IDChromosomeAllelesdbSNPNO: 2ChromosomePosition(A1/A2)genome_letterdeduced_iupac5230512291210842129t/cgR6936203681210842268t/caR25883495831210842483g/agR258835024241210844324t/ctY61938136251210845525c/tcY375925237091210845609c/agK375925137501210845650t/atW241810747241210846624g/cgS730305447811210846681t/ccY183834561611210848061a/ggR62087870971210848997t/ggK253781780251210849925t/ctY154880383981210850298c/tcY667123101441210852044g/aaR1838346103841210852284a/ggR2159903111161210853016a/ggR3944035111321210853032a/ggR3741845114821210853382t/caR2110096145441210856444c/tcY759055156881210857588t/atW589377173111210859211g/cgS7960194178311210859731g/ttK7978242200121210861912a/ggR601051219971210863897g/agR4262797228611210864761a/gaR2215714234701210865370a/ggR1373434235151210865415g/agR2215715238631210865763g/agR612456241081210866008c/acM612808241381210866038t/ccY689118264691210868369t/ctY597468277691210869669a/ggR592864296831210871583t/ctY640372304911210872391a/ccM7966559307451210872645a/taW654834314291210873329t/ctY4763216317791210873679c/gcS668521321941210874094a/ccM669503324411210874341t/ccY3906864324541210874354t/cgR3906863324591210874359c/taR7957888351511210877051a/ttW9300230353621210877262a/ttW7306214356301210877530g/cgS763839369301210878830g/cgS2418105374901210879390g/agR666841384321210880332c/tcY3851578386881210880588a/ggR7138797395241210881424t/ccY7295252415801210883480a/caM2418106425311210884431t/ctY7299578426651210884565a/gaR621112430381210884938a/gaR3863320441831210886083g/agR1373432462711210888171a/ttW1047699490751210890975c/ttY1063193491471210891047c/tcY2232959491801210891080c/ggS2227296503011210892201a/gaR1548804507731210892673g/agR2232958512431210893143g/acY2232957515301210893430t/caR2232956521071210894007a/gcY1972571528211210894721a/gaR3759250533411210895241t/caR3759249533761210895276c/ggS1541525540471210895947c/ttY2098248543921210896292t/ctY2900550544821210896382t/aaW7302130554681210897368c/aaM4763583569901210898890a/gaR4360778577121210899612a/taW1607695596671210901567c/taR1607694596841210901584t/cgR2192139620431210903943a/caM7978300632931210905193t/ctY7397871634851210905385g/tgK4763217637781210905678c/ttY2159900642221210906122a/gaR10772370657221210907622a/gaR7398682663151210908215c/tcY2900551668291210908729a/gaR2900552669661210908866c/tcY2418214669711210908871a/ccM2418215670131210908913t/ccY965243703751210912275a/ttW1117548741181210916018t/atW1520225752241210917124c/tcY1520226752361210917136t/ctY1520227752461210917146g/cgS971919758121210917712c/aaM2159901789681210920868c/ttY2159902789981210920898t/ctY2110099793281210921228a/ccM7314847809221210922822t/ctY7296003810551210922955t/ccY4281556814121210923312g/aaR4763219817851210923685a/ggR3851579820791210923979g/aaR3851580820871210923987g/agR1049119829581210924858a/gcY2298866833511210925251t/gaM2298865834421210925342c/taR2298864834721210925372a/ctK2298863839661210925866a/gtY3180393844141210926314t/ctY2070837865631210928463c/gcS7956204867881210928688g/agR2418216867961210928696t/gtK3741844876341210929534g/acY4262798885301210930430g/aaR2418217892021210931102a/gaR2418218896321210931532t/ctY7137492896971210931597t/ctY2110100897231210931623g/agR1013312910631210932963c/gcS4579993913351210933235c/ggS1013313915041210933404t/ctY7397106916191210933519c/ttY2215716937151210935615a/ggR2192140939451210935845t/ccY4763589942351210936135t/ctY1468697958511210937751t/ccY20708371308601210972760c/gcS31803931328151210974715t/caR22988651337781210975678c/ttY


Assay for Verifying and Allelotyping SNPs


The methods used to verify and allelotype the proximal SNPs of Table 12 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 13 and Table 14, respectively.

TABLE 13dbSNPForwardReversers#PCR primerPCR primer523051CTCTGCTCAGAGCATAGATGTTCCATGCATTTTAACCCCG693820GTAGGTCAATAAAAGAGGAGGTTAGGCCGAGATTTTCAGAG2588349GTTCAAGAGTTTGATGTCAAGCAGGGCATCTAAATTGAACG2588350TGTATCTGGGACATACCATCGTTAGTACAGGGTTGATCAC619381AAAGCATAGTTTCTCTTCAGGCATCTCTAAAGGTGATTTGG3759252GCTGTGATTTTTGGTGAGTCTATTGTTCCCCAGTATTAGG3759251TTGTCCTTTCTCATTGCCACATTAGAGCTATGGACTCACC2418107AGGTAAATGGGCATACAGTGTGAAGACTGGAGCTATCTTC7303054AGGGAATTGGCCCAATTTGCCCATTTACCTACTCAGCAGG1838345CCCAGGTTCAAGTGATTCTCAATTAGCCAGGCATGGTTGC620878CCAGACCAAACGTTTCAATAAAAGAAGAAACGAATGTTTAC2537817GTCAGAATGCTGACATGTAGGGGGAAAAATGAGAATAGAC1548803ATGGGACAATTGCAAACAGGACTGAAATGTTCCATGTGAG667123TAAATACAAGAAGCCCTAGGAGGGAAAGTACAACTTAGCC1838346GTTAGAAGGCTAGAGAGAACTTCATGAGTACTCTAGCTGG2159903AGTCAGGATACTCTTTAGGGGGGAAGCTTTTCTGAAGATG3944035GGGTCTCTATGGAACAAAAGTGAGGGAAGCTTTTCTGAAG3741845TGCTTGGTGTGTCTAACTAGCAAACAGTTAACCCTGAACC2110096ATCAAGAACAGGATACTGCGGGGTAGGAGATAAAGTCAGC759055CCCCTATCTTTTTGTTGGATGGCTCTGTTTTCATGAGGTTC589377TTCACTGTTCAGATTGCTGGACTCCAGTTGTAGGTAGAAG7960194TGCTATCTTCCATGGAAGAATTTTTTTCCCTGTATGCCTC7978242GACGCTAAGCATCATTAGTCTAGCCATTCTAGTGGATGTG601051TTTTTACGTCTGTGTGAACCCACAGAAACCGAAAACCAAC4262797ATTTTAGTGCACCCATCACCGTCTTTAGAGACTCAAAAGGG2215714GAGTTAAACATCAGTCGTTGTTTATTATATAACGTAGGAA1373434CGTTTAAGATGATAGATCTTCCTACGCAATAGGCTATTTTC2215715ACATGGATGGAAAGGAAGACTATGAGCGAGAATATGTGGC612456TATCAACAAGCCAAGATCCCCTTTAGCCTTTTGTTGGACG612808GGCTGAGTGTTAAGTATTCCAAGGCAAACCCTTAATAGGC689118GAAATGTTCTGTCTTCAGGCAACGTTTCTGTGAGTGCAAG597468TACATGTTGAGATCCCAGACTGCATACATTGCGAAGATTC592864AAATTGTGTTTCTTGTAAGCAATGAACTAAATACTCCAAG640372ATCTGAAACTCTTTGAGCGCTCCAAAATGTTCCAATGAGC7966559CCTAATTCTTTTCTATCGGTGGAAGCTAGAAAGCTAAGAGTG654834CTGTCCTTTTTCTGGCTTTCCAAACAAAATAGAGTCCAGCG4763216TTGTAACCATAGAAAGCAGGTCCCTCTATTTTTCTACTAC668521TGCTGCTGATGTAACTGCAGGTGCAATAGTAACTGGGCTC669503GTAATCCACTCATTCAGATCTACCTAGAGGAAATAAGTGG3906864TTTCTAACATCCACCTTCTGGGTGTGAATAAGTTGTAATCC3906863CAGGACTGACCTCTAAAATAGACATCCACTTTCTGTAGATC7957888ACCTTAACAAAGTTCTGTGGGAGCCACGAAAAAAAAAATG9300230CCAGACAAGCTAAAATACAGCAAATACACACAGACACATC7306214CTATAGCACAGTAGGGTGACTCTTCGTGTTGGGCACATTC763839TATTCATGTAACACCGAAGGGGAACAGCAAACTGAAACAG2418105GGAGGCATTCCATTCTTTTCGTGTATCCAAAGCTTTAGTG666841TAATCCCCAAGAGAGAGGACAACTAACACAGATGGCCACC3851578GTGTGTATTTGCCCTTCTGCGGCATGTGATAGGAATGTGC7138797GTTCTGAAGTACATGTGCAGTTAATACCTAGGTGATGGGC7295252CAAGTTTACAATCACAGCTGGGTAAATGTATTTGACAGTTG2418106CAGCCCAGAATGGCTTTGAAACTAACGATGGGTGATGAGC7299578ATCTGCCCCATGATCCAATCCCCCTGAAAACCTCATGTTG621112TATGTTGGGTCACAAACCTGAGCAAGGCGTACAAAACAAC3863320GTTGCTCACAATACTGGAGGTGTCTTCAGCAGAACTCATC1373432TAAGGCAGAGGGCTACTTACGCATTTTACAAGACTTAAATCG1047699ATTACCAGAGTGGTTGCTCCATTTCCTTCTGTCAGCCTGC1063193AGGCTGACAGAAGGAAATCGTCAGCAGAGACCACCAAAAC2232959TCAGCAGAGACCACCAAAACGGTGGTCGTTGCTGATTTTG2227296TGAGAAGAAGACACTGAAGGATCCCAATGATCCTCAATCC1548804CCCATTTTTCTTCCAATCACGGAGCAACCAGGAGTAAATA2232958TCTTCTCAACCTCCTTCCTCATGACTCTTCTAGGGCCTCA2232957TTTATAAACATGAGCAGAACCGCATTCAACTTTATGAGAGG2232956GCCAATTTTGCCTTACTAACCCTAGCATTAACCAGAGATAC1972571ATCACCAGCTGCCACTTTTCCCTCAAATTATCACCAGCCC3759250TTCTGCCTAGGTGGCTTATGAATCATGTCTGCATGGCACG3759249CACACAGTGAATCATGTCTGATGGTAGACCATCAGGTAGG1541525TATCTGTAGACGTGCATCCCCTGACACCTGTCCTCATAAG2098248GGGAGAATCATGGCTTGAGTACTGCCCTTAGCAAATCC2900550TCAACAGTCTCCAGCTGATCACTCTGGCTGTTGTAAGGAG7302130TACACCTGTGAGCACTGACACCTTTTCTCAAGGTGTGTGC4763583AATGGTTTAGCACCATCCCCGGGAGGTGACACACACTTTT4360778AGGCTGCAAGTTTTCCAAACGCCTAAGCAAAGAAATGAGC1607695TTCTTCTCACTGACCTATTCATCAAACAGAAACGCTGGAG1607694ATCAAACAGAAACGCTGGAGCTCTTTTTTTGTCTGACTGGG2192139GGTCTTTTGTTTGCTAGGACGTAACCTGCCAAGATTGAAC7978300TCTGAGTCTTTTGTGGTACCTGCAGATTCAATGCAATCCC7397871AGGAGCTGAAACGATGGTTCCAAAATGGCATGACACTGGC4763217ACATTGTGTCTGTGCTTCTCGCAGTCTCTTATTGTCTGAG2159900TTACAACAAGTGCTCAAGGGGTGTCTTCTCTAACAGTGAG10772370GAATGACCATATGATCCAGCTAGGTATCCCTTTGATGTCC7398682GACAGATACCCTAACTTGATCGCAGTAAAGCTATCAATCCTG2900551GTACCTCAACACAAAAAGGCGAGGAAATCTTTCACCTTTCC2900552GCTAGATATACTAGGCAAGAGTGTCATCCGAAAAGATGAAC2418214TGTCATCCGAAAAGATGAACGCTAGATATACTAGGCAAGAG2418215CTATTCTGCAACTTTACCAGTAGAAGGAAGTCAATTGTTC965243GGCTGTGTAGGTTTGTCCTCTTCATCCCATTCCATCCAGC1117548GTGGTACATCACATTAACAGTTCCTTCTTTGTGTAGTTCG1520225CGTGACTCTCTGTACAGCATCAGCACTAGGCTGTGAAAAG1520226TAGGGTAAAATGTGCACAGCGCATTGTTAGTGGTTGCTCC1520227TAGGGTAAAATGTGCACAGCGCATTGTTAGTGGTTGCTCC971919TTAGTGACCTTCATAGAACCCAGGCATTCTTAGAAGACAG2159901CATATCTACTTGTGAACTGCGAAGGTAAAACCACTGATGC2159902CCCCTATAAGAGCAAAATACGAACTTTTCAGAAAGCATCAG2110099ATTCCTTCTCAACCCACATCACATTACAGGAAGGCCTTTC7314847CCTCTGCATAGATACAGTAGCTCTTATACACCCTGATTGG7296003TGGTTACTTAGGTTGATGCCCTACTGTATCTATGCAGAGG4281556GGCCTTAGGGTTTCCATAACAAGCCTTGGAAGAGTGAGTG4763219AGGAGAATCGCTTGAACCTGTGGAGTCTCATTCTGTCACC3851579AGGCTTTCAAACAAAATAGGTTACGGGTCTGATAAGAAAG3851580AGGCTTTCAAACAAAATAGGTTACGGGTCTGATAAGAAAG1049119GATAACAGTGTTTCAAATGCGAAATTGCAAGCTGATTGTT2298866TAACCAATCCCTGTCACTGGACAAAGATGGGCACTGCAAC2298865CCTGAGTTCATTTAGATCTCACGGAACAACCAAACAATAG2298864CCAGTAAACACTGAAGAGATCGATTTGTGTCTTACTCACTGG2298863AGCTCTTGAAGGCAATTCTGTATGTCCTCATTGTCAACCC3180393AACAAGGTCCACCACCTCCTTTGTGGCCTTCCTTGAGGAG2070837ACACACCCACACAAACTCACTGGAAAGACTGCTATTCTGC7956204TTTGGACAATTCTTGTAGCCTGTGAGATGTGTGAGGACAG2418216CCCAGGCACACATATATGAGGCCTGAGTGTAGTGAGATTC3741844GCTGATTGCTCTGTGATACCAAGTGCAGCTGGTGATTCTG4262798TCTAGGTACCCAAGCTCCTGAAGAGCTGAAAGGGACACTG2418217GCCTGGAACACTAAAGATGGCTCACTGACTCTCAGAGAAG2418218AAATTAGTCAGTCATGGTGGTTCAAGCAATTCTCCTGCCT7137492TCCTCATTTACTACAGTGACCCCATCTCTACTAAAAATAC2110100CTGGAATTACAAAGAGAAGAGCCCATCTCTACTAAAAATAC1013312ATTGTGTTTGCCCACTTTCCGTGGAACATCAAGAATGAAG4579993ATTTGTGCTCCTTTCTACTGAGCAGAAAGAAGGAAATGAC1013313TTCCAAACACAGCAAAGAGCTTGGTTGTATTCTGGTTGGG7397106TCTGAAACTCAGAATGCATGATACTCTAAACAATACAGGG2215716GTACTAGCAGTAGTCAGAGGGACACCACTACTTGCACATG2192140CCTTGGGATTTAGAAATAGGGGTAAGCAAATATCTCTGGAG4763589TTGGCAACTGTGTAACCTTGTCAAACATACTGTTTGCTCAC1468697GAACACAATCGCAAGTTTAAGGTTCTTCAAAATCTGCTTCC2070837ACACACCCACACAAACTCACTGGAAAGACTGCTATTCTGC3180393AACAAGGTCCACCACCTCCTTTGTGGCCTTCCTTGAGGAG2298865CCTGAGTTCATTTAGATCTCACGGAACAACCAAACAATAG












TABLE 14








dbSNP
Extend
Term



rs#
Primer
Mix


















523051
TCAGAGCATAGATGATGGCAA
ACT






693620
AGAGGAGGAAACCTTAATTTCT
ACT





2588349
AGAGTTTGATGTCAAGGAAATG
ACG





2588350
TACCATCAAAAGCACATCATTC
ACT





619381
GAATTTTCTTCCTTTTAGAATAGA
ACG





3759252
TGGTGAGTCCATAGCTCTAAT
CGT





3759251
CCAGCTACTTTATGCCAGAG
CGT





2418107
TGGCCAGGCCAAGGATCG
ACT





7303054
CAGCCTAAATTAACCGTATGTG
ACT





1838345
CCTGCCTGAGCCTGCCAA
ACT





620878
TTCAATAATATTATAGTGAGGATG
ACT





2537817
GACATGTAGAAAAATTGCCTGC
ACT





1548803
TTGCAAACAGGTTAAAGAGAGT
ACG





667123
AAGCCCTAGGGTATTGTGATT
ACG





1838346
AAGGCTAGAGAGAACATTCCA
ACT





2159903
AGGGGTCTCTATGGAACAAAA
ACT





3944035
AACAAAAGGCTTTCTTCTTCTAA
ACT





3741845
CAAAGGATAAAGGGAACCATC
ACT





2110096
CAGGATACTGCGATACTGTC
ACG





759055
GTAATCTTGTTTGTTGTATTTTTC
CGT





589377
CTGGTGTGTAGAAACACAACA
ACT





7960194
GCCCAGGGCTCAGGGAAG
CGT





7978242
GCAAACCAAAACCACAGTCAC
ACT





601051
CCCGCTTATAAGCAAGAGCA
ACG





4262797
TTATCCCTATCCTCCCTTCC
ACT





2215714
GCATCACTCTTTCTACGCAATA
ACT





1373434
TGTTTCAAAACATCACTATGTAC
ACG





2215715
GGAAAGGAAGACATTATGGTAC
ACG





612456
CCAAGATCCCTGAAAGGCAAA
CGT





612808
CTACTTTAGCCTTTTGTTGGAC
ACT





689118
GCTTCATACACACACACACAT
ACT





597468
CCCAGACTGTGTCATTCTTC
ACT





592864
GTGTTTCTTGTAAGCAGTATAC
ACT





640372
AAACTCTTTGAGCGCTGACAT
ACT





7966559
TCTATCGGTGATTTCTGCTGT
CGT





654834
CACAATTGGCTTTTAAAACTCC
ACT





4763216
CCATAGAAAGCAGGACTGGTT
ACT





668521
AAATTAGTCTAGAACTTGTGGAA
ACT





669503
CCACTCATTCAGATCTACAGAA
ACT





3906864
ACATCCACCTTCTGTAGATCT
ACT





3906863
GTGTGAATAAGTTGTAATCCAC
ACG





7957888
TGTGGAAATATTTGAAGACTCTT
CGT





9300230
ATACAGAGAAGTAGAGGACAAA
CGT





7306214
CACAGTAGGGTGACTACAATTA
ACT





763839
TAACACCGAAGGTTCCTCAG
ACT





2418105
CATTCTTTTCCAGTGTCAATCAA
ACG





666841
GGACTTGGCAGCATTATTTATTA
ACG





3851578
CAGCTAATTGTGCTCCCTCA
ACT





7138797
AAGTACATGTGCAGAATGTGC
ACT





7295252
ATCACAGCTGATAATGTCATAAT
ACT





2418106
GAATGGCTTTGAATATGACCCA
ACT





7299578
CAGGTGCTATCACAACATCG
ACT





621112
CACAAACCTGCCATTTTACTTT
ACT





3863320
AATACTGGAGGCTGGAAGAC
ACG





1373432
CAGAGGGCTACTTACAAGAATT
CGT





1047699
TCTTGCTGGTCTGTCCCTC
ACG





1063193
AGTTGACGGTGTCCTCGT
ACG





2232959
ATCACCGCCATCCTCCCC
ACT





2227296
GAAATTCTAGTGGAAAAAG
ACT





1548804
AAAATTTCAATATGTTGCAGGCAG
ACG





2232958
CCTCCCCTCCTGCTCTTC
ACG





2232957
GGACCTCACCACCTGAAAG
ACT





2232956
TGCCTTACTAACCTCCAGG
ACT





1972571
CTGCCACTTTTCATTACAGGC
ACT





3759250
TAGGTGGCTTATGGTAGACC
ACT





3759249
TCTGCATGGCACGCCCCT
ACT





1541525
CCCTCTGTGGTCTGTGCTAA
ACG





2098248
GAATCATGGCTTGACTCAGG
ACT





2900550
GCCCCTCACCACATCCCA
CGT





7302130
CCCACCCAGCAGGAAGAC
CGT





4763583
CCTGCGTACTATTCTTATGAC
ACT





4360778
TTTTACACTCTGCTTCCCTTTT
CGT





1607695
TTCTCACTGACCTATTCTATTTT
ACG





1607694
AGCTTCAAAAATAGAATAGGTCA
ACT





2192139
CTTTGATCTCATCACTTGTTATT
ACT





7978300
TTCTGTTTCTGTGAAGAATGTC
ACT





7397871
GCCAGGCTCACAGTCCAAA
CGT





4763217
TTGGACGTAGGACAAAGAACT
ACG





2159900
GCTCAAGGGAGTTCTACATCT
ACT





10772370
GACCATATGATCCAGCAATTTC
ACT





7398682
GCTTATAACAAAATATCATGTGTC
ACG





2900551
GCCATATATGACAAACCCACA
ACT





2900552
ATATACTAGGCAAGAGATAGAAA
ACG





2418214
CTTCCTTCTATTCAATTTCAATTT
ACT





2418215
CTATAAATAAGATCATGTCATCC
ACT





965243
CAGACCCATCAGAGAAGTAC
CGT





1117548
CCAAATAAGCATATGAATAGATG
CGT





1520225
CAGCATTGTTAGTGGTTGCTC
ACG





1520226
GCTGTGAAAAGCTATGTATGC
ACT





1520227
CAGCACTAGGCTGTGAAAAG
ACT





971919
ATAAGATAGGTCTGTTGGAAAG
CGT





2159901
TGATTTCTTCAGCCATTATCCA
ACG





2159902
TTAAGCTTGCATGAAAGAAGGT
ACT





2110099
TTATGTCAGCAGAAAAACAGAAA
ACT





7314847
GAGTTTTAGTTCTTTGAGAAATC
ACT





7296003
GGTTGATGCCATATCTTTGCT
ACT





4281556
GGTTTCCATAACAAGAATAACAAA
ACG





4763219
CCGATATCTTGCCACTGCAG
ACT





3851579
CAAAATAGGAACACACTGAGTAT
ACG





3851580
CTTTCAAACAAAATAGGAACACA
ACG





1049119
TGGCATCATGCTCTAACTTCA
ACT





2298866
CCTGTCACTGGATATTAAGGC
ACT





2298865
CATTTAGATCTCTTCAGTGTTTA
ACG





2298864
CTGAAGAGATCTAAATGAACTCA
ACT





2298863
CAATTCTGATTTTGAGAATCACT
ACT





3180393
GCCACAAGGACCACCCCA
ACT





2070837
CCACACAAACTCACATACACA
ACT





7956204
AGGCTGCCAGCACCTTTCT
ACG





2418216
GCACACATATATGAGAGAAAGG
ACT





3741844
GTGATACCTAGAAATTCCCTG
ACG





4262798
CGTCTCCCTTTCACCCACC
ACG





2418217
TGCCAGGAAAGATGAACATTG
ACT





2418218
CAGTCATGGTGGCGAGGG
ACT





7137492
GCCATGTGACTTAATTTCTTTAG
ACT





2110100
TCCTCATTTACTACAGTGACC
ACG





1013312
GCCCACTTTCCCCCTTTCT
ACT





4579993
ACTGTTATTTCTGGTTTCTGGT
ACT





1013313
ACAGCAAAGAGCATAAACCTAC
ACT





7397106
CTCAGAATGCATGAATAGTACA
ACG





2215716
CGTACTATTTCTTCAAGCTTCA
ACT





2192140
TAGGGTATCCCTCTTGGTCA
ACT





4763589
CTGTGTAACCTTGATCTTGGG
ACT





1468697
CAATCGCAAGTTTAAGGTAACA
ACT





2070837
CCACACAAACTCACATACACA
ACT





3180393
GCCACAAGGACCACCCCA
ACT





2298865
CATTTAGATCTCTTCAGTGTTTA
ACG









Genetic Assay


Allelotyping results are shown for female cases and controls in Table 15. The allele frequency for A2 allele is noted in the fifth and sixth columns for control pools and case pools, respectively, where “AF” is allele frequency. Some SNPs do not have an allele frequency disclosed because of failed assays.

TABLE 15Female Allelotyping ResultsPosition inLow BMDdbSNPSEQ IDChromosomeA1/A2Controls (highCases (LowAssociatedrs#NO: 2PositionAlleleBMD) AFBMD) AFp-ValueORAllele52305122910842129T/CT = 0.00T = 0.00C = 1.00C = 1.0069362036810842268T/CT = 1.00T = 1.00C = 0.00C = 0.00258834958310842483G/AG = 1.00G = 1.00A = 0.00A = 0.002588350242410844324T/CT = 0.34T = 0.280.02950.76CC = 0.66C = 0.72619381362510845525C/TC = 0.86C = 0.910.00651.67CT = 0.14T = 0.093759252370910845609C/AC = 1.00C = 1.00A = 0.00A = 0.003759251375010845650T/AT = 0.01T = 0.01A = 0.99A = 0.992418107472410846624G/CG = 1.00G = 1.00C = 0.00C = 0.007303054478110846681T/CT = 0.00T = 0.00C = 1.00C = 1.001838345616110848061A/GA =A =G =G =620878709710848997T/GT = 0.07T = 0.030.00980.37GG = 0.93G = 0.972537817802510849925T/CT = 0.19T = 0.160.44850.85CC = 0.81C = 0.841548803839810850298C/TC = 0.47C = 0.410.05640.78TT = 0.53T = 0.596671231014410852044G/AG = 1.00G = 1.00A = 0.00A = 0.0018383461038410852284A/GA = 0.76A = 0.800.13291.26AG = 0.24G = 0.2021599031111610853016A/GA = 0.00A = 0.00G = 1.00G = 1.0039440351113210853032A/GA = 0.00A = 0.00G = 1.00G = 1.0037418451148210853382T/CT = 0.54T = 0.490.08770.81CC = 0.46C = 0.5121100961454410856444C/TC = 1.00C = 1.00T = 0.00T = 0.007590551568810857588T/AT = 0.45T = 0.370.00840.72AA = 0.55A = 0.635893771731110859211G/CG = 0.01G = 0.00C = 0.99C = 1.0079601941783110859731G/TG = 1.00G = 1.00T = 0.00T = 0.0079782422001210861912A/GA = 0.62A = 0.680.06111.27AG = 0.38G = 0.326010512199710863897G/AG = 0.01G = 0.00A = 0.99A = 1.0042627972286110864761A/GA = 0.61A = 0.540.03910.76GG = 0.39G = 0.4622157142347010865370A/GA = 0.00A = 0.00G = 1.00G = 1.0013734342351510865415G/AG = 1.00G = 1.00A = 0.00A = 0.0022157152386310865763G/AG = 1.00G = 1.00A = 0.00A = 0.006124562410810866008C/AC = 0.03C = 0.02A = 0.97A = 0.986128082413810866038T/CT = 0.20T = 0.110.00010.52CC = 0.80C = 0.896891182646910868369T/CT = 0.68T = 0.710.34851.15TC = 0.32C = 0.295974682776910869669A/GA = 0.99A = 1.00G = 0.01G = 0.005928642968310871583T/CT = 0.10T = 0.110.92921.04TC = 0.90C = 0.896403723049110872391A/CA = 0.96A = 0.960.67801.21AC = 0.04C = 0.0479665593074510872645A/TA = 0.79A =T = 0.21T =6548343142910873329T/CT = 0.04T = 0.030.39220.74CC = 0.96C = 0.9747632163177910873679C/GC = 0.50C = 0.450.09510.82GG = 0.50G = 0.556685213219410874094A/CA = 0.98A = 0.99C = 0.02C = 0.016695033244110874341T/CT = 0.96T = 0.960.46851.26TC = 0.04C = 0.0439068643245410874354T/CT = 0.99T = 1.00C = 0.01C = 0.0039068633245910874359C/TC = 0.34C = 0.410.02881.35CT = 0.66T = 0.5979578883515110877051A/TA = 0.87A = 0.930.01552.12AT = 0.13T = 0.0793002303536210877262A/TA = 1.00A = 1.00T = 0.00T = 0.0073062143563010877530G/CG = 1.00G = 1.00C = 0.00C = 0.007638393693010878830G/CG = 0.82G = 0.880.00471.61GC = 0.18C = 0.1224181053749010879390G/AG = 0.21G = 0.160.01980.69AA = 0.79A = 0.846668413843210880332C/TC = 0.89C = 0.930.01801.72CT = 0.11T = 0.0738515783868810880588A/GA = 0.89A = 0.930.02431.67AG = 0.11G = 0.0771387973952410881424T/CT = 0.97T = 0.970.98150.99TC = 0.03C = 0.0372952524158010883480A/CA = 1.00A = 1.00C = 0.00C = 0.0024181064253110884431T/CT = 0.35T = 0.300.17840.80CC = 0.65C = 0.7072995784266510884565A/GA = 0.30A = 0.230.00360.67GG = 0.70G = 0.776211124303810884938A/GA = 0.87A = 0.920.00861.69AG = 0.13G = 0.0838633204418310886083G/AG = 0.52G = 0.490.22710.87AA = 0.48A = 0.5113734324627110888171A/TA = 0.00A = 0.00T = 1.00T = 1.0010476994907510890975C/TC = 0.79C = 0.850.00621.53CT = 0.21T = 0.1510631934914710891047C/TC = 0.75C =T = 0.25T =22329594918010891080C/GC = 1.00C = 1.00G = 0.00G = 0.0022272965030110892201A/GA = 0.77A = 0.770.99341.00AG = 0.23G = 0.2315488045077310892673G/AG = 0.24G = 0.150.00050.54AA = 0.76A = 0.8522329585124310893143G/AG = 1.00G = 1.00A = 0.00A = 0.0022329575153010893430T/CT = 1.00T = 1.00C = 0.00C = 0.0022329565210710894007A/GA = 0.87A = 0.920.01701.64AG = 0.13G = 0.0819725715282110894721A/GA = 0.13A = 0.130.81171.04AG = 0.87G = 0.8737592505334110895241T/CT = 0.99T = 1.00C = 0.01C = 0.0037592495337610895276C/GC = 1.00C = 1.00G = 0.00G = 0.0015415255404710895947C/TC = 0.00C = 0.00T = 1.00T = 1.0020982485439210896292T/CT = 0.00T = 0.00C = 1.00C = 1.0029005505448210896382T/AT = 0.89T = 0.930.05351.59TA = 0.11A = 0.0773021305546810897368C/AC = 0.36C = 0.360.95501.01CA = 0.64A = 0.6447635835699010898890A/GA =A =G =G =43607785771210899612A/TA = 0.00A = 0.01T = 1.00T = 0.9916076955966710901567C/TC = 0.00C = 0.01T = 1.00T = 0.9916076945968410901584T/CT = 0.81T = 0.830.34691.17TC = 0.19C = 0.1721921396204310903943A/CA = 0.30A = 0.280.45550.89CC = 0.70C = 0.7279783006329310905193T/CT = 0.36T =C = 0.64C =73978716348510905385G/TG = 0.00G = 0.00T = 1.00T = 1.0047632176377810905678C/TC = 0.89C = 0.900.86981.05CT = 0.11T = 0.1021599006422210906122A/GA = 0.02A = 0.02G = 0.98G = 0.98107723706572210907622A/GA = 0.31A = 0.270.14780.82GG = 0.69G = 0.7373986826631510908215C/TC = 1.00C = 1.00T = 0.00T = 0.0029005516682910908729A/GA = 0.00A = 0.01G = 1.00G = 0.9929005526696610908866C/TC = 0.61C = 0.590.51500.92TT = 0.39T = 0.4124182146697110908871A/CA = 0.51A = 0.570.05651.27AC = 0.49C = 0.4324182156701310908913T/CT = 0.82T = 0.860.12321.29TC = 0.18C = 0.149652437037510912275A/TA = 0.82A = 0.850.16371.25AT = 0.18T = 0.1511175487411810916018T/AT = 1.00T = 0.99A = 0.00A = 0.0115202257522410917124C/TC = 0.27C = 0.220.09560.79TT = 0.73T = 0.7815202267523610917136T/CT = 0.99T = 0.98C = 0.01C = 0.0215202277524610917146G/CG = 0.91G = 0.820.000010.46CC = 0.09C = 0.189719197581210917712C/AC = 0.00C = 0.00A = 1.00A = 1.0021599017896810920868C/TC = 0.99C = 0.99T = 0.01T = 0.0121599027899810920898T/CT = 0.54T = 0.510.35990.90CC = 0.46C = 0.4921100997932810921228A/CA = 0.60A = 0.630.40801.11AC = 0.40C = 0.3773148478092210922822T/CT = 0.51T = 0.490.60590.94CC = 0.49C = 0.5172960038105510922955T/CT = 0.63T = 0.650.47991.09TC = 0.37C = 0.3542815568141210923312G/AG = 0.85G = 0.870.53271.17GA = 0.15A = 0.1347632198178510923685A/GA =A =G =G =38515798207910923979G/AG =G = 0.34A =A = 0.6638515808208710923987G/AG = 0.56G = 0.540.56180.93AA = 0.44A = 0.4610491198295810924858A/GA = 0.00A = 0.00G = 1.00G = 1.0022988668335110925251T/GT = 0.72T = 0.690.32400.87GG = 0.28G = 0.3122988658344210925342C/TC = 0.95C = 0.970.18041.67CT = 0.05T = 0.0322988648347210925372A/CA = 0.36A = 0.340.59360.93CC = 0.64C = 0.6622988638396610925866A/GA = 1.00A = 1.00G = 0.00G = 0.0031803938441410926314T/CT = 1.00T = 1.00C = 0.00C = 0.0020708378656310928463C/GC = 0.43C = 0.430.94030.99CG = 0.57G = 0.5779562048678810928688G/AG = 0.86G =A = 0.14A =24182168679610928696T/GT = 1.00T = 1.00G = 0.00G = 0.0037418448763410929534G/AG = 0.50G = 0.480.38270.90AA = 0.50A = 0.5242627988853010930430G/AG = 0.60G = 0.620.41301.10GA = 0.40A = 0.3824182178920210931102A/GA = 0.53A = 0.520.65620.95GG = 0.47G = 0.4824182188963210931532T/CT =T =C =C =71374928969710931597T/CT = 0.75T = 0.760.70431.07TC = 0.25C = 0.2421101008972310931623G/AG = 0.53G = 0.520.54030.93AA = 0.47A = 0.4810133129106310932963C/GC = 0.29C = 0.260.19280.84GG = 0.71G = 0.7445799939133510933235C/GC = 0.00C = 0.00G = 1.00G = 1.0010133139150410933404T/CT = 0.61T = 0.580.38930.90CC = 0.39C = 0.4273971069161910933519C/TC = 0.02C = 0.04T = 0.98T = 0.9622157169371510935615A/GA = 0.45A = 0.360.03720.69GG = 0.55G = 0.6421921409394510935845T/CT = 0.00T = 0.00C = 1.00C = 1.0047635899423510936135T/CT = 0.53T = 0.520.68060.95CC = 0.47C = 0.4814686979585110937751T/CT = 0.02T = 0.01C = 0.98C = 0.99207083713086010972760C/GC = 0.43C = 0.430.94030.99CG = 0.57G = 0.57318039313281510974715T/CT = 1.00T = 1.00C = 0.00C = 0.00229886513377810975678C/TC = 0.95C = 0.970.18041.67CT = 0.05T = 0.03


Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in FIG. 2. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in FIG. 2 can be determined by consulting Table 15. For example, the left-most X on the left graph is at position 10842129. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.


To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20 kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W. M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J. M. Chambers and T. J. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10 kb sliding window with 1 kb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10−8 were truncated at that value.


Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3′ end of each gene to show the direction of transcription.


Example 5
GRID2 Proximal SNPs

It has been discovered that a polymorphic variation (rs1948017) in a gene encoding GRID2 is associated with the occurrence of low BMD (see Examples 1 and 2). One hundred five additional allelic variants proximal to rs1948017 were identified and subsequently allelotyped in low BMD case and high BMD control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 16. The chromosome position provided in column four of Table 16 is based on Genome “Build 34” of NCBI's GenBank.

TABLE 16Position inSEQ IDChromosomedbSNPNO: 3ChromosomePositionAlleles (A1/A2)genome_letterdeduced_iupac1433661206494744306t/cgR1485009243494744343a/ggR76819472467494746567t/ctY18164323550494747650a/gtY14850184994494749094c/ggS14850175167494749267g/tcM74383975193494749293c/tcY68343115273494749373g/agR13687175733494749833a/gcY10173917817494751917a/cgK28707017818494751918t/aaW76798398612494752712t/gtK13854049158494753258a/gaR13687169285494753385g/acY469331610680494754780g/aaR190570711866494755966t/ccY190570811958494756058a/gaR190570912044494756144a/ttW391244212753494756853g/ttK208255315585494759685a/gcY683163817299494761399c/tcY586032918816494762916—/ggN287070224022494768122c/ttY287070324994494769094c/ttY194801626637494770737g/ttK683583627635494771735c/ggS199425328773494772873t/ctY190571029430494773530a/taW148501929876494773976t/atW97819130364494774464c/taR138540531057494775157c/atK769436131782494775882c/ttY190571133400494777500a/ccM190573435588494779688a/ctK148501237663494781763c/gcS148501337865494781965t/ccY469298138218494782318a/taW767055239375494783475t/ccY767093239559494783659c/tcY768809139833494783933a/ggR744054040135494784235a/ggR217100041698494785798g/atY287070442249494786349t/ctY765575842571494786671g/ccS766143642977494787077g/agR766228943548494787648t/ccY766704443631494787731g/aaR769192943705494787805t/ctY586033043817494787917tt/t—t—N90101344374494788474a/cgK90101244464494788564a/cgK90101144788494788888t/cgR194801848962494793062a/gcY287070548993494793093t/gtK194801749110494793210c/taR190573349434494793534c/taR138540849523494793623t/gtK138540949742494793842c/gcS138541049907494794007g/cgS148502650028494794128g/cgS148502750089494794189g/ttK290448351588494795688c/aaM138540652899494796999c/aaM190573254088494798188a/ctK204641856538494800638c/taR220037759071494803171t/cgR190573159110494803210a/ctK190573059178494803278a/gcY97571361087494805187t/caR682098561300494805400c/gcS767044162171494806271t/ccY681079462783494806883t/atW767662362983494807083t/ccY115486163908494808008c/ttY103212564088494808188g/tgK148502264941494809041a/taW148502465050494809150a/ggR391365168953494813053c/tcY469331970093494814193t/ccY187238371308494815408c/agK220037673009494817109t/atW766809074002494818102a/ggR769293074294494818394t/ctY96709674879494818979g/cgS682224976936494821036g/ttK653240577195494821295g/agR101789777683494821783t/ccY767267478283494822383t/ctY769456878331494822431c/tcY290448479362494823462g/ccS734083080357494824457c/tcY148503380653494824753t/cgR287070680840494824940a/ggR190572983203494827303a/gcY469332085405494829505t/ctY684874986441494830541g/ttK653240686967494831067g/agR653240787121494831221t/ctY190572889617494833717t/cgR681986690969494835069t/aaW190572794249494838349g/cgS767406995811494839911t/gtK190572496690494840790t/gcM190572396731494840831a/gcY148502097267494841367c/gcS681410197414494841514t/ggK


Assay for Verifying and Allelotyping SNPs


the methods used to verify and allelotype the proximal SNPs of Table 16 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 17 and Table 18, respectively.

TABLE 17DbSNPrs#Forward PCR primerReverse PCR primer1433661CTCCCAAAGCCATGGGATTCCAGGAATGCAATCTAAGGCC1485009CCTAACCCTCTTCTGGAAAAGACCTATAAAGACAGGAATGC7681947ACCAGAACAGGACGAATTAGCCCCAATGTTATGCATACTC1816432GTTCTAGCCTTACTGAGATAGGCTTAAAGACCTTCAAACTAC1485018AAAGATCGCTTGAAACTGGGTTGCTCTGTTGTCAAGGCTG1485017TGACCAGGCTGGTCTAAAACTAATCCCAGCAGTTTGGGAG7438397GAGATCTAGCAATCCTCCTGGAAACCTAATTTTGAGCCTG6834311TCATTGTGTTACAGATGCTCCCAGGCTCAAAATTAGGTTTC1368717AAATCTGCAGACAAGGACAGAGCAACCTGGTTTTAAGAGC1017391ATGCACAAATGACAGTAGGGGGACATTGTAGTAGTCAGGG2870701ATGCACAAATGACAGTAGGGGGACATTGTAGTAGTCAGGG7679839CCACAGGAACTATTTGCTGGGGAACAGCACAAGCAAAAAC1385404CCCAGCATCCTTGCTAATACCCTGTCAAGATGCATAGGAG1368716TGGGAGAACTGGGAAAATGGTGCTACATACTGTAGCAGCC4693316ATCCTGTACTGCACTTCAGCACCCTCCATGGGAGTTTTTC1905707TTTTCTGTAGTTTCCCGAGCAATGCAATCCACAGAGCAAG1905708GGAACAAATGAAGATAGATGGGACCTATGTTTTATGAGTTC1905709TAGAATAGTTTCTCAGTGTCGAACTCATAAAACATAGGTCC3912442CATAACTCAGGCAAAACAACGTTGAAAAAGCTCTATATTGG2082553TGGAGCCCACTCAGATATTCCCCTGGAACATGTAAATGTG6831638CCATATACTTACCTTTACTGAATGTGAGTTCTGAAGATGG5860329CCATGCTGGCTTTTGTGAACTCCTGACCCTTAGTCCAATG2870702CAAAGAATGAGAGGGAAGGCTGTGGCCTACCAGAATTTGC2870703AATAAAGAGGACAGCAGGAGCACAGTTGTACTCCTAGCTC1948016GAATGAATGCAGTGTGCCAGTGAACCTATCTTGCAGGTGG6835836TTATTTAGGAAGCACTCAGCGAGTCCAAGACTAGTAAAGAG1994253TTCACCTTTCTGTGTTCTCCAAGAAGAAGAACAACTGTAC1905710CATTAAGTGAAGAGCTATTCCCTTAAAAGCTATTCGTTAAGC1485019TTTAAGCTCCCCAAAAGGTGTACTGTGACATTCCCTTCTC978191AGGTCTTATCTCTTGGAATGCCCATTCAGATATATAGACAG1385405CATTCAGACCTGTGACAGGATGATGGGACTGTTCTTCAGG7694361CTAGTGATTCTGTGAATGTTGCAATGTGATTGTGTTGGAAG1905711CAGTTAACACTCCATATCCACGAGCCTCAGTTTGTTGAATC1905734AATTTCAAGATCAGAGATCCCCTAACATGAGTCCATTCTG1485012ATACACCTATGCTAAGAAGCGCAGAAAAACTAGTACGATAC1485013ACACATCATAGTTTTACTGCGGATGAAACTATGTGAAAGC4692981GCTAGCCTGGAATCAAACACCCGAAAACAAAAGCACCCTG7670552TTTGGCTGCAATCAACCATGATCCCAAGAGAAATGAAAAC7670932CCTTGAAAGCATGCTAAGGGTGAGTCCCTATAGATTTGTC7688091TGGATTGTGCACTTTGGATGACCAGACTCTCTCTTTTTTA7440540TGCACAGACTGTTAAGGGAGTCATCCTTTAAGCCTTGCCG2171000TGAGCCAAGTATGGAAAAACCTGGGATAATTGTTGGGATC2870704ATGCTCTTGGAGCTCAGAAGACATATTTCCCTGACCTCCC7655758GTCAAAACCTCTTACTGTGCCATGGCAGCCTTACCAAAGA7661436ACTGAAATTCCTTGCTGAACTCTCCAGGTAAACTTCCAAG7662289AAAACAGTGAAAGACCTTGCTATTGAGGCCGAGTAGTCTG7667044ACTGATAAAACAAAGGAGGGGAAAGCAAGGTCTTTCACTG7691929TTTCTCAGCATATGTTCCAGATCAGTCTCAGGGAAGATGC5860330CTGCCTAGATGAAACAAATGCTGCTGGAACATATGCTGAG901013AAGGTGCATCCCTCAGAAAGGCCTGGCTGATCTAAGGTTT901012CTGAAATAGTGAGGGTAGTGAAGATGTGGAGAGAACAAGG901011AAAAGGGAAGGGAAGTGTGGACTCTCCTCCAAGAGCTTTC1948018TTTATCAGCAAGCATGTGAGGTTTTCTGGAAAACTTTTACC2870705TAGTGCATGAGAAAGTCTACTTGCTTATCTGACTGGCAAG1948017GTTTAACAGCAACCATTGAGGCCCCAAAGGTATGTTAAGAG1905733TGGAAGAGTATTAACTTCTGTTAGTCTATTGATTGAAAGC1385408ACTCTTCCAAAGACTGATGCGGATGTGGGGTTATAAGAAC1385409TTGCCTCTTCCAGTCTATTGCAGAGGAGAGACATGATCAG1385410AGAGACAGAAGAGACACTAGCCCCATCCAAATACATTGCC1485026GAGAAGAAGGCATATGTGAGCTCACTCTTTCTTCTGTCTG1485027TGGTGATGATAGGTGCTGTGACACAGGTGCTTTCTAATTG2904483CTTCTCTCCATGAAACTCAGAGGAGATATCAAGACACCAG1385406CTCCATTATCTGTTTGCAGTCTCTGAGTAGTGTTTTCTGG1905732CTGTTCCTTGTTTCTTCTGCGTGGTGTTTGCCATTAAAAG2046418AGGAGAGAAGTCTATGTCCCTTCTTACATTCTAGAGCCTT2200377GGATGGACTATTGTTTTCTTCCTATCTTGATTAGATTACAG1905731TCACTGCTTAGAAACTAATCAAACACCTTTCTGAGAATTG1905730AAACTGAAGCAGATTCTGACCTTTGTTCTTTCAATTCTCAG975713GCTAATTTTCCTAGGATCTCAGTGAGCCCCAAAATCTGTG6820985CTAAGCCTAATAAAGGAGGGATATATAGAAAAGACTGGAG7670441CAATAATGACATGCTCTTACCGTATAGCAATCATACACAAG6810794ATGATGGAGCTCCAGAAAAGCAGAGATATTTAGTGGCAAC7676623TTCAGAGCTCACTTTCCAACGGGGCTACCAAACTTAAAAG1154861GACACTGAATCCATAGATCGCCTTTTTAAATAACCAGTGAC1032125CCTCATGCTTTAATAGGTAGCACACATTTCTATAGTACTTG1485022AAATTAGGCTGAAGGAACAGGCTTGATGGTTATTACAATGG1485024CGTTTCCACCACCTGGAAATCTGGCTTTCTTCCATTGTTG3913651CCTTGAGTATCTAAGAAAGGCAAAATATACTTGTTTTGAGC4693319TCAAGAGTGGAAAGGGAGAGCAGCTCCACTCACTATCTTG1872383TGGCCTCAAATGCATGTGTCCTTTGGAGCTATCCAAATGG2200376GTGTTTGAGAAAGAAGTGTGGAGTTCAGACAGAGTATGAG7668090GTAGGCCTGAGAATGCATTGGACATTCCATTATTCCTCCC7692930ATGAGAACACATGGACACGGTCTCCTAATGCTATCCCTCC967096GATTGGAAAAGGGCAACAGGTCCATGAGAATGTTCCTCAG6822249AAAGGATGTTTCCATTTCTCCCTAGAAAGGTAGTTGATGC6532405CTCAGGATCATTGAGACTTAGCTTGAAAGATAACTGCGGAC1017897TGCCCAAACTGCAAATACACGCTACATTAAGTGAATTCTAC7672674CTACAACAGACAAGGATGGGCAATGCCTTCAGCATTTTCC7694568CCATTTCTAATGGGTACCTCTGCCATACACTACAACAGAC2904484ATTTTCACATTGCTTTGCCCGAACAAGCAGAGCAAGTAAG7340830CAATCTCAAAACAGTGTTTACACTAAGAAAGGAGAGAACAG1485033CTGGCTGGAATGTTAATAGGTGTGCTCCTCAGTACATAGC2870706CCTGCAGGAAGAAAATAGGCAGGGAAGCAAAACTAAGATG1905729GGGAATTACTCTAGCTCTTCAGGAAAGAGTAGGCCAAATG4693320TCAAACTAGTAGCCCACAAAGTATAGATTACAGTAGATGTG6848749CCATCTTTTTGTCTGCATTCCAGTCAATTTTCATATTGCC6532406GCATGGCTCTTAGGAGAAAGGCTGGAAGGGAAAATGGTAC6532407TTGTTTTCCTAGGCTCCAGCTGGCTACAATAGGGAGACTG1905728GCAAGTTCATTTTCATATAGCTAAAACAGTGTGAAATTTTGG6819866CACACATAGCTCTTCTGTAAGGCCTCGAGGAAAAAAAAATAG1905727AAGGGATAACAAGACAAATGACCCCATGATCTACTATTTC7674069CAGTTACTCCAAACTTACGGGGTAACAAAGGCACTCAAGG1905724GCTCTCAGTGTCTTTTAATGCGCATATGATTAGCTACTTC1905723GGGTTTATAAGCCTTTTCTTCCTTGCTAACAATGAAAAGGTG1485020GTTGTCATTTTATGTCCTCCGTAGAGTCACTGCCAATAAAC8814101GAGGACTTCAATGACTTTGCTCAGACACAAACATCTGAAG












TABLE 18








dbSNP
Extend
Term



rs#
Primer
Mix


















1433661
CATGGGATTCCAGGTGT
ACT






1485009
CCTCTTCTGGAAAATCTTAA
ACT





7681947
ACGAATTAGTCCAAGGA
ACT





1816432
TGAGATAGTTAATTTTGTTTTCCA
ACT





1485018
CAGTGAGCCATGACTGT
ACT





1485017
GGTCTAAAACTCCTGAGAT
CGT





7438397
CTCCTGCCTTGGCCTCC
ACG





6834311
GAAGAGAAAGAGATGGC
ACG





1368717
AGGGATCGGAAATTTAAGAAGAA
ACT





1017391
AATGACAGTAGGGATTATAGTAA
ACT





2870701
GACAGTAGGGATTATAGTAAG
CGT





7679839
ATTTGCTGGCCCTTTAA
ACT





1385404
CCTAAAGCAGCCACTGT
ACT





1368716
CAATGAGAAATGCCAGC
ACG





4693316
GCGATAGAGTGAGATTCTG
ACG





1905707
TGTAGTTTCCCGAGCTAGATT
ACT





1905708
AGATAGATGAATGGAGAACCC
ACT





1905709
GTTTCTCAGTGTCATCAAATA
CGT





3912442
AAAAAGACATATCTTCTTTTAGTG
CGT





2082553
CCACTCAGATATTCCATAAC
ACT





6831638
CCTTTACTGTGATATTTATTTCTT
ACG





5860329
GCTCCTGAAACATATTCATG
ACT





2870702
GAAGGCATTATGACATGAAT
ACG





2870703
TTGTTTATTCAAATCTGCCA
ACG





1948016
GCCAGTAATCTCTCCAATGAT
CGT





6835836
CACTCAGCTGAATAGACA
ACT





1994253
CTGACTCATACATCCTTTG
ACT





1905710
GAGCTATTCCAATGTGCT
CGT





1485019
AAGCTCCCCAAAAGGTGTTTAATT
CGT





978191
TGTACAAATCTGAGGGC
ACG





1385405
CCTGTGACAGGATTCCAGCA
CGT





7694361
GGATTACAGTAGTTTCCC
ACG





1905711
CCATATCCACAGGTTCT
ACT





1905734
CTTAGCCACTCTGATAATCT
ACT





1485012
ACACTGCAAAAAGCACT
ACT





1485013
TGCAGAGATAATGTATGTAGAA
ACT





4692981
TCAAACACAGTTTATATGAGATAA
CGT





7670552
CAACCATGCTGCTATGA
ACT





7670932
CATGCTAAGGGAAAGAAG
ACG





7688091
GGATGGGTGAATTGTATATTAT
ACT





7440540
TTAAGGGAGAGCATGAAA
ACT





2171000
GGTAGAAATGGACTTTGA
ACG





2870704
GCAGCTTCCTAACAAAAA
ACT





7655758
GCCTTTGAAAGAATCCAA
ACT





7661436
CTTTTTTGTTTCTATCCAGG
ACG





7662289
TGCTTCTTTATTCCCCA
ACT





7667044
GCTTTGTTTTTGATGAGTG
ACG





7691929
TTAATTCCTGAGACGTGT
ACT





5860330
CTTGCAAGTGATTAAAAAAAAAA
ACT





901013
GAAAGCATTCATCTCACTA
ACT





901012
GTAGTGTCTACAAAGGGTATA
ACT





901011
GTTGATCTCCTTCCTGG
ACT





1948018
GAGAAAGTAGACTTTCTCAT
ACT





2870705
CTTTCTCACATGCTTGC
ACT





1948017
CAGCAACCATTGAGGGTGAAT
ACG





1905733
TGTCCTTGACTGATTTTTAG
ACG





1385408
TCTAGGAAGTATGAGATGG
ACT





1385409
CAATAGTAACTGTCAACTGT
ACT





1385410
CAAGGAAGCTAGAGCCA
ACT





1485026
CTTCAATTAGAAAGCACCT
ACT





1485027
GTGCTGTGAAGACAAATTA
CGT





2904483
GGATTGTTTCTTCCTCT
CGT





1385408
TGTATACAGAAAAAAGCATGA
CGT





1905732
GTTGGTGCAAAAGTAACT
ACT





2046418
GTCTATCTCCCTGACAC
ACG





2200377
AAAAATTAAAACATTCACTGCTTA
ACT





1905731
TTCTGTAATCTAATCAAGATAGG
ACT





1905730
TCTGACAGGACTAAACAA
ACT





975713
GGTCACCTAAGGATTTTACA
ACT





6820985
AAAGGAGGCCTCTACCC
ACT





7670441
CATGCTCTTACATGCAAATA
ACT





6810794
CCACAAAACCAAGCTTATTA
CGT





7676623
TCTTCTTTAATGTGATGGTAC
ACT





1154861
GAATCCATAGATCGTATACTAAT
ACG





1032125
ATTTATATTCCGCCCCA
CGT





1485022
TCCAAAACGACCAGTCA
CGT





1485024
TTCATGCTAACTGATTATCAAAT
ACT





3913651
GGCAAAATTCCATGGCC
ACG





4693319
GAGTAATTGGACCTCTAC
ACT





1872383
CCATTCCATATCCTTACC
CGT





2200376
TTTTACATCTCACCCCA
CGT





7668090
GAATGCATTGGAGTGAG
ACT





7692930
ATCACACTCCGGGGACT
ACT





967096
AGGGCAACAGGGACACA
ACT





6822249
GTATTCACCATTGCAAAAA
CGT





6532405
GAACAACTGAAATCTGAAGTA
ACG





1017897
AACTGCAAATACACATTTCA
ACT





7672674
GTTTTGAACACTTAATGTTTG
ACT





7694568
GATTTCACCCCTTTCCC
ACG





2904484
AAATGTTCTCCAAGAAAGAT
ACT





7340830
GTTTACATATGAGGAAATGTAG
ACG





1485033
GCCCTCTAAAGACATGA
ACT





2870706
GAAGAAAATAGGCTGATTTTAT
ACT





1905729
CTAGCTCTTCAGAATTAATTGG
ACT





4693320
CCCACAAAGTCTTATGCA
ACT





6848749
CCAACAGAGAGAGGTATTTA
CGT





6532406
CATGGTCTACACACCTTTA
ACG





6532407
CCTTGTAAGACTACCTGAA
ACT





1905728
CAGTTAATAATTGTAGATCCATG
ACT





6819866
GCTCTTCTGTAAGAAGTCT
CGT





1905727
ATGATTGTAGATCATTTTGATGTA
ACT





7674069
TTCCTAACTCTTCACCTT
ACT





1905724
CATTGTTAGCAAGTGGAA
ACT





1905723
GAGCATAAAGATGCTCTCAGT
ACT





1485020
CTCCGTTATCTCCATGT
ACT





6814101
GCAAATGTAGTTGTATGTAATTT
ACT









Genetic Analysis


Allelotyping results are shown for female cases and controls in Table 19. The allele frequency for the A2 allele is noted in the fifth and sixth columns for control pools and case pools, respectively, where “AF” is allele frequency. Some SNPs do not have an allele frequency disclosed because of failed assays.

TABLE 19Position inLow BMDSEQ IDChromosomeA1/A2Control AFCase AFAssociateddbSNP rs#NO: 3PositionAllele(High BMD)(Low BMD)p-ValueORAllele143366120694744306T/CT = 0.11T = 0.170.00891.64TC = 0.89C = 0.83148500924394744343A/GA = 0.00A = 0.00G = 1.00G = 1.007681947246794746567T/CT =T = 0.89C =C = 0.111816432355094747650A/GA = 0.56A = 0.610.07791.23AG = 0.44G = 0.391485018499494749094C/GC = 1.00C = 0.99G = 0.00G = 0.011485017516794749267G/TG =G =T =T =7438397519394749293C/TC = 0.94C = 0.940.88040.96CT = 0.06T = 0.066834311527394749373G/AG = 0.51G = 0.560.12121.20GA = 0.49A = 0.441368717573394749833A/GA = 0.10A = 0.130.15731.31AG = 0.90G = 0.871017391781794751917A/CA = 0.64A = 0.630.64020.94CC = 0.36C = 0.372870701781894751918T/AT = 0.00T = 0.00A = 1.00A = 1.007679839861294752712T/GT = 0.97T = 0.900.00000.31GG = 0.03G = 0.101385404915894753258A/GA =A = 1.00G =G = 0.001368716928594753385G/AG = 0.89G = 0.830.02510.62AA = 0.11A = 0.1746933161068094754780G/AG = 0.57G = 0.530.24310.87AA = 0.43A = 0.4719057071186694755966T/CT = 0.07T = 0.130.00081.99TC = 0.93C = 0.8719057081195894756058A/GA = 0.97A = 0.920.00030.35GG = 0.03G = 0.0819057091204494756144A/TA = 0.05A = 0.060.88821.08AT = 0.95T = 0.9439124421275394756853G/TG = 0.00G = 0.00T = 1.00T = 1.0020825531558594759685A/GA = 0.00A = 0.11G = 1.00G = 0.8968316381729994761399C/TC = 1.00C = 1.00T = 0.00T = 0.0058603291881694762916—/G— = 0.00— = 0.00G = 1.00G = 1.0028707022402294768122C/TC = 0.66C = 0.650.85960.98TT = 0.34T = 0.3528707032499494769094C/TC = 0.63C = 0.620.76130.96TT = 0.37T = 0.3819480162663794770737G/TG = 0.52G = 0.470.13670.84TT = 0.48T = 0.5368358362763594771735C/GC = 0.00C = 0.00G = 1.00G = 1.0019942532877394772873T/CT = 0.92T = 0.870.01340.61CC = 0.08C = 0.1319057102943094773530A/TA = 0.39A = 0.340.27840.83TT = 0.61T = 0.6614850192987694773976T/AT = 0.14T = 0.190.03381.42TA = 0.86A = 0.819781913036494774464C/TC = 0.00C = 0.00T = 1.00T = 1.0013854053105794775157C/AC = 0.68C = 0.660.65190.94AA = 0.32A = 0.3476943613178294775882C/TC = 0.21C = 0.240.16291.22CT = 0.79T = 0.7619057113340094777500A/CA = 0.00A = 0.00C = 1.00C = 1.0019057343558894779688A/CA = 0.92A = 0.880.02290.61CC = 0.08C = 0.1214850123766394781763C/GC = 0.96C = 0.910.00320.47GG = 0.04G = 0.0914850133786594781965T/CT = 0.00T = 0.00C = 1.00C = 1.0046929813821894782318A/TA = 0.68A = 0.720.17411.19AT = 0.32T = 0.2876705523937594783475T/CT = 0.11T = 0.220.00002.26TC = 0.89C = 0.7876709323955994783659C/TC = 1.00C = 1.00T = 0.00T = 0.0076880913983394783933A/GA = 0.00A = 0.13G = 1.00G = 0.8774405404013594784235A/GA = 0.00A = 0.00G = 1.00G = 1.0021710004169894785798G/AG = 0.00G = 0.00A = 1.00A = 1.0028707044224994786349T/CT = 0.53T = 0.530.84181.02TC = 0.47C = 0.4776557584257194786671G/CG = 0.21G = 0.250.05311.32GC = 0.79C = 0.7576614364297794787077G/AG = 0.44G = 0.450.72431.04GA = 0.56A = 0.5576622894354894787648T/CT = 0.24T = 0.290.16251.27TC = 0.76C = 0.7176670444363194787731G/AG = 0.18G = 0.220.06691.31GA = 0.82A = 0.7876919294370594787805T/CT = 0.93T = 0.900.04390.64CC = 0.07C = 0.1058603304381794787917T/—T = 0.48T = 0.520.14491.19T— = 0.52— = 0.489010134437494788474A/CA = 0.00A = 0.00C = 1.00C = 1.009010124446494788564A/CA = 0.00A = 0.00C = 1.00C = 1.009010114478894788888T/CT = 1.00T = 1.00C = 0.00C = 0.0019480184896294793062A/GA = 0.10A = 0.190.00022.20AG = 0.90G = 0.8128707054899394793093T/GT = 1.00T = 1.00G = 0.00G = 0.0019480174911094793210C/TC = 0.12C = 0.170.00681.60CT = 0.88T = 0.8319057334943494793534C/TC = 0.02C = 0.030.58811.41CT = 0.98T = 0.9713854084952394793623T/GT = 1.00T = 1.00G = 0.00G = 0.0013854094974294793842C/GC = 1.00C = 1.00G = 0.00G = 0.0013854104990794794007G/CG = 0.53G = 0.510.53130.93CC = 0.47C = 0.4914850265002894794128G/CG = 1.00G = 1.00C = 0.00C = 0.0014850275008994794189G/TG = 0.00G = 0.00T = 1.00T = 1.0029044835158894795688C/AC = 0.68C = 0.650.41250.90AA = 0.32A = 0.3513854065289994796999C/AC = 0.00C = 0.00A = 1.00A = 1.0019057325408894798188A/CA = 0.48A = 0.470.80780.97CC = 0.52C = 0.5320464185653894800638C/TC = 0.64C = 0.650.92291.01CT = 0.36T = 0.3522003775907194803171T/CT = 0.00T = 0.04C = 1.00C = 0.9619057315911094803210A/CA = 1.00A = 1.00C = 0.00C = 0.0019057305917894803278A/GA = 0.74A = 0.730.92700.99GG = 0.26G = 0.279757136108794805187T/CT = 1.00T = 1.00C = 0.00C = 0.0068209856130094805400C/GC = 0.99C = 0.99G = 0.01G = 0.0176704416217194806271T/CT = 0.67T = 0.660.71670.96CC = 0.33C = 0.3468107946278394806883T/AT = 1.00T = 1.00A = 0.00A = 0.0076766236298394807083T/CT = 0.00T = 0.00C = 1.00C = 1.0011548616390894808008C/TC = 0.73C = 0.700.24060.84TT = 0.27T = 0.3010321256408894808188G/TG = 0.50G = 0.510.93421.01GT = 0.50T = 0.4914850226494194809041A/TA = 1.00A = 0.98T = 0.00T = 0.0214850246505094809150A/GA = 0.04A = 0.120.00003.18AG = 0.96G = 0.8839136516895394813053C/TC = 0.40C = 0.410.68841.05CT = 0.60T = 0.5946933197009394814193T/CT = 0.81T = 0.800.72600.95CC = 0.19C = 0.2018723837130894815408C/AC = 0.35C = 0.380.47691.10CA = 0.65A = 0.6222003767300994817109T/AT = 0.65T = 0.630.61170.92AA = 0.35A = 0.3776680907400294818102A/GA = 0.61A = 0.590.47620.92GG = 0.39G = 0.4176929307429494818394T/CT = 0.00T = 0.00C = 1.00C = 1.009670967487994818979G/CG = 0.00G = 0.00C = 1.00C = 1.0068222497693694821036G/TG = 0.20G =T = 0.80T =65324057719594821295G/AG = 0.44G = 0.460.52461.08GA = 0.56A = 0.5410178977768394821783T/CT = 0.75T = 0.720.38730.89CC = 0.25C = 0.2876726747828394822383T/CT = 0.81T = 0.820.66611.07TC = 0.19C = 0.1876945687833194822431C/TC = 0.82C = 0.910.00042.33CT = 0.18T = 0.0929044847936294823462G/CG = 0.67G = 0.660.80070.97CC = 0.33C = 0.3473408308035794824457C/TC = 1.00C = 1.00T = 0.00T = 0.0014850338065394824753T/CT = 0.74T = 0.730.68090.95CC = 0.26C = 0.2728707068084094824940A/GA = 0.65A = 0.650.95761.01AG = 0.35G = 0.3519057298320394827303A/GA = 0.66A = 0.620.11860.82GG = 0.34G = 0.3846933208540594829505T/CT = 0.67T = 0.730.03351.32TC = 0.33C = 0.2768487498644194830541G/TG = 0.14G = 0.220.00161.68GT = 0.86T = 0.7865324068696794831067G/AG = 0.98G = 0.950.04600.44AA = 0.02A = 0.0565324078712194831221T/CT = 0.95T = 0.910.03010.57CC = 0.05C = 0.0919057288961794833717T/CT = 0.00T = 0.00C = 1.00C = 1.0068198669096994835069T/AT = 0.51T = 0.420.01570.70AA = 0.49A = 0.5819057279424994838349G/CG = 0.06G = 0.090.16891.48GC = 0.94C = 0.9176740699581194839911T/GT = 1.00T = 1.00G = 0.00G = 0.0019057249669094840790T/GT = 0.06T = 0.070.30321.31TG = 0.94G = 0.9319057239673194840831A/GA = 0.71A = 0.700.77680.96GG = 0.29G = 0.3014850209726794841367C/GC = 1.00C = 1.00CG = 0.00G = 0.0068141019741494841514T/GT =T = 0.00GG =G = 1.00


Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in FIG. 3. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in FIG. 3 can be determined by consulting Table 19. For example, the left-most X on the left graph is at position 44917643. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.


To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20 kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W. M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J. M. Chambers and T. J. Hastie, Wadsworth & Brook/Cole). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10 kb sliding window with 1 kb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10−8 were truncated at that value.


Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3′ end of each gene to show the direction of transcription.


Example 8
PDE4D Proximal SNPs

It has been discovered that a polymorphic variation (rs1498608) in a gene encoding PDE4D is associated with the occurrence of low BMD (see Examples 1 and 2). One hundred sixteen additional allelic variants proximal to rs1498608 were identified and subsequently allelotyped in low BMD case and high BMD control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 20. The chromosome position provided in column four of Table 20 is based on Genome “Build 34” of NCBI's GenBank.

TABLE 20Position inSEQ IDChromosomedbSNPNO: 4ChromosomePositionAlleles (A1/A2)genome_letterdeduced_iupac6886495249558309549g/cgS6450498543558309843a/taW1472456973558310273g/acY47003151076558310376a/gaR47003161276558310576g/cgS77147081599558310899a/gaR77104792755558312055c/tcY29680132911558312211g/ccS29680144466558313766a/gaR29680155754558315054t/ccY13916485762558315062a/gcY20552975967558315267a/gcY20552965972558315272a/gtY39891386390558315690—/aaaN47003176984558316284c/ttY20362207234558316534g/acY77272068196558317496g/ttK77234328369558317669a/gaR15462219565558318865c/tgR447980111084558320384c/tcY439559511153558320453c/tcY439559611187558320487t/ccY469993211290558320590g/aaR293620111386558320686a/gtY735667211441558320741c/tcY293620012373558321673a/gcY190929612602558321902c/agK770313113763558323063c/gcS744530818697558327997a/ttW308774818854558328154t/cgR432172319107558328407c/tgR296801619310558328610c/tcY586815120074558329374c/—cN187485820145558329445t/cgR187485720281558329581a/ctK771292223117558332417c/ttY463114023585558332885g/aaR446916623906558333206t/ctY107836924046558333346c/ggS107836824450558333750g/acY296800624619558333919a/gtY296800524637558333937g/tcM293619024894558334194c/tcY240961325030558334330g/cgS441504825732558335032g/cgS296800427106558336406a/cgK296800327395558336695g/atY296800228971558338271a/gcY293619129755558339055t/atW149861030988558340288a/ggR687466231827558341127c/aaM306039331843558341143a/acaaN772972232773558342073g/aaR773388432787558342087t/ctY771448933099558342399t/ccY773557036854558346154t/ccY293619338026558347326g/tgK229185138397558347697t/ccY229185238680558347980a/gaR149860239626558348926t/ctY199516639682558348982t/ctY149860339710558349010g/ttK149860439745558349045c/aaM149860539901558349201g/agR194865139925558349225c/ttY469993440356558349656g/ttK470031940393558349693c/tcY227973741230558350530a/gaR772036141733558351033c/tcY770641941877558351177g/tgK100643143555558352855t/ggK135374744066558353366g/ttK149860644134558353434c/tcY135374844181558353481t/ggK155311345022558354322a/caM296801246856558356156t/gcM296801148231558357531c/atK149860849652558358952a/ttW293618950393558359693t/aaW149860951103558360403c/ttY296801951733558361033t/ccY689123854733558364033t/ctY296801057173558366473a/ttW296800958192558367492c/tgR293620358506558367806g/cgS149860159572558368872g/atY149860059738558369038a/gtY149859961617558370917g/atY293620263980558373280c/gcS773007064161558373461c/ggS645050166871558376171a/ggR645050267063558376363a/taW688945667084558376384a/gaR689461867477558376777c/ttY770604469282558378582t/ctY770754170363558379663a/taW771207670647558379947c/ttY689286071834558381134c/tcY686705372130558381430c/gcS773726973495558382795c/ttY686415674542558383842t/ctY95044775280558384580t/caR293619680740558390040a/ggR771934782579558391879t/ctY139164982591558391891c/aaM139165082976558392276t/ccY139165183040558392340g/aaR135374985894558395194g/aaR1068214986020558395320g/gcctgN586815386947558396247g/aggN136388288922558398222c/ggS240962689662558398962t/ctY296801892367558401667g/acY95474093154558402454a/gcY98606794979558404279t/ccY686940097598558406898t/ccY501078298532558407832t/aaW


Assay for Verifying and Allelotyping SNPs


The methods used to verify and allelotype the proximal SNPs of Table 20 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 21 and Table 22, respectively.

TABLE 21DbSNPrs#Forward PCR primerReverse PCR primer6886495AGTTTGCTTCCTGAACAATCATGCAGTTGAATCTCAATAC6450498GGACAGCTTTATGTTTAATACACAAATACTCCATTGATGGT1472456GGGAGGTAAGGAATCATGACTTTTGAAGGACAAGTTCCCC4700315GGGAACTTGTCCTTCAAAAAGCATTTTCTGTTACTCTGAGG4700316ATTGTGTCCATGCTTGGCAGCCTCCTTCTATTGTGGAGAC7714708GCAACATACTAACTGGAATCCGTTCTTCTGTTTGTCATGTGG7710479TGCTCCAAAAATGGCAATCGATTTCTACATCACCAGGGAG2968013CACCCCTAGATTTTGAAGGTCAATGACACATTCCCTCACC2968014CCTTCCCTCCTTCATTCAACTGGATTCAGATTACGGGAGG2968015TGTCAGCTGTATGGTGAAGGAACGCCAAGCCTATTTTCAG1391648AATTTGGTAAGACAGAGATGTTGCTCTGTTCCTGAAAGAC2055297AAGCTTTGTTTCTCTTTCTCAACGATTCTACATCTGCCCC2055296AAGCTTTGTTTCTCTTTCTCAACGATTCTACATCTGCCCC3989138GCCTTCCCCCTCCTTTAAAACATTTCAGGATGAATACTTG4700317TTTTCCTGATATGATGAATGCTAGTAATGCAGCAATAGTG2036220TGTATCCCAGGACATCTAGCAACATTCAGGAAATTTCAGG7727206AAGGACTGGGTTTGCATTTCCTAATCTTGGCAACATTCTG7723432TGAATCTAGGAGTGGATTTGAGATCTGACCATGGTGATAG1546221GGAAAACTCCTTATGTTGGAGCTGTATATTATATTACTGTG4479801ACTTCTAGAAGAAAACACAGTATGCTTCATGCTTTTGTGG4395595AAACCACAAAAGCATGAAGCTGGCTTGTTGTTCTGTTTTC4395596ATATTCCCTTCTCAAGTCTGCTGGACTTTACCAAATTTCTC4699932CCATCTTTTCACTGGATTGTCCAGACTTGAGAAGGGAATATG2936201GCATCTCACTGTGGTTTTACCACAATAAGAGGACAATCCAG7356672GACCATCATTAGACATTAGGGTTAATTTGCTCTGCATCCAG2936200TCACAACTGGGAATTCACTGGAGCTCCACCATTATTTCCC1909296CCGAGTAGCTGGGATTACATTGGTGAAACCCTGTCTCTAC7703131AGAGAAGAAGGCTTCAGACGTTTAGCTTCTTTGCGATGGG7445308ATACAGCGGTTGGGACTATCGCACATTGTGCACATGTACC3087748TAGTCCATAGGAATCTGCTGGCTGCTGTACATTACAACAC4321723GAATTTTACTTGGAACCCTGGCCTATCTTACTACTGAACTC2968016GTAAACCTTGGACTTATGGGACGATGTTACCCTCTTTTCC5868151TAGAATAGACTACATCCATCGGATAAGGAAGTTTCTTAGG1874858GCCTAAGAAACTTCCTTATCCATATTGCCAACTAGGAGTAC1874857ATGAAGACTTTACTGAAGGCCATACACTACTAACCTGTTGC7712922CTCTTTCTAAGGGCTTCTGGAGAGGAGTCGGACTTTGTTC4631140TTGAAGTTGAGAGGGTCTCCAAGCAAAGCACAAGCAACAG4469166TTAGGAGGGATGAGGAATGGCTCCAATTGCACTGGGTTAC1078369TCCCTGAGCCTCTGTTTTCCATATGTCCCCACCACACTAC1078368ATGACTCATGGAGGCAACAGGGAGAGCGATTTATGGATGG2968006CAGGGTTCATTTGGTGAAACACTGACCTGTCTGGGATTTC2968005ACTGACCTGTCTGGGATTTCCGCAGGGTTCATTTGGTGAA2936190AACAGACCTCCAACACAACCTAGGATAAACTCACGGAAGG2409613AATAGGGTCAGTGGGATGAGCCCACCTCCAAATCCTTTAC4415048CACCCAGCCTCAGAATATTTTTCCCCACCAATACAACATC2968004CCCAAACATTATCTTCTGGCGATCTCCATAAGGGTAAGTG2968003ACAAGAGGACAAGTGTTTAGGGCCAGAGCTGTTCATAAAT2968002CCTTTGACTTTCCACAGAACACACTCACTGGGTTGGGCTA2936191TGACCTTGATAACCTGGCTGAGCTGTGCATATTGACTTCC1498610CATTAAATCACCACAGCAACTCCTTAGGCAGAATGGTC6874662ACTCTAGCCTGGGCAACAGAATGTCTTGTAGTTTCCAGTG3060393CCAGTGTATAGATCTTTCACCAGAGCGAGACTCCATCACAA7729722GAGGAAAGTGTGTCTATTCAGCCATACATCTGATAAGAGGC7733884TGTATCTCTGTTGGCCATTCCCATACATCTGATAAGAGGC7714489AGGGTCTTGCTCTTTTGTTCATTGAGCCCGAGAATTTGAG7735570AGGATCTTCATAGAAGTGGCAACTGAGGCTGTTTTCTCTC2936193CTTAGCATACAATGGGCACCACAGTGCCTACTATTGTCAG2291851GTTTCTTGCTTGTTGATGGCTAGCCTTGGCCAAGAATTCA2291852ATCCTGATCTCTTACTAGTGTTCTGTGTTCTCTCTTGAGG1498602CAGTAGTTTTTCAGCTAAATGATCCAAACATAGATCTCAAC1995166GCCACTTAGCAATGTGCAAGGGGAAAGTAACTAGCTGCTC1498603GTGTGGTTGATTCTGTGTAAGACTACTGTCGAATCACCTTG1498604GCTTGCACATTGCTAAGTGGCCATGGGCCTGAGTTCTTAA1498605CTGTGGCATTAGGCACCTTTAGGACACTGGACATATTCAG1948651CAGATGAGAATAAAGGTGCCTATTGCTCTCTTACTGGGAC4699934AGGACTGGTAATGTTGTGAGGACCTTGTAAATAGGTGGCC4700319GACCTTGTAAATAGGTGGCCGCTGAAGGATTCAGCCAGTA2279737AAAACCTCTCAATTTATTTCATGGCCTCCAACAAGGTAAG7720361ACTATGCGACTTTTCAACTGACCCCCTCGCCATCCGCTA7706419ACCCGGCCGCGGCTGATTCATGCCCCGCCTGCCGAGCCTT1006431CCTTGCCAGGTGAATTAAAGCTATACAGAGCAGGTATTTT1353747TGAGAAAGTTGGAGTGCAGGAATCATTGGTTACAATGAAG1498606ACTCCAACTTTCTCAAAGCCTTGGTGAAGATGGAGGAAGG1353748CTCCATCTTCACCAAGTTCCGAAATATAATGTGTGGAGCC1553113AGCCTTTAGGGAGTTTAGCCGCACCAAATCTTGCTAAGTC2968012CAGTTCTATCTACTGTAGACCAGTTCCAGCTTCTCTTCTC2968011ATAATGGTTGCACTGACTTCACTGTGTGACATGGGATCTG1498608GAATCCCTGTTCATTCCTTGATAACCTCGGGGTCCAGAAA2936189TGATCTCAGACTTCCAGCTCTTTGTCTTAGCTCAAGCTGC1498609TAGCTCAACTGTTCTTCAGGCAGAGTGAGTGTAAATATAC2968019CCCAGGCCAGTATTACTGTTTGACATTTACAGGCACTCAG6891238CCTTTATTCAGGCTGCAGACTGTGGTTTTAATGGCTGTGG2968010ATGTATGATTCACTCTGATGCAAACCAATTGGTAGATTTC2968009GTAGGCAAAGATGAATCACGTGTTTTACCTAGCAAGGAGC2936203AGTTCAGAGGTTCCAGACAGAGCCAAGCTTGCAAACTCTG1498601TTGGTTAGATCCAGCTCTGCTAAGAGGAACAGGGATCTGC1498600ATATAGGTACTGCTTTCTCCCCTTGTTTCCAAATCTGAGC1498599GGAACATTTGGCTACATCATGCCACAGAGCTGATTTAATTTC2936202TGTAAGAGGAGGGTGTGATGTGACTCTGCAGGACTGTCTG7730070AAATATACTTGGGTAGAGAGGATAGCTAACACATTTCTGAC6450501AGCTAGACTACATAGCCTCCTGTAGGACATGACAGCAAAC6450502TAACAAGTCAAAACAGATGGATTTTCAATATTCTGCACAC6889456GGATCTCTATTAAACCTCTCTTCAAGGGTTACTGATACTC6894618CCATCAACAGATGAATGGACTCCTTCCTTTTTTAGGGCTG7706044GACTTGGTATTTTGTGAGGGTCCACCATGTGAGGACAAAG7707541TTTTGAGTCATGAAAAACTGCACATGTATTAATTAAGTAGG7712076AAGCCATACCACAAGCATTCGTTCACGTGAAATACACTACC6892860CAGAAGATGCAATGAAAAGACAGAACAAAATGTTAGGACGC6867053TTATCCGCATTCCACTCTTGACACTGGTCCTCATAACAAG7737269TTTAAAGGCTCGCACCTCAGTCCGAAGGAAAGTGATTCTC6864156GTTGGATCATCAAAAAGTGGGGCTAGAGTACTAAAAATCAG950447GTGAGTAGTCTGAATTTGTCAGGCTTCAGAATCGGTCATC2936196CTCCAAAACATAGTAAGTGCTGAACATTTAGAATTAGGGG7719347ACATTCTGAGGTCATGCAGGCTCAGAGCCTGCATTATCTC1391649GCTAATGCTTTACTCTGGTCCACACTCCAAAATGTGCAAC1391650TTCAGCTGATACTTGCTCCCCTCTACCTACCAACATCGTC1391651TTGACGTGATAGAAGTTTGGCTGAAAAGGGTGGCTTTCTC1353749TATAGAGCAAAAAGCCAAGGCCACTTCTACCACATTCTTC10682149GGGAGAATATAACCATTAAGTGAATTGCATTTTATCCAATC5868153CATAGGGACTATTTAAACTTCGAGTGTTCTTTAGAGATTAAG1363882CTCACACAGGCAATGAGTAGAGCCACTACTTCTCAATCTC2409626CCTGGTCTCAAGCAATCATCATAAGGCCAGATGTGGTGAC2968018GCAGAGAGATGAGAGGAAACCCTCATATCTAATCTCTCCC954740ATACTTGGGAGCACTCAACGCAACAAGACGGAATCCAAAG986067CTACAAATTGCTTAAGCAGGGTGATAGAGTAGAGAGACTCC6869400ACAAGATCGTTGAATGGTGGGACTTTGTATACTGCCACTC5010782AATCTGTGGGAGTTAGTGGTTTCCTCATCCTCATCTTCCC












TABLE 22








dbSNP
Extend
Term



rs#
Primer
Mix


















6886495
CCTGAACAATCTTAAATGC
ACT






6450498
GTCTTATGCATTTTGAAGG
CGT





1472456
GGAATCATGACTACTTGGA
ACG





4700315
GAAACAAAGCAAACGAC
ACT





4700316
TGCTTGGCAGGCTTTTT
ACT





7714708
CAGTATAAGTAATTTGGCCC
ACT





7710479
GAGCATTTTAATTGCTTCC
ACG





2968013
AGCTGAGAGCAGCCATG
ACT





2968014
GAGCTGTTTCTTTCAGTTT
ACT





2968015
ATGGTGAAGGTGGAGGA
ACT





1391648
TCAGCTGTATGGTGAAG
ACT





2055297
GTGCCTGACATAGAGTAG
ACT





2055296
GGCAGTGCCTGACATAG
ACT





3989138
CCCCTCCTTTAAAAAAAAAAA
CGT





4700317
CAAATGTAACAAAGTGCCA
ACG





2036220
GCCTCCCTGGCCTCTGC
ACG





7727206
AATCCTGTCACCTATGG
CGT





7723432
GTGCCTTGAATTAAAGAATC
ACT





1546221
CTTATGTTGGAGAGGTC
ACG





4479801
TAGAAAGTAGTTGTGATCTTG
ACG





4395595
AAAAATGGTATACTGGACTTTA
ACG





4395596
CTGTGGCTTGTTGTTCT
ACT





4699932
CACTGGATTGTCCTCTTA
ACG





2936201
CCTAATGTCTAATGATGGTC
ACT





7356672
CACAGTGAGATGCCACA
ACG





2936200
CTTGGATAACTGTATGCCT
ACT





1909296
TTACATGAGTGCACCAC
CGT





7703131
GGTAATAAACTTTTCCGAG
ACT





7445308
GTTGGGACTATCTACTTTTTT
CGT





3087748
CATAGGAATCTGCTGCCTCAC
ACT





4321723
ACTTGGAACCCTGGTATTTT
ACG





2968016
GGGGCAAAAAGACAATAAA
ACG





5868151
GAATAGACTACATCCATCAAAATA
ACG





1874858
GAAACTTCCTTATCCAAGGCC
ACT





1874857
GCAATTAAAAGTGGTACAATAA
ACT





7712922
CAATAAAAGGAAAGAGACTTC
ACG





4631140
AGAGGGTCTCCTGTAGG
ACG





4469166
GAGGAATGGAACTATTTTTAAAC
ACT





1078369
CTCTGTTTTCCCTGTAAAT
ACT





1078368
GCAACAGGTGAAGCTGA
ACG





2968006
GACTGAACCTTTAGGAGA
ACT





2968005
TTCTCCTAAAGGTTCAGT
CGT





2936190
CCAACACAACCTCTTAA
ACG





2409613
CCAAGTGACTAAAGCAGAT
ACT





4415048
AAAACCTAATGCTCAGTTAAA
ACT





2968004
TCTGGCATAAAGTAAACTAATC
ACT





2968003
GGGGACTAGTCAACAAA
ACG





2968002
TCTGATGAGGTCTTCTAC
ACT





2936191
GGCTGAAGTAGTGATAGG
CGT





1498610
GAAGCACAGAAGGCAAC
ACT





6874662
CAGAGCGAGACTCCATC
CGT





3060393
GATTTGCTCCTAAGTTTTTT
ACT





7729722
GTGTCTATTCAGATCCTTTG
ACG





7733884
TTGAGGAAAGTGTGTCT
ACT





7714489
GGCTGGAGTGCAGTGGC
ACT





7735570
TCCACATTATGCAACTACA
ACT





2936193
AAAAGTCAGTGTAAGAGTTC
CGT





2291851
TGATGGCATTGAAGCAG
ACT





2291852
GTTTTTATTGTGCTTTTCAATCT
ACT





1498602
GAATTTGAGCAGCTAGTT
ACT





1995166
TGTGCAAGCATTAGTGTAT
ACT





1498603
GAGCAGAATCAAAAGCC
CGT





1498604
GCTCTTCATTTTCTTACACAG
CGT





1498605
AGGCACCTTTATTCTCAT
ACG





1948651
GAATAAAGGTGCCTAATGC
ACG





4699934
GTAATAGTTGCCTCGTC
CGT





4700319
TTACTAATTGTCTCACAACATTA
ACG





2279737
TCGCCGGCATGGGAATC
ACT





7720361
AGTCCCAGTCCAGGAGC
ACG





7706419
TTCATTCACTTCAAGTGC
CGT





1008431
GTGAATTAAAGTTTCAGATTGAA
ACT





1353747
GGAGAGGAGCCACAGAA
CGT





1498606
CAAGTGATTTCCCAGTAG
ACG





1353748
ACCAAGTTCCCAAAGCT
ACT





1553113
GGAGTTTAGCCAATAGTTTTTGC
ACT





2968012
GACAGTATCAATTCCTTCC
ACT





2968011
TGACTTCAACTTTACTTTCTT
CGT





1498608
CCCTAAAAACTGTTCCAGGTA
CGT





2936189
CCAGAACTGTGAGAAATAAA
CGT





1498609
GTTTTCTATTTGAAATTGAGGTAT
ACG





2968019
CCAGTATTACTGTTTGAATCTC
ACT





6891238
CTGCAGACATTTCCTAC
ACT





2968010
TTCACTCTGATGTTTTCTATTT
CGT





2968009
CATAACCTCTGGTTTCC
ACG





2936203
GGAGGATATCCATGCCCC
ACT





1498601
AGCTCTGCCTCCCCCATTT
ACG





1498600
AGGTGCCAAGCTAGTCA
ACT





1498599
GGCTACATCATGTTTTGG
ACG





2936202
CCCTGGTAACTGTAGTG
ACT





7730070
TAGGCATGCTCAAACTC
ACT





6450501
GCCTCCTAAAAAAGCAC
ACT





6450502
GTTTAATGACATTTTAGAGAGG
CGT





6889456
AACCTCTCTAAAATGTCATTAA
ACT





6894618
GGACAAAGGAAATGTGATATATA
ACG





7706044
GGCTCATTTCCTGGGTC
ACT





7707541
GAAAAACTGACAACATATGAG
CGT





7712076
CCCAGAGGATATAGATTTCAT
ACG





6892860
GGATATTTCAGTGGTGCT
ACG





6867053
CACCATTAACCTGGTCTA
ACT





7737269
ACTCTTGATCAATAGTTTGG
ACG





6864156
GTAGTTGACAAATCTTACCT
ACT





950447
TTGTTAGTGTATTAGCCATTG
ACT





2936196
GTGCAAAGATCAATCACA
ACT





7719347
GGTCATGCAGGAAATAG
ACT





1391649
TCTGGTCTATTTCCTGC
CGT





1391650
CCCACAGGTTTTTCACA
ACT





1391651
GGGCCCCCGTTTTGCCCTG
ACG





1353749
CAAAAAGCCAAGGATATAAAATA
ACG





10682149
GTATGATCTGATTTCCATAAATAG
ACT





5868153
GAAATGAATAAATGGCAAAAAA
ACT





1363882
GCAATGAGTAGACTAAAAAAA
ACT





2409626
AGCAATCATCCCACCTC
ACT





2968018
CAGACACCCACTGACCA
ACG





954740
ACGAAGGTCCCGTCTGA
ACT





986067
CAGGGATTTAAAATGAAACC
ACT





6869400
AATGGTGGGTCATTAGTT
ACT





5010782
GCACCTACAGAGGAAAT
CGT









Genetic Analysis


Allelotyping results are shown for female cases and controls in Table 23. The allele frequency for the A2 allele is noted in the fifth and sixth columns for control pools and case pools, respectively, where “AF” is allele frequency. Some SNPs do not have an allele frequency disclosed because of failed assays.

TABLE 23Position inLow BMDdbSNPSEQ IDChromosomeA1/A2Control AFCase AFAssociatedrs#NO: 4PositionAllele(High BMD)(Low BMD)p-ValueORAllele688649524958309549G/CG =G = 0.87C =C = 0.13645049854358309843A/TA = 0.81A = 0.850.17801.29AT = 0.19T = 0.15147245697358310273G/AG = 1.00G = 1.00A = 0.00A = 0.004700315107658310376A/GA =A = 0.95G =G = 0.054700316127658310576G/CG = 0.87G = 0.840.15200.75CC = 0.13C = 0.167714708159958310899A/GA = 0.35A = 0.460.00131.60AG = 0.65G = 0.547710479275558312055C/TC = 1.00C = 1.00T = 0.00T = 0.002968013291158312211G/CG = 0.84G = 0.800.12560.79CC = 0.16C = 0.202968014446658313766A/GA = 0.22A = 0.250.28341.16AG = 0.78G = 0.752968015575458315054T/CT = 0.88T = 0.860.20380.80CC = 0.12C = 0.141391648576258315062A/GA = 0.25A = 0.240.85660.97GG = 0.75G = 0.762055297596758315267A/GA = 0.00A = 0.00G = 1.00G = 1.002055296597258315272A/GA = 0.94A = 0.940.88571.04AG = 0.06G = 0.063989138639058315690—/AA— = 0.53— = 0.500.37030.90AAA = 0.47AA = 0.504700317698458316284C/TC = 0.00C = 0.00T = 1.00T = 1.002036220723458316534G/AG = 0.44G = 0.440.92721.01GA = 0.56A = 0.567727206819658317496G/TG = 0.27G = 0.250.39540.89TT = 0.73T = 0.757723432836958317669A/GA = 0.82A = 0.820.76711.05AG = 0.18G = 0.181546221956558318865C/TC = 0.83C = 0.840.72821.06CT = 0.17T = 0.1644798011108458320384C/TC = 0.86C = 0.870.74401.07CT = 0.14T = 0.1343955951115358320453C/TC = 0.93C = 0.930.72411.09CT = 0.07T = 0.0743955961118758320487T/CT = 0.01T = 0.02C = 0.99C = 0.9846999321129058320590G/AG = 0.13G = 0.100.14400.76AA = 0.87A = 0.9029362011138658320686A/GA = 0.17A = 0.190.36091.15AG = 0.83G = 0.8173566721144158320741C/TC = 0.88C = 0.890.47571.17CT = 0.12T = 0.1129362001237358321673A/GA = 1.00A = 1.00G = 0.00G = 0.0019092961260258321902C/AC = 0.98C = 0.99A = 0.02A = 0.0177031311376358323063C/GC =C =G =G =74453081869758327997A/TA = 0.00A = 0.00T = 1.00T = 1.0030877481885458328154T/CT =T = 0.21C =C = 0.7943217231910758328407C/TC = 0.19C = 0.240.10331.30CT = 0.81T = 0.7629680161931058328610C/TC = 0.45C = 0.440.79590.96TT = 0.55T = 0.5658681512007458329374C/—C = 0.44C = 0.430.66590.95— = 0.56— = 0.5718748582014558329445T/CT = 0.12T = 0.170.15581.43TC = 0.88C = 0.8318748572028158329581A/CA = 0.96A = 0.960.54850.83AC = 0.04C = 0.0477129222311758332417C/TC = 0.05C = 0.00T = 0.95T = 1.0046311402358558332885G/AG = 0.10G = 0.090.49030.87AA = 0.90A = 0.9144691662390658333206T/CT = 0.97T = 0.980.65101.30TC = 0.03C = 0.0210783692404658333346C/GC = 0.88C = 0.880.82790.96CG = 0.12G = 0.1210783682445058333750G/AG = 0.50G = 0.470.30330.89AA = 0.50A = 0.5329680062461958333919A/GA = 0.34A = 0.350.52161.08AG = 0.66G = 0.6529680052463758333937G/TG = 0.37G = 0.360.73320.96TT = 0.63T = 0.6429361902489458334194C/TC = 0.22C = 0.220.90711.02CT = 0.78T = 0.7824096132503058334330G/CG = 1.00G = 1.00C = 0.00C = 0.0044150482573258335032G/CG = 0.94G = 0.960.26661.36GC = 0.06C = 0.0429680042710658336406A/CA = 0.92A = 0.880.12100.70CC = 0.08C = 0.1229680032739558336695G/AG = 0.61G = 0.660.23641.23GA = 0.39A = 0.3429680022897158338271A/GA = 0.81A = 0.810.81961.04AG = 0.19G = 0.1929361912975558339055T/AT = 1.00T = 1.00A = 0.00A = 0.0014986103098858340288A/GA = 0.00A = 0.00G = 1.00G = 1.0068746623182758341127C/AC = 0.00C = 0.00A = 1.00A = 1.0030603933184358341143—/CA— = 1.00— = 1.00CA = 0.00CA = 0.0077297223277358342073G/AG = 0.01G = 0.01A = 0.99A = 0.9977338843278758342087T/CT = 0.96T = 0.970.52821.26TC = 0.04C = 0.0377144893309958342399T/CT = 0.15T = 0.140.76680.95CC = 0.85C = 0.8677355703685458346154T/CT = 0.08T = 0.090.45931.18TC = 0.92C = 0.9129361933802658347326G/TG = 0.25G = 0.280.36381.14GT = 0.75T = 0.7222918513839758347697T/CT = 0.05T = 0.060.21141.40TC = 0.95C = 0.9422918523868058347980A/GA = 0.98A = 0.98G = 0.02G = 0.0214986023962658348926T/CT = 0.67T = 0.610.04960.77CC = 0.33C = 0.3919951663968258348982T/CT = 0.54T = 0.550.78401.03TC = 0.46C = 0.4514986033971058349010G/TG = 0.03G = 0.02T = 0.97T = 0.9814986043974558349045C/AC = 0.16C = 0.130.23290.79AA = 0.84A = 0.8714986053990158349201G/AG = 0.88G = 0.890.37131.18GA = 0.12A = 0.1119486513992558349225C/TC = 0.58C = 0.560.51990.93TT = 0.42T = 0.4446999344035658349656G/TG = 0.13G = 0.050.00430.35TT = 0.87T = 0.9547003194039358349693C/TC =C = 0.98T =T = 0.0222797374123058350530A/GA = 0.82A = 0.800.35200.87GG = 0.18G = 0.2077203614173358351033C/TC = 1.00C = 1.00T = 0.00T = 0.0077064194187758351177G/TG = 0.89G = 0.920.15091.38GT = 0.11T = 0.0810064314355558352855T/GT = 0.22T = 0.300.00771.49TG = 0.78G = 0.7013537474406658353366G/TG = 0.23G = 0.150.00250.61TT = 0.77T = 0.8514986064413458353434C/TC = 0.85C = 0.870.34751.17CT = 0.15T = 0.1313537484418158353481T/GT = 0.65T = 0.660.86451.02TG = 0.35G = 0.3415531134502258354322A/CA = 0.95A = 0.970.17301.54AC = 0.05C = 0.0329680124685658356156T/GT = 0.66T = 0.660.90691.01TG = 0.34G = 0.3429680114823158357531C/AC = 0.67C =A = 0.33A =14986084965258358952A/TA = 0.19A = 0.130.01180.64TT = 0.81T = 0.8729361895039358359693T/AT = 0.63T = 0.650.60211.08TA = 0.37A = 0.3514986095110358360403C/TC = 0.34C = 0.400.03141.30CT = 0.66T = 0.6029680195173358361033T/CT = 0.62T = 0.640.54171.08TC = 0.38C = 0.3668912385473358364033T/CT = 1.00T = 1.00C = 0.00C = 0.0029680105717358366473A/TA = 0.90A = 0.950.00122.28AT = 0.10T = 0.0529680095819258367492C/TC = 0.65C = 0.700.09591.24CT = 0.35T = 0.3029362035850658367806G/CG = 0.17G = 0.140.17300.80CC = 0.83C = 0.8614986015957258368872G/AG = 0.81G = 0.780.38990.83AA = 0.19A = 0.2214986005973858369038A/GA = 0.48A = 0.460.59910.94GG = 0.52G = 0.5414985996161758370917G/AG = 0.69G = 0.690.97391.00GA = 0.31A = 0.3129362026398058373280C/GC = 0.20C = 0.140.02860.68GG = 0.80G = 0.8677300706416158373461C/GC = 0.74C = 0.730.57440.93GG = 0.26G = 0.2764505016687158376171A/GA = 0.00A = 0.09G = 1.00G = 0.9164505026706358376363A/TA = 1.00A = 1.00T = 0.00T = 0.0068894566708458376384A/GA =A = 1.00G =G = 0.0068946186747758376777C/TC = 0.69C = 0.730.15421.21CT = 0.31T = 0.2777060446928258378582T/CT =T = 1.00C =C = 0.0077075417036358379663A/TA = 0.63A = 0.610.58740.93TT = 0.37T = 0.3977120767064758379947C/TC = 0.00C = 0.00T = 1.00T = 1.0068928607183458381134C/TC = 0.81C = 0.830.40911.14CT = 0.19T = 0.1768670537213058381430C/GC = 0.46C = 0.440.45630.91GG = 0.54G = 0.5677372697349558382795C/TC = 0.00C = 0.00T = 1.00T = 1.0068641567454258383842T/CT = 0.99T = 0.99C = 0.01C = 0.019504477528058384580T/CT =T = 1.00C =C = 0.0029361968074058390040A/GA = 0.00A = 0.00G = 1.00G = 1.0077193478257958391879T/CT = 1.00T = 1.00C = 0.00C = 0.0013916498259158391891C/AC = 0.42C = 0.350.01620.74AA = 0.58A = 0.6513916508297658392276T/CT = 0.75T = 0.750.95680.99TC = 0.25C = 0.2513916518304058392340G/AG = 0.58G = 0.590.88311.02GA = 0.42A = 0.4113537498589458395194G/AG = 0.43G = 0.390.15960.85AA = 0.57A = 0.61106821498602058395320—/CCT— = 0.37— = 0.390.53821.08CCT = 0.63CCT = 0.6158681538694758396247A/—A = 0.72A = 0.710.74700.96— = 0.28— = 0.2913638828892258398222C/GC = 0.45C = 0.430.52280.93GG = 0.55G = 0.5724096268966258398962T/CT = 0.84T = 0.850.85811.03TC = 0.16C = 0.1529680189236758401667G/AG = 0.75G = 0.750.84110.97GA = 0.25A = 0.259547409315458402454A/GA = 0.00A = 0.00G = 1.00G = 1.009860679497958404279T/CT = 0.04T = 0.060.24751.43TC = 0.96C = 0.9468694009759858406898T/CT = 0.00T = 0.00C = 1.00C = 1.0050107829853258407832T/AT = 0.68T = 0.690.86441.02TA = 0.32A = 0.31


Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in FIG. 4. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in FIG. 4 can be determined by consulting Table 23. For example, the left-most X on the left graph is at position 58309549. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.


To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20 kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W. M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J. M. Chambers and T. J. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10 kb sliding window with 1 kb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 10−8 were truncated at that value.


Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3′ end of each gene to show the direction of transcription.


Example 9
GPX3 Proximal SNPs

It has been discovered that a polymorphic variation (rs869975) in a gene encoding GPX3 is associated with the occurrence of low BMD (see Examples 1 and 2). Two hundred thirty-three additional allelic variants proximal to rs869975 were identified and subsequently allelotyped in low BMD case and high BMD control sample sets as described in Examples 1 and 2. The polymorphic variants are set forth in Table 24. The chromosome position provided in column four of Table 24 is based on Genome “Build 34” of NCBI's GenBank.

TABLE 24Position inSEQ IDChromosomedbSNPNO: 5ChromosomePositionAlleles (A1/A2)genome_letterdeduced_iupac14783982315150385031a/gtY14783973305150385130t/caR11601145825150385382g/cgS11601135895150385389a/gcY138232310605150385860a/gcY116011210665150385866g/atY770987013115150386111g/aaR771064315565150386356g/tgK773046716555150386455t/ctY657982916925150386492a/caM657983018025150386602g/agR657983120615150386861t/aaW689623221125150386912t/atW135113121535150386953t/cgR103807426675150387467c/tgR147839631155150387915t/caR688051231865150387986g/aaR495885856215150390421t/ctY495843157355150390535t/ggK495843258295150390629g/cgS689846366585150391458a/ccM495885979015150392701g/ccS4130064114475150396247g/agR4130065114665150396266a/gaR4133119119845150396784t/cgR4958860158035150400603t/gtK4958861162575150401057t/gtK4437356176045150402404c/acM4958868197625150404562c/ttY1478400223675150407167a/ggR6889375227095150407509a/ggR1600159236315150408431g/ccS6875892236865150408486t/atW4608909255995150410399t/ctY2345000269735150411773a/ccM4516840284575150413257g/ttK2054440286695150413469a/gaR707141299085150414708c/taR707142301055150414905a/gtY841236307115150415511a/gaR707143308515150415651g/atY707144312035150416003t/cgR6869405314465150416246a/ccM707145316385150416438c/tgR707146330645150417864c/tgR707148339585150418758c/atK707150351825150419982a/ttW5872184383325150423132a/acaN3763015408755150425675g/acY2042235416245150426424t/ctY3763013416715150426471a/gcY2042236418255150426625g/agR1946234429205150427720c/aaM1946235429355150427735t/ctY1946236430015150427801t/aaW8177402430125150427812t/ccY8177403432035150428003c/tcY8177404432945150428094t/ctY8177405432955150428095t/ccY8177406433445150428144c/ttY8177407435095150428309t/ccY8177408435495150428349g/ccS8177409435605150428360t/aaW6888961435785150428378a/ttW8177410436405150428440a/ggR8177411437925150428592g/cgS8177412437975150428597c/ttY8177413439645150428764c/ggS870407442975150429097c/taR870406443115150429111c/tgR6873202445885150429388a/gaR8177414447755150429575c/tcY8177415449215150429721c/tcY3805435450065150429806g/atY8177416450985150429898t/ccY3792799451855150429985c/gcS3792798454755150430275t/cgR3828599455065150430306t/caR8177417455435150430343g/cgS3792797456015150430401t/gaM8177418456525150430452t/ccY8177419457565150430556ag/ggN8177420458265150430626t/ctY8177421459745150430774c/ggS4958872460445150430844t/ccY3792796462005150431000c/ggS8177422462185150431018a/gaR8177423462215150431021c/tcY4958434462805150431080c/taR8177424463305150431138—/gagtcctgggagtcctggN8177425465835150431383t/ccY8177426466505150431450a/gaR8177427467215150431521a/gaR8177429468085150431608g/cgS6889737472425150432042c/acM3792795475125150432312g/acY8177430476005150432400t/ccY8177431477065150432506a/ggR4958873478065150432606a/gaR8177432479785150432778t/gtK8177433480215150432821t/ccY8177434480255150432825g/aaR8177435480935150432893t/ggK3763011484135150433213t/cgR8177436489335150433733c/ttY8177437490975150433897c/ggS4958874491055150433905t/ctY8177439495705150434370g/agR8177440495915150434391c/tcY8177441497045150434504g/cgS8177442497055150434505a/taW8177443497985150434598c/tcY869975500825150434882a/ggR869976501475150434947g/aaR8177444503565150435156a/taW8177445507255150435525t/ctY7721469509685150435768c/aaM8177446510295150435829a/caM7704191510865150435886t/ctY8177447511665150435966t/ctY11548514935150436293c/tcY2230303515395150436339g/ttK7722386515625150436362g/aaR8177448516455150436445g/agR8177449516495150436449t/ccY2070593516505150436450t/cgR8177450516565150436456g/aaR8177451516575150436457t/ccY8177452520095150436809g/aaR8177453521435150436943a/ccM8177454523495150437149g/cgS3763010524215150437221c/tcY8177455525325150437332a/ggR8177456526825150437482a/ggR736775530585150437858t/ctY2277940531875150437987t/ctY8177458533775150438177g/agR8177834536995150438499g/acY3924538455150438645a/ggR2233312539205150438720a/gcY2233311539295150438729t/gcM2233310554735150440273t/cgR2233309556905150440490a/gcY4958875558505150440650a/ggR2233308567615150441561c/tgR2233307568405150441640c/gcS2233306570005150441800c/tgR2233305571165150441916t/gaM2233304584195150443219t/gcM2233303584205150443220c/tgR2233302588085150443608g/ccS2287719589065150443706a/ggR2287720590485150443848c/tcY7727034591875150443987c/gcS7727250593615150444161c/tcY7709800612185150446018g/agR3840312617005150446500ag/aaN2287721622905150447090g/agR6875293625965150447396t/ccY3805434640495150448849g/cgS2080982660775150450877g/ttK2080983660795150450879g/tgK2287722660865150450886t/ccY2233301661155150450915t/gcM2233300661505150450950c/gcS4958876664755150451275c/aaM2233299691775150453977a/ggR2233298692105150454010a/gcY2287723693125150454112t/gtK2161359702445150455044a/ggR7734456708825150455682g/cgS4292439719055150456705t/ccY4958878722945150457094a/taW6862024725815150457381a/ggR3834819727865150457589—/cacaN2233297729505150457750g/atY2233296731065150457906g/acY2233295731625150457962t/cgR2233294732735150458073g/taM7713028741315150458931g/agR7713223744065150459206t/ccY7713567746655150459465c/tcY888989747405150459540t/ccY2233293753825150460182a/gcY3749657754005150460200g/tcM2233292754605150460260g/acY2112635758635150460663c/tcY871269760985150460898t/ccY3792794784325150463232a/gcY6579837786045150463404g/tgK3805433791905150463990c/gcS5872186798705150464670—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—/agagN


Assay for Verifying and Allelotyping SNPs


The methods used to verify and allelotype proximal SNPs of Table 24 are the same methods described in Examples 1 and 2 herein. The primers and probes used in these assays are provided in Table 25 and Table 26, respectively.

TABLE 25DbSNPrs#Forward PCR primerReverse PCR primer1478398TTCCCTCCCTTCCTTTCTTCAAGATTACCCCACTGCACTC1478397CACATACTTGTCTGAGGATCAGCACTCAGAATACTACCTG1160114AGCTGGATTCAGAGCCTTTGTCTGCTATCACCTTGTTCCC1160113TCTGCTATCACCTTGTTCCCAGCTGGATTCAGAGCCTTTG1382323AGAAGGACAGTTGCAACAGGGTTCCTCATCCAGTCCTTAC1160112GTTCCTCATCCAGTCCTTACAGAAGGACAGTTGCAACAGG7709870TTATGACTCATAACTTTTTGCTTTCTTGAAATGCTCAGGG7710643ATAAAGTCTGGGCTCAGATGATAGACCAGGGAACTGAGAC7730467TGTGGCATATCTTCTATTGCAATGTGGCTGTTATGGTAGG6579829GGAGGCTTTTTCACATTCACAATGTGGCTGTTATGGTAGG6579830TGAGTATGGATTCTCAGGTGACCATAAGAGAGAAAAGCCC6579831GTGTGTGATGAATATGGGAGTTTCTCTCCTGTGTGTATTC6896232GTCACACCTCTTTGTACATCCACTGAAAGCTCTCTCACAC1351131AAGTGTGAGAGAGCTTTCAGGTATAAGGTTTCTCTCTAGTG1038074TCATATCTTGTGGGTTGTCCTTCACTGTGGACCACAAAGG1478396CATGGCCTCTTACAAGACTCGGGTAATTGTACCCACCAAG6880512GAGGTATTGGTGATTAGGGCTAAAAAGGAATTCTTGGTGG4958858GCAAGTGAGATCTTGGTAGGCAGACTGGCAGGAGTACATT4958431CAGAGGTGTCACTTCAGGAACCATCTTGCTTCTTTCCCTG4958432TGCCTTAATTCATGCAACCCTTATATCCAGGGAAAGAAGC6898463CAAATCTACTTTTGAGTACCGACTCATCAAATGGAGAATG4958859GTGGTATAACTCCTCAGAAGATGATGAAGTTGTCTTCAGG4130064AATTCCTCACATTAACCCAGCCACAGCAAAGACAAAAGGG4130065CCACAGCAAAGACAAAAGGGTCCTCACATTAACCCAGGAG4133119AGTGAGGTATAATGCCAGCCAAAATCTCCCTGTGTCTGCC4958860TATGCGGTGGAGAAGAAAGGTCAACCCGGACAACAAAACC4958861ACTGGGATTTTCTGGTGAAGATGGGTGAGTCTCCCTTTAC4437356AGGTTTCTGGGTTTTCTCTCATGGTAGTGTGTTTGTTTGC4958868TTGTTGGCCTTGTTCATGTCCCTGTAATCCCTGCACTTTG1478400TGGACTCCTGTGGGATAATGCAAGACTTCCAAGTGCATCC6889375TACCTGTCCACAGAAATAGCCCTGAGACCCTATGACTTTA1600159GGTTCATGTGATTTGGAAGCTGACTCTCCTAGTTCTTCAG6875892GGGACTTCTCAGCTTCCAAAAGGGTTCTCCAGAGAAACAG4608909CTGATAGAGGTTTATCTCAGTCTAGCCAAACTCCTATGTGC2345000TAACAAGCCCCTAACTAGTCTCAGGTGAAACCAACTGAAG4516840GTGCAGTGGATCCTTTTTCCCTAGACTCTAGGTAGGACAC2054440CCCTTGAATGAGATGGAGACTGGGAAAGGAAGGGAATGTC707141ACAGTGCTAAGCACTTTCCCACAGTAGACACACAGGATAA707142AGCCTGGCTTCTTCGTCTACATTTCCACCCTGGGCACTTC841236ATGTGTGCATGAGAGGAGAGCCAAAAAGGAGGAATGTGGG707143CTTTTAAAGCCAGATGGACCCCACCCTGTTCTTACTGTAG707144ACTGCACCAGACGCTTTCACTTGGGCAAGGCGTGTTTCCT6869405TCTCTCATCATGGCTTGTGGCTGGCCAAGCGATAACACTA707145TAAAGTCTGGGGAGGTCAGGAGTGGCTGCTTTCGGAACAG707146GCAACAAGAGCGAAACTCTGAAATGGGCAACATGGCAAAG707148ACCTTTCATATACAGCTGGGCTGTGTTCCAGCATCATCTG707150ACTGATCTGGGCTAGGAATCAAGGACAGCCAATTAACACG5872184TAAAATGTTGTTTACCAGGGAAGGATGCCTATGTGACCAG3763015GCCAAATATTGTTTTCCTTGACATCGACCCTTTGTTGTAC2042235TCCTTCTCTGATCTCAGTTGTTAGGAATGAAAAGCCACAG3763013AGAGACCTGAGATGCTACCCACAGGTGGACAACTGAGATC2042236AAAGGTGTTTCCAGCAGATAAAAATGTAGAGAGATGCCCG1946234AACAAGTCATCTAGCCAGAGCTGGCTTAGAAGCAGAAAAT1946235CCTGGCTTAGAAGCAGAAAAGGCACTGGAGATCACTAATC1946236GCACTGGAGATCACTAATCCAAACCACCTGGCTTAGAAG8177402TATCTGTGGCCAAACCACCTCACAGGGAGCAAATTTATT8177403TTTCCTTGAGTCTTTGGGTCGCCTGTAGAAAAAGGTTAGC8177404ATTAGGACTGTAGGGACAGAGCTAACCTTTTTCTACAGGC8177405ATTAGGACTGTAGGGACAGATTTTCTACAGGCATGTCAGC8177406ATGTCAGCTGTGATCCTTATGAAAACCCCATTCTGGGTAG8177407TGATGGAAGTCTCCATTCTGAATTTCCAGAGGACCATCGC8177408GGGCTAATAGCTCCCTAGAACGCCAGGTGTTTTTAAAACC8177409ATGCTTCCCAGAATGGAGACTCCATTACAGCCAGGGCAAG6888961TCCTCTTTTGGCTCCAAAGTTTCCATCAGTTCTAGGGAGC8177410TCCTTTCGCACTTTGGAGCCATAAGCAAATCTGGGCAGAG8177411TGTGACCAATCCGCGGCCAATGAAATCCCAGCCGCCTAGC8177412TGAAATCCCAGCCGCCTAGTTTCAAGCCCTCGGGTGTGAC8177413TGCAGGCGTCCTGCCTGCTTCACTCACCTTCGACTTCTC870407GTGACATAGATGTAGCAAGGAGAATGACTAAGGGAGGAAG870406CGGAGGTGACATAGATGTAGAGAATGACTAAGGGAGGAAG6873202TAGAAATGGCCACTTGGATTAGTGTTCTGCACTGTCACTC8177414GGGATGCTTGGAGAAGCTGAAATGAGGACAGTGGGTCCTG8177415CCTCAGTCTATTTCCAGCAGATAAGCATGCTGGGTCATCC3805435GACAGTATGTACTGGGGTGGTTTGAGTCTATCCCTACACC8177416GAAGACCCAGAGGATTTTAGAGGGATAGACTCAAAGCGAG3792799GGACAGAATTTTGGAAACGGCTAAAATCCTCTGGGTCTTC3792798ATTTTCCAGGTCAGGAATGGCCAAAACTGAAGGTTGGGAC3828599AGTCAGTCCCAACCTTCAGTCAGGGCCCAATTGTATCTTC8177417AGTTATTCATGGAGTCCACGTTTTGGAAGGGTCAAAGAAG3792797GAGTCCATTTATCCTTCCCCACGTGGACTCCATGAATAAC8177418AAGTCCTGACTGGTTGTATGCTCAGAGAGAATAGGATGGG8177419ATGCCCATCTCTGCTCCCAATCCTAACCCAGAGCTAAGAC8177420ATTCCATTCTCCACATGCCCTAAGAGTTCAGATGTCTTAG8177421ATTGAAAGGGAGATGCTAGGTTGTAGAGACAAGGAGCGTG4958872AGTCACCTAGAAACCAGCAGACAAAAGGACTGCAGAAGCC3792796CAATATGATGCTGTGAGAAGATCTTACAATGGAGGAGCTG8177422ATCTTACAATGGAGGAGCTGTATGATGCTGTGAGAAGTGG8177423ATCTTACAATGGAGGAGCTGTATGATGCTGTGAGAAGTGG4958434CTGCTGGTCTTGTGTCTTTCAGACCACTTCTCACAGCATC8177424GGCTTGAGAGTTGGATGATGGGAGAGGAGAAAGACACAAG8177425AGAGCAAAACAGGCCTGGAGACCCATGGGCCACCTTCTGA8177426ATTTCGTTCCAAGAGACTCCATATGTCCAGGGAGATAAGC8177427TTATCTCCCTGGACATATGCGGCAAGGAGAACCCTATTTC8177429CAGGTTGTCCTAATAATGGGATGAAATAGGGTTCTCCTTG6889737CATGACAGAGGCAGCTCTTCTGAAGGGAGTGATATATGCT3792795GGCCACAAAGGACCTTAAAGTGACACAATTTGGCAGGTGG8177430AGTAGGATGTGGCCTATGAGATTGTGTCAATGATGCAATG8177431CATGATCCTATCAAGCCATCGACCTGAGTTTCCTCATTTA4958873GCCAGTCCAAGACCACACAGTGGGAGACCTGGGCTCCAT8177432CCCGGAACATTAACACATGCTTACCAAATAGGGAAGCAGG8177433GGACAGGAAAGATGAAGCTGATGCAGGTACTGTTGCTTTT8177434GGACAGGAAAGATGAAGCTGATGCAGGTACTGTTGCTTTT8177435ATTGGGAGCCTCTGAATCACGGCCAGTGTGAAGGAAAAAC3763011GTGCTTTTTAAGCACTTAATCTCCTAATTCCTTGTTTAAG8177436CACTGTGTTCCGTGGTTTTGCCTAGAACATGTCCAAAGGC8177437GAGATGGTAACTGAAGCTCCTGCCAAGAGAAGCACCAAAG4958874TGCCAAGAGAAGCACCAAAGGAGATGGTAACTGAAGCTCC8177439AGAGAAGCATCCCAGAAAAATCCATGCTCTGCCTGGCAAT8177440GCAATCACAGGCGAATTCCCGCATCCCAGAAAAAGCACTC8177441TCCCCAGTTTCCTCAGTGTCAACAGAGCAGAGTGCGTTTG8177442TCCCCAGTTTCCTCAGTGTCAACAGAGCAGAGTGCGTTTG8177443TGCCAAAGATTATGGGAGGGGAGCAAGAACTATCCATCCC869975CTTTCTCGGGCCTCAGTAGTCTGTCTCATCCACACCACTC869976AGTGCATTCAGTTCTGGGCCAGTGGTGTGGATGAGACAGG8177444AGGAGAGTAGTTCTTGGTGGAGAAAGCTCCTCTCACATGG8177445TTCTCTCCATTGACATCCCCTCAACAGGTATGTCCGACCA7721469ACTATTGTTCCAACTAGAGGATGTTCACTCTGGGTCCTTC8177446AGTTTGGGAGTTAGAAGACTCAGAAGGACCCAGAGTGAAC7704191TTCCTGGGGAATAGCCTGGCCGCTGGCAGTCTTCTAACTCC8177447TGGGAGGACAGGAGTTCTAGGCCTCAAGCAAGGTTGACAC11548TGTTCAGGAAGAAATCCGTGGGGGCCTTGAGTGATAGGAT2230303TGCCTGGCAGTACACAGAACACTATCTACCCATCACAGAC7722386CCTGTAGGCATGTGTGTAAAGCACAAATGGATGCATACAG8177448CAGATGGTACACATTCCCAGGCCTACAGGTATGCGTGATT8177449CAGATGGTACACATTCCCAGGCCTACAGGTATGCGTGATT2070593ACACATGCCTACAGGTATGCCAGATGGTACACATTCCCAG8177450CAGGCACACAGATGGTACACGCCTACAGGTATGCGTGATT8177451CAGGCACACAGATGGTACACGCCTACAGGTATGCGTGATT8177452TGGCCCTTGCTGTCACATCTTACATCCCCACCCCACAGTT8177453AGGGGTGGCATCCCTGCCCATGAGGGGCCAGCCCTTAGTG8177454TGCACCCACTGTAAAAAGTAAGTGAGGAGGAGAAGGTGG3763010AGTGGGTGCAAAGGTAATTGTGATCTCAGGGAGAATTGTG8177455ATGTAGCCCTATTAGGGGTGAGCTAACTATCAGGTTGTTG8177456CCCGGGAGTTTGAGGCTATAAGTGCAGTGGCTCTTCACAG736775TACTCTTGAGTAATGGTGACTGGCCTAGGCTCCTTCCACT2277940CGAATCATGGACATAAATCCTCAGGGAAAGGAAGAAAAGG8177458ACAGTAGCCTTGCTGAAGCCCAGCTTCAGGCTGGCGCCC8177834TCTTAGGATTGCTGCTCCTGGAAAAACTCCTTCCCTGCTG3924TCCCCAGTCCTGTAAACAGCGAGCCTCAGCTGGATGAGAG2233312ATTGTGTCATTTGGCTCCACCACACCGTGCAAGTGGCTTC2233311TTGTGTCATTTGGCTCCACCCGTGCAAGTGGCTTCTAGTT2233310CACTGTTTTGGAAAGCTGGGTTATCTGCCAGCATTGCCTG2233309ATTTAGTATTGTCCTGGCACTATTCCGGCTGCGACAAAAC4958875GGGATAACTTGCTGAAGGTCGCTTAAGAGATTGGCTCTGG2233308AGACACCTTCCAGAGAGGAAGAGCCAGGCCCTGGACAC2233307TCTTCCATCTGGTGAGTCTGTCCTCTCTGGAAGGTGTCTG2233306CCACCCAGAACATCTCTGCATGGTGTGGCACCATGGCTG2233305CTAGCCTTCAGAGAGCTAACTCTGGCTTTGGCCTGCAACA2233304TGGCCCAGAGGGAAGCATCACCTGGATCCAGGGCCTAAC2233303TGGCCCAGAGGGAAGCATCACCTGGATCCAGGGCCTAAC2233302ACCAGGGCCCTCCAATCCATAAATGCCCAGGTAAGAGTGA2287719CTGCAGCTTCTCCACTTGCTTCGTGAGCGCATGAATGAGG2287720AGGGAGGGTGAAGAGAGGGAATCTGTGACCCCAGCAGGAG7727034AGAGTAGTTCTGTGTCCCTCTGGTTGATGGCTTTCAACGT7727250TTGGATCTGCTGGTTCTGAGATGTGAAACTACAGGCTAAG7709800TTGCTCATGACCTAGGCATCCTTTATCTTCCTACTCCACC3840312GAAATGTGCTGGAAAGCAGGCCTCTCCAGTTCAGTTTTGC2287721CCTTGAGTCCAGCTGCAATGGGGTTACCCTTCCTAAGCTG6875293ATGGACATTACTGTACCGACTGGCCCAGCCCTTACGTTCT3805434AAATAAGGCCCCTGGTGTCCGGGCATGGTCTTTTGCCTAG2080982CTGCCTCTTTAGCAGCTTTGAACTTCTCCTCTGGGCCATA2080983CTGCCTCTTTAGCAGCTTTGAACTTCTCCTCTGGGCCATA2287722CTGCCTCTTTAGCAGCTTTGAACTTCTCCTCTGGGCCATA2233301CACAGGGCATGCCTGGTCTTCCACTCCCCAAGGTTCAAAG2233300TGAACAAGCAGTGGGACCAGAAGACCAGGCATGCCCTGTG4958876TTTTACCTTGCCAGGAAAGCCAAAGAGGTGTGTGTGTTCC2233299CCAGCATCTTCACCTTCTTCTTTTGGTGAAGGCTCCTCTG2233298TTTTGGTGAAGGCTCCTCTGAGCATCTTCACCTTCTTCTC2287723AATTATCTCACCCAGTCTCGTGGGAGGAATAGGGAGACAG2161359ACAGCTCTTCCTTACAAAAGTTAGTGACCATTGGTGGATC7734456AATAGTCTAGAGAGTTCCCCCCTGGGTTCTATAAGATGTTG4292439CCCTGGACAGGTCTCTTTACAGGAAGAGCATCTGGCTCGG4958878AGAGTTTACCCAGGACATGCTAGAATGGAATACTAGTCCC6862024GTGCTGGGACTAGAGGATAGTGTTGGCTAGTGTCTGTGTG3834819TGGGAACCACTCTCTAAGACGTGTTGAGTCGTTTGCTCAG2233297ATGAAGCCACAGTGACTACCGTGGTAGAAGGTTCTAGCTG2233296AACCAAGGATGCTACAGAAGATGGAAGGGACAGGCAAGAA2233295TTGCCTGTCCCTTCCATCTTATCCCAGGGAGGAAAATTTG2233294TGGGATGGAGGTAAACAGAGCAACTCATGCGATAGTGAGC7713028CTGGTGAAATACATCACCACTTGAGTAGCTGGGACTACAG7713223CTTTTGGATGGCCAAGGATGCCAGCTTCAGTTTCTGAATC7713567AGCTGGTACCCACCAGATGAATCCTGTGAGTGGCCACAATT888989CAGGGACTTGATTGGAGTCTACTCACAGGATGGAGAGCAA2233293TCAGAGAAGGGGTGAGGAGTAACCCAGAAATCAGTGCTGC3749657AGAAATCAGTGCTGCACACCTAAGTTCAGGCCCCTCAGAGA2233292TGAACTTACCGCAGCCTCTCCCAAGTTGGATAAGGGCCTG2112635TCCATCCCTTCTCCTTCATGGACTTCTCTGAGGAGATGG871269TTCCACAAACTTTGAGCTGGTAATTAATTCCTGAGCTCCC3792794TCTGCTAGAAGGTAAGCTTGAGTGTGTATGAAGTGCCACG6579837ATAGATCCTAGGCCCCTTAAAGGAAATAAACAAGGAGGGGA3805433CTTAGCCTTGTGGGCTTTAGAAGCCTCCGTTTTGCCATCT5872186TCCCGTATTTCCCCATTTCCGCTTTTTGTTCAGGGTGATG2233291CCTTATCCTGTTCATCACCCAATCCACTGGTACCATGGGG2233290CTGCAGGTGCAGCATCAGGTACTCAGGCCTTGGTGAAGA2233289TCAGGCCTTGGTGAAGAGTGATCAGGTTGCCGTCCTCAC4958435AAGTTCTGCTCATCCTTCCCGATCTCTGAGGCTCCCTGTA4958880TCTGGAGGAATGGCAATGACATTTCCTCTTGTTAGAATGC1422673ATGCTTGTGTTCACTGGTTGCATGCTAGTTAGCCAGACAG2042234GCACCTATTGCTCGCATAACTCTACCTTCTCCATTCTCCC3805432AAGGCCCAGGGCCCTGTAAGAACCTCCTTCCTGTGTGCTCCA3805431AAATCACCTGTCTTACAGGGTTTGGGTCTGTGGGCTTCCA2233288ATATGTGAGCGAGAAGCACCACAGAACCTGTTCAGATCCC2233287ATGACAGGCTTGTCGAGAATTTTTGAGTACACAGGGACCG3815720TGCTGGTTCAAGGTCAGCTATAATGTGAGGTCATATCCCC3792792TTCTCAGATCAGTTCACTCCAACACAGATGGCAGCTGTTAC3792791GATTGCATAGTTCAGCATCCCATTACCCGTGTAACCTCAG2303018CAAATGTCACAGCATCTCCCTAAAACTTACACTGGATGGA3792790CATAAAAGCCCCATATCCCCAGGGAGGGCCAAGTCTCAGT4958436GCCTTGGGGTCTTTATCAGCATATGCCAGCTCCAAGTGAC2233286ATGAATGGAAGGGTAGCCTGATCCTTCACAGTGAACTCCC2233285TTCCAAAAGCTCCCCTAGAGACGGGGAGAAGCAGCACAC7732451CATCTCTCGTGCCCCAGAAAGCTGGAAGGCCCAGTTAATG2233284TACATGGTGCATAGAGACAGATATGCCTCTGCCCAAGTCA1422674TGCTGATAATTCCTCAGCACGTCCATTCACTCATCCATTC3792789GAGGATTCCTGATGAAACAGTTCACTGGGGACCTCAGAAG4562032ATTTTACAAGGGAGAAACTGCTGACTTTGCATCTTGGCTC6865077CTGACTTTGCATCTTGGCTCATTTTACAAGGGAGAAACTG1559126CACCATACTCACACAGCCAGATGGTGCTGCCCTACAAAGA3792788CCCTTCTCCCAAAGACTGACAGTGTGGGTAGCTGTCCTTT1559127ACTGTTTCTTAGTTCGGTGGGGTGACTTGTTTTTAACCTG3792786TGAGGACAGAGGCAAGCAGAAACAGTGTGGGGGCTGCACTT6880110TCAAGAACAGTGAAACAGAGTGGTGGACAAGAACCAGGAC6861227CATGCCTTCATGTGGTGTTGAGCAGTGTCCTGGTTCTTGT3805430TCCAGAGAGGGTTTTCCCACGGGAGAAAGAAAGGCAGTGG1862364AATCCCATGGCACACCACAGTGTAGTTTGTGGAACCAGGC4958881GGACTGGAGGTCATCATAACTTCCACCCAAGGATGAAAGG3792785TTTGTTCTACCACTAACCAGCTACATGGATGAGGAAGCAG6869605TTTGTCCAGCTTCTGTGTACAGGTGTGAGTTACCTAAGGG6870205GAATCATCAAGAAGGGACTGACCCCATTCTTTTTGATGGC4246047AAGCTGGTCTCAAACTCCTGTGTTATTTAGGCTGAGCGTG4958882TTGTTGGTGGCTGATGAAGGGCTCACTCATCTGGTTTAAG3792784ATGATTTTCCCATGACTGGCAAACAGCCAGCTGCTGCTCA3792783AATCTGAAGAGTGACTGTCCAAAGACCTTGGCGGCCACCAT5872188CCTTTGCCGACTTTGGTTTCAGACTTGGAAGAGAATGCCC












TABLE 26








dbSNP
Extend
Term



rs#
Primer
Mix


















1478398
TGAGACAGGGCCTCACTCT
ACT






1478397
GTCTGAGGATCAGTAATAATAC
ACT





1160114
CTTAATTGCAATGCCTCTT
ACT





1160113
CTTGTTCCCTACCTAGC
ACT





1382323
CTGACCAGGGTAACAAC
ACT





1160112
TCTCCAATCACCGTTGT
ACG





7709870
CCTACAAGAAATATCAAGGC
ACG





7710643
GAGCATTACAGTTGTCAC
CGT





7730467
TTGCCACTAAATAAATCCAA
ACT





6579829
CATTCACTATGCTCTTTTTTT
ACT





6579830
ATTCCCTGCTGAAGGTT
ACG





6579831
AATATGGGAGAGCCTTC
CGT





6896232
AATACACACAGGAGAGAAA
CGT





1351131
GAGAGCTTTCAGTGAAGT
ACT





1038074
GTGGGTTGTCCACATAT
ACG





1478396
CAAGACTCACTGCAATTTA
ACT





6880512
GGGCTTCAACATATGAAT
ACG





4958858
GAAGATGAAGGCCTGAG
ACT





4958431
CTTCAGGAAAATCCGGC
ACT





4958432
AAATACAGTCAGCCCCC
ACT





6898463
CTTCATTTCAGGTATTCTACT
ACT





4958859
TCAGAAGAGGAGAGCAC
ACT





4130064
CCTTCCAAAATTTCCCT
ACG





4130065
GGGAAATTTTGGAAGGT
ACT





4133119
GCCAAGTATCCTGTATCAA
ACT





4958860
AGGGCAACAATAAGGGA
ACT





4958861
AAGGAGCAGAAGCATGA
ACT





4437356
CTGAGCAGCCCTAGTGA
CGT





4958868
CTCCTGACCTCGTGATC
ACG





1478400
TGGGTGAAAAAATTGGTA
ACT





6889375
CTGCTGATGATGTAGGAAT
ACT





1600159
GAAGCTGAGAAGTCCCG
ACT





6875892
CCAATTCATTATAGGAAATTTTTT
CGT





4608909
GGTTTATCTCAGCATTGTTTAT
ACT





2345000
CTAGTCTCCTTGTTCTCTTA
ACT





4516840
TCCTTTTTCCACCTTGC
CGT





2054440
GTAAACATCCAAAAGCATTTC
ACT





707141
ACATCCTGAGATGAAGG
ACG





707142
CAGGCAGCAGCAGCACA
ACT





841236
ACCTTCTCTGAGGGTATTCTA
ACT





707143
CCCTTAGAGGTCATCTGGTC
ACG





707144
CCATACAAAATCCCCTTG
ACT





6869405
TGACTGGGACCCAGGCT
ACT





707145
GGCCCAGCAGCCAGAAG
ACG





707146
GAAAAGAAAGGCTAAGTGA
ACG





707148
ACTGAGGCCCAGAGAGG
CGT





707150
GTCTGCGCCACCTTCCC
CGT





5872184
GGAGACTCAATGCCAGG
ACT





3763015
CTGTGCTGGTGCTGGTG
ACG





2042235
ATCTCAGTTGTCCACCT
ACT





3763013
TACCCCTGGATTGCTAC
ACT





2042236
AGGCACCTAGGGTCACA
ACG





1946234
CACTGGAGATCACTAATC
CGT





1946235
CCTCAGTTTCCTCAGCT
ACT





1946236
ACACAGGGAGCAAATTT
CGT





8177402
CCAAACCACCTGGCTTA
ACT





8177403
GTCTTTGGGTCTTCATTT
ACG





8177404
TCCTCCCCATCATAAGG
ACT





8177405
TTCCTCCCCATCATAAG
ACT





8177406
CTCTGTCCCTACAGTCC
ACG





8177407
GCATTTCTTATTCCTATCGAG
ACT





8177408
GCTCCCTAGAACTGATG
ACT





8177409
GAGACTTCCATCAGTTCT
CGT





6888961
CCATTACAGCCAGGGCA
CGT





8177410
CTTTGGAGCCAAAAGAG
ACT





8177411
GCGGCCAAGCCGAGACC
ACT





8177412
GATTGGCTGCAAGGGTC
ACG





8177413
TCCTGCCTGCTTTCCCT
ACT





870407
GACCCTCGAGGTGGCAG
ACG





870406
AGATGTAGCAAGGCGAC
ACG





6873202
CAGAGATCTGTGCTAGAA
ACT





8177414
TGTTCTCTGAAATTTCCTC
ACG





8177415
AGCAGGTGTGTGGCCCA
ACG





3805435
TACTGGGGTGGGCTCTG
ACG





8177416
TGCATGTTGGGAAGTTG
ACT





3792799
CGGAATCCTAGACTCATAA
ACT





3792798
ATAGACAGGCCAGCACC
ACT





3828599
CAACCTTCAGTTTTGGAA
ACT





8177417
ACGTTCTCCCCACTAGC
ACT





3792797
ATCCTTCCCCAGAGTGC
ACT





8177418
CTCACCCTAAAACTTTTCTA
ACT





8177419
CTGCTCCCAAGTTCTTA
ACT





8177420
ACATGCCCCATAACCCT
ACT





8177421
TCCCCAGTCCAACTTCA
ACT





4858872
GCAGTTACTAGGATCCC
ACT





3792796
TTGCTGTGTCTCTGATG
ACT





8177422
CATCAGAGACACAGCAA
ACT





8177423
CAGAGACACAGCAAAGC
ACG





4958434
TCTCCTCTCCCGTCTTAT
ACG





8177424
TGGATGATGGGACTCAG
ACG





8177425
GAACGAAATCTCATGTCAA
ACT





8177426
AGCAGATTCCCACAACC
ACT





8177427
GACTTGCTCAGGGCCAC
ACT





8177429
CCTAATAATGGGAACTTGTAAA
ACT





6889737
GGCAGCTCTTCTGCACT
CGT





3792795
TTCAAGGTTTCTCCTTTC
ACG





8177430
ATGAGCCTACTCTGCCC
ACT





8177431
CATGGTTGACCTGGTTG
ACT





4958873
ACAGGGAGTTAATGGCA
ACT





8177432
TGTTGCTTTTCCCTACC
ACT





8177433
GCTGTTGTTACCAAATAGG
ACT





8177434
GAAGCTGTTGTTACCAAA
ACG





8177435
GAATCACCATGTCCATAC
ACT





3763011
AAGCACTTAATATTAAGTACCC
ACT





8177436
TGTGAAGATGATTATATAAGCC
ACG





8177437
AAGCTCCATCTTGCTGA
ACT





4958874
TGGGGCTGAGGGAAAAT
ACT





8177439
TTTCACTTCCGGGAATT
ACG





8177440
TCCCGGAAGTGAAAGGA
ACG





8177441
TCAGTGTCCCCTGGTCT
ACT





8177442
CTCAGTGTCCCCTGGTC
CGT





8177443
GAGGGTTGTAACCTCAC
ACG





869975
GGGCCTCAGTAGTTCCAGC
ACT





869976
CCAAAGAGAAAGAGCAGA
ACG





8177444
GATAAATGTCCACCATGA
CGT





8177445
CTGGAAATTAGGGACAA
ACT





7721469
ACCCTGACTAGGGTCTC
CGT





8177446
GCTGTGGCTCTAGAAGA
ACT





7704191
ATAGCCTGGCCCTGAGA
ACT





8177447
AGTTCTAGAGCAGGGAT
ACT





11548
CACACTATCTACCCATCA
ACG





2230303
GTACACAGAACTGTATGC
CGT





7722386
ACCCACACCCACATGCC
ACG





8177448
CATAGGTAGACACGTGG
ACG





8177449
AAGACACATAGGTAGACAC
ACT





2070593
GCATGGGTGTACAGCCAC
ACT





8177450
CCAGAAAGACACATAGG
ACG





8177451
CCCAGAAAGACACATAG
ACT





8177452
TGTCACATCTGCCTTGG
ACG





8177453
CCTGCCCAGGGGCCTTA
ACT





8177454
TCTTTTCTCATCCTCCC
ACT





3763010
AAAGGTAATTGCGGTTTT
ACG





8177455
GGTGGCATCTTCATGAG
ACT





8177456
TGAGGCTATAGTGTGCC
ACT





736775
TCCCTGAGGGTAGGGCA
ACT





2277940
CATGTTCATTTATGCGCT
ACT





8177458
GCCATGCCAGCCACGTC
ACG





8177834
CCTGGAGGCTTCTGCAA
ACG





3924
CTCAGTTCAGGGACTGGT
ACT





2233312
TGATCTCAGATTGCCAA
ACT





2233311
CAGAGCCAGCTGATCTCA
ACT





2233310
CCAAGAGCAGAAACTAAC
ACT





2233309
TGCTATTGTAATTTTTGGGT
ACT





4958875
CTGAAGGTCATCTAGCAA
ACT





2233308
CTTCTGAACTAAACAGCAC
ACG





2233307
GCTCCAGGGCACACACA
ACT





2233306
CTACCCCTACGCCTACC
ACG





2233305
GATGAGATGGGTGTCCT
ACT





2233304
TCAGCCGGTCAGTCCTC
ACT





2233303
ATCAGCCGGTCAGTCCT
ACG





2233302
TCCATGCCCCCTCTCCC
ACT





2287719
CTCCACTTGCTTCTTCA
ACT





2287720
TTCTCCTCAGGCCCAGA
ACG





7727034
ACATTCTGGGCTTCAAG
ACT





7727250
AGAGACCCTACAAACTC
ACG





7709800
CCTAGGCATCTCCCTGT
ACG





3840312
CTAGAGCCGTTCCCACC
CGT





2287721
CCCATCACTGGCACCCC
ACG





8875293
GAGCATTGTGAAGTGATG
ACT





3805434
TGCTGACGGGAGGAACT
ACT





2080982
AACCTTGGGGAGTGGCC
CGT





2080983
TGAACCTTGGGGAGTGG
CGT





2287722
GCAGCTTTGAACCTTGG
ACT





2233301
TGCCTGGTCTTCATCTC
ACT





2233300
GGTAATGTGGGGTTCCT
ACT





4958876
CTAAGACATGGAAACTACAT
CGT





2233299
TCACCTTCTTCTCGGCTGC
ACT





2233298
CCCCAGGCTAGTGTGAC
ACT





2287723
AAGACCCCTCACCCAAG
ACT





2181359
CATTCCATTACTACAGTAATAACT
ACT





7734456
CCCTTCCTTTACTTCCC
ACT





4292439
CCCTTTAATCTCCACTC
ACT





4958878
CAGGACATGCAAATCTATT
CGT





6862024
CTAGAGGATAGGGGAGT
ACT





3834819
CTTGACAAACTGGAATGT
ACT





2233297
ATGGAGGTCAGGCCAAG
ACG





2233296
ACATACCTGCTGCTGTC
ACG





2233295
AGCCTGGCCGCCCAGAC
ACT





2233294
CCCTGAGTTAAGAAACCT
CGT





7713028
TACATCACCACCCCTCC
ACG





7713223
GGGGTTTTTATAGCCCTA
ACT





7713567
ACCAGATGACTCATCAC
ACG





888989
GATTGGAGTCTTACAACA
ACT





2233293
GGGGCTGCAGGAGGAGG
ACT





3749657
CCTCCTCCTGCAGCCCC
CGT





2233292
TCTCGGCAGCCTGATCC
ACG





2112635
CCCCAGCTGACTTCTAC
ACG





871269
CTGGCAGTGAACAAGAG
ACT





3792794
TGTTGTATTCACTGTTGC
ACT





6579837
AGGGGTCCTGCCAACCT
CGT





3805433
TGGGCTTTAGCAGCGGG
ACT





5872186
CCTCATCCCTCCCCACA
CGT





2233291
GTCTGCCCACAACACAG
ACT





2233290
GTTGCCGTCCTCACGGG
ACT





2233289
CCCTTTCCCTCTCCAGG
ACG





4958435
ATGGGAATCACAGGACA
ACT





4958880
GAATGGCAATGACTATAACC
CGT





1422673
TGTCAGTGCCCAGTGCA
ACT





2042234
CTCGCATAACAACAATTAAAG
ACT





3805432
CCTGTAAGACAGGTGATTT
ACT





3805431
GGGCCCTGGGCCTTCCT
ACT





2233288
CCCCAAGTGACTCCAGG
ACT





2233287
AATCCTGCTTTGTGATCT
ACG





3815720
AAGGTCAGCTAGTCCCA
ACG





3792792
GGGAAGGCCAGCACAGG
ACT





3792791
AGGTGCAGGGAAAGAAG
ACT





2303018
CAGCATCTCCCACAGCC
ACG





3792790
GCTTGGGAAGGTCATCA
CGT





4958436
TGTGTGCCAGGCATCGC
ACT





2233286
GATAAACGAGAGAATGTGG
ACT





2233285
GGAAGCAAAAGCATTTACT
ACG





7732451
GTGCCCCAGAAAGAGGAG
ACT





2233284
GTGAGGCAGGAGCCAGC
ACT





1422674
CACCCAGACTGGTGCCT
CGT





3792789
CCTTGGGAGGAAGGTGC
ACG





4562032
TAACTCAGCCACGATGA
CGT





6865077
GCATCTTGGCTCTTATTG
ACG





1559126
ACAGCCAGGACACAGAG
ACT





3792788
CAGATACAAGATGAATACACC
ACT





1559127
TCGGTGGAAACATCTGC
ACT





3792786
GACCCCCAATGTCTGCC
ACT





6880110
GCCACCTTGCATGACAA
ACT





6861227
GAGTTCCATTTAGGGTG
CGT





3805430
CAATAGGATATTTCTCCTGC
ACT





1862364
CCCCACCACATCTTCTC
ACT





4958881
GCAATGTGATATCATGGC
ACT





3792785
TCTCAGGCAAATGACTT
ACT





6869605
CTCTAGATTCCTAGATAGGG
ACT





6870205
ACAAACCACCATTCATTC
ACT





4246047
TGCTCTGCCTCCCAAAG
CGT





4958882
TGATGAAGGAGAAATTTCAA
ACT





3792784
TCACTCTTCAGATTGGAA
ACG





3792783
AAATCATCAAGAACTTCCC
ACT





5872188
GAATGAAAATGTTTCACTCT
ACT









Genetic Analysis


Allelotyping results are shown for female cases and controls in Table 27. The allele frequency for A2 allele is noted in the fifth and sixth columns for control pools and case pools, respectively, where “AF” is allele frequency. Some SNPs do not have an allele frequency disclosed because of failed assays.

TABLE 27Position inLow BMDdbSNPSEQ IDChromo-someA1/A2Control AFCase AFAssociatedrs#NO: 5PositionAllele(High BMD)(Low BMD)p-ValueORAllele1478398231150385031A/GA = 0.28A = 0.340.03341.31AG = 0.72G = 0.661478397330150385130T/CT = 0.61T = 0.670.06211.29TC = 0.39C = 0.331160114582150385382G/CG = 0.96G = 0.920.00340.44CC = 0.04C = 0.081160113589150385389A/GA = 0.96A = 0.930.01690.51GG = 0.04G = 0.0713823231060150385860A/GA = 0.67A = 0.630.12880.83GG = 0.33G = 0.3711601121066150385866G/AG = 0.91G = 0.850.00250.57AA = 0.09A = 0.1577098701311150386111G/AG = 0.11G = 0.120.57961.11GA = 0.89A = 0.8877106431556150386356G/TG = 0.87G = 0.860.71000.93TT = 0.13T = 0.1477304671655150386455T/CT = 1.00T = 1.00C = 0.00C = 0.0065798291692150386492A/CA = 0.92A = 0.890.14230.74CC = 0.08C = 0.1165798301802150386602G/AG = 0.91G = 0.890.43770.86AA = 0.09A = 0.1165798312061150386861T/AT = 0.31T = 0.320.79481.04TA = 0.69A = 0.6868962322112150386912T/AT = 0.90T = 0.890.78800.94AA = 0.10A = 0.1113511312153150386953T/CT = 0.51T = 0.490.41520.91CC = 0.49C = 0.5110380742667150387467C/TC = 0.23C = 0.270.10621.25CT = 0.77T = 0.7314783963115150387915T/CT = 0.92T = 0.900.11230.71CC = 0.08C = 0.1068805123186150387986G/AG = 0.64G = 0.600.23130.86AA = 0.36A = 0.4049588585621150390421T/CT = 0.06T = 0.13˜0.000012.54TC = 0.94A = 0.8749584315735150390535T/GT = 0.98T = 0.950.01320.44GG = 0.02G = 0.0549584325829150390629G/CG = 0.86G = 0.850.43570.87CC = 0.14C = 0.1568984636658150391458A/CA = 0.86A = 0.820.03410.71CC = 0.14C = 0.1849588597901150392701G/CG = 0.95G = 0.900.00300.48CC = 0.05C = 0.10413006411447150396247G/AG = 0.26G = 0.300.15141.21GA = 0.74A = 0.70413006511466150396266A/GA = 0.16A =G = 0.84G =413311911984150396784T/CT = 0.95T = 0.940.22160.72CC = 0.05C = 0.06495886015803150400603T/GT = 0.10T = 0.170.01631.88TG = 0.90G = 0.83495886116257150401057T/GT = 0.13T = 0.170.05811.38TG = 0.87G = 0.83443735617604150402404C/AC = 0.10C =A = 0.90A =495886819762150404562C/TC = 0.55C = 0.530.66230.94TT = 0.45T = 0.47147840022367150407167A/GA = 0.96A =0.940.05840.57GG = 0.04G = 0.06688937522709150407509A/GA = 0.59A = 0.610.53781.09AG = 0.41G = 0.39160015923631150408431G/CG = 0.62G = 0.610.73400.96CC = 0.38C = 0.39687589223686150408486T/AT = 1.00T = 1.00A = 0.00A = 0.00460890925599150410399T/CT = 0.98T = 0.920.00080.27CC = 0.02C = 0.08234500026973150411773A/CA = 0.57A = 0.550.57080.93CC = 0.43C = 0.45451684028457150413257G/TG = 0.00G = 0.00T = 1.00T = 1.00205444028669150413469A/GA = 0.62A = 0.660.18351.18AG = 0.38G = 0.3470714129908150414708C/TC = 0.45C = 0.460.64901.06CT = 0.55T = 0.5470714230105150414905A/GA = 0.54A = 0.530.73490.96GG = 0.46G = 0.4784123630711150415511A/GA = 0.55A = 0.540.77310.97GG = 0.45G = 0.4670714330851150415651G/AG = 0.64G = 0.660.60491.07GA = 0.36A = 0.3470714431203150416003T/CT = 0.69T = 0.750.01631.38TC = 0.31C = 0.25686940531446150416246A/CA = 0.08A = 0.090.57341.13AC = 0.92C = 0.9170714531638150416438C/TC = 0.62C = 0.610.82230.97TT = 0.38T = 0.3970714633064150417864C/TC = 0.53C = 0.480.12140.83TT = 0.47T = 0.5270714833958150418758C/AC = 0.46C = 0.480.62491.06CA = 0.54A = 0.5270715035182150419982A/TA = 0.67A = 0.670.94450.99AT = 0.33T = 0.33587218438332150423132—/C— = 0.00— = 0.00C = 1.00C = 1.00376301540875150425675G/AG = 0.61G = 0.600.79760.97AA = 0.39A = 0.40204223541624150426424T/CT = 0.13T = 0.200.00141.70TC = 0.87C = 0.80376301341671150426471A/GA = 0.97A = 0.82˜0.000010.14GG = 0.03G = 0.18204223641825150426625G/AG = 0.90G = 0.860.04200.69AA = 0.10A = 0.14194623442920150427720C/AC = 0.00C = 0.00A = 1.00A = 1.00194623542935150427735T/CT =T = 0.87C =C = 0.13194623643001150427801T/AT = 0.19T = 0.200.54821.10TA = 0.81A = 0.80817740243012150427812T/CT = 0.00T = 0.00C = 1.00C = 1.00817740343203150428003C/TC = 1.00C = 1.00T = 0.00T = 0.00817740443294150428094T/CT = 0.97T = 0.940.03630.52CC = 0.03C = 0.06817740543295150428095T/CT = 0.00T = 0.00C = 1.00C = 1.00817740643344150428144C/TC = 0.09C = 0.110.12221.36CT = 0.91T = 0.89817740743509150428309T/CT = 0.00T = 0.00C = 1.00C = 1.00817740843549150428349G/CG = 0.00G = 0.00C = 1.00C = 1.00817740943560150428360T/AT = 0.23T = 0.280.07791.29TA = 0.77A = 0.72688896143578150428378A/TA = 0.08A = 0.070.31760.79TT = 0.92T = 0.93817741043640150428440A/GA =A = 0.00G =G = 1.00817741143792150428592G/CG = 1.00G = 1.00C = 0.00C = 0.00817741243797150428597C/TC = 0.15C = 0.180.09431.31CT = 0.85T = 0.82817741343964150428764C/GC =C = 0.01G =G = 0.9987040744297150429097C/TC = 0.07C = 0.110.06411.49CT = 0.93T = 0.8987040644311150429111C/TC = 0.89C = 0.880.56750.87TT = 0.11T = 0.12687320244588150429388A/GA = 1.00A = 1.00G = 0.00G = 0.00817741444775150429575C/TC = 1.00C = 1.00T = 0.00T = 0.00817741544921150429721C/TC = 1.00C = 1.00T = 0.00T = 0.00380543545006150429806G/AG = 0.10G = 0.070.13180.71AA = 0.90A = 0.93817741645098150429898T/CT = 0.00T = 0.00C = 1.00C = 1.00379279945185150429985C/GC = 0.00C = 0.00G = 1.00G = 1.00379279845475150430275T/CT = 0.05T = 0.100.09062.06TC = 0.95C = 0.90382859945506150430306T/CT = 0.55T = 0.550.99931.00TC = 0.45C = 0.45817741745543150430343G/CG = 1.00G = 1.00C = 0.00C = 0.00379279745601150430401T/GT = 0.46T = 0.520.05201.27TG = 0.54G = 0.48817741845652150430452T/CT = 0.00T = 0.00C = 1.00C = 1.00817741945756150430556A/—A = 0.00A = 0.00— = 1.00— = 1.00817742045826150430626T/CT = 1.00T = 1.00C = 0.00C = 0.00817742145974150430774C/GC = 0.07C = 0.02G = 0.93G = 0.98495887246044150430844T/CT = 0.81T = 0.810.91670.98TC = 0.19C = 0.19379279646200150431000C/GC = 0.40C = 0.410.53821.08CG = 0.60G = 0.59817742246218150431018A/GA = 1.00A = 1.00G = 0.00G = 0.00817742346221150431021C/TC = 1.00C = 1.00T = 0.00T = 0.00495843446280150431080C/TC = 0.86C = 0.830.18640.79TT = 0.14T = 0.17817742446330150431138—/— = 1.00— = 0.98GAGTCCTGGGAGTCCTGG = 0.00GAGTCCTGG = 0.02817742546583150431383T/CT = 0.02T = 0.030.50801.30TC = 0.98C = 0.97817742646650150431450A/GA = 0.31A = 0.360.04471.29AG = 0.69G = 0.64817742746721150431521A/GA = 0.26A = 0.320.02961.33AG = 0.74G = 0.68817742946808150431608G/CG = 0.91G = 0.950.01321.89GC = 0.09C = 0.05688973747242150432042C/AC = 1.00C = 1.00A = 0.00A = 0.00379279547512150432312G/AG = 0.89G = 0.970.00003.53GA = 0.11A = 0.03817743047600150432400T/CT = 0.01T = 0.01C = 0.99C = 0.99817743147706150432506A/GA = 0.71A = 0.700.63160.94GG = 0.29G = 0.30495887347806150432606A/GA = 0.31A = 0.380.02791.32AG = 0.69G = 0.62817743247978150432778T/GT = 1.00T = 1.00G = 0.00G = 0.00817743348021150432821T/CT = 0.26T = 0.230.23750.85CC = 0.74C = 0.77817743448025150432825G/AG = 0.00G = 0.00A = 1.00A = 1.00817743548093150432893T/GT = 0.81T = 0.790.44690.89GG = 0.19G = 0.21376301148413150433213T/CT = 0.01T = 0.02C = 0.99C = 0.98817743648933150433733C/TC = 0.00C = 0.00T = 1.00T = 1.00817743749097150433897C/GC = 0.17C = 0.07˜0.000010.38GG = 0.83G = 0.93495887449105150433905T/CT = 0.44T = 0.490.08801.24TC = 0.56C = 0.51817743949570150434370G/AG =G = 1.00A =A = 0.00817744049591150434391C/TC = 1.00C = 1.00T = 0.00T = 0.00817744149704150434504G/CG = 1.00G = 1.00C = 0.00C = 0.00817744249705150434505A/TA = 1.00A = 1.00T = 0.00T = 0.00817744349798150434598C/TC = 1.00C = 1.00T = 0.00T = 0.0086997550082150434882A/GA = 0.37A = 0.25˜0.000010.57GG = 0.63G = 0.7586997650147150434947G/AG = 0.00G = 0.00A = 1.00A = 1.00817744450356150435156A/TA = 1.00A = 1.00T = 0.00T = 0.00817744550725150435525T/CT = 1.00T = 1.00C = 0.00C = 0.00772146950968150435768C/AC = 0.00C = 0.00A = 1.00A = 1.00817744651029150435829A/CA = 1.00A = 1.00C = 0.00C = 0.00770419151086150435886T/CT = 1.00T = 1.00C = 0.00C = 0.00817744751166150435966T/CT = 0.27T = 0.350.00301.50TC = 0.73C = 0.651154851493150436293C/TC = 0.90C = 0.950.00022.40CT = 0.10T = 0.05223030351539150436339G/TG = 0.00G = 0.01T = 1.00T = 0.99772238651562150436362G/AG = 0.00G = 0.00A = 1.00A = 1.00817744851645150436445G/AG = 0.99G = 0.99A = 0.01A = 0.01817744951649150436449T/CT = 0.17T = 0.140.20090.80CC = 0.83C = 0.86207059351650150436450T/CT = 0.31T = 0.280.25400.86CC = 0.69C = 0.72817745051656150436456G/AG = 0.00G = 0.00A = 1.00A = 1.00817745151657150436457T/CT = 0.00T = 0.00C = 1.00C = 1.00817745252009150436809G/AG = 0.00G = 0.00A = 1.00A = 1.00817745352143150436943A/CA = 0.00A = 0.00C = 1.00C = 1.00817745452349150437149G/CG = 0.99G = 0.98C = 0.01C = 0.02376301052421150437221C/TC = 0.76C = 0.800.13371.30CT = 0.24T = 0.20817745552532150437332A/GA = 0.00A = 0.00G = 1.00G = 1.00817745652682150437482A/GA = 0.45A = 0.500.10981.22AG = 0.55G = 0.5073677553058150437858T/CT = 0.56T = 0.590.39451.12TC = 0.44C = 0.41227794053187150437987T/CT = 0.92T = 0.970.00042.75TC = 0.08C = 0.03817745853377150438177G/AG = 0.98G = 0.980.94451.03GA = 0.02A = 0.02817783453699150438499G/AG = 0.93G = 0.890.01130.58AA = 0.07A = 0.11392453845150438645A/GA = 0.75A = 0.740.73500.95GG = 0.25G = 0.26223331253920150438720A/GA = 0.00A = 0.00G = 1.00G = 1.00223331153929150438729T/GT = 0.15T = 0.200.01061.49TG = 0.85G = 0.80223331055473150440273T/CT = 0.00T = 0.00TC = 1.00C = 1.00223330955690150440490A/GA = 0.00A = 0.00G = 1.00G = 1.00495887555850150440650A/GA = 0.56A = 0.530.21310.86GG = 0.44G = 0.47223330856761150441561C/TC = 1.00C = 1.00T = 0.00T = 0.00223330756840150441640C/GC = 0.00C = 0.00G = 1.00G = 1.00223330657000150441800C/TC = 1.00C = 1.00T = 0.00T = 0.00223330557116150441916T/GT =T = 0.27G =G = 0.73223330458419150443219T/GT = 0.00T = 0.01G = 1.00G = 0.99223330358420150443220C/TC = 1.00C = 1.00T = 0.00T = 0.00223330258808150443608G/CG = 0.98G = 0.87˜0.000010.14CC = 0.02C = 0.13228771958906150443706A/GA = 0.00A = 0.00G = 1.00G = 1.00228772059048150443848C/TC = 0.39C = 0.420.28521.14CT = 0.61T = 0.58772703459187150443987C/GC = 0.24C = 0.300.03741.36CG = 0.76G = 0.70772725059361150444161C/TC = 0.33C = 0.430.00031.57CT = 0.67T = 0.57770980061218150446018G/AG = 1.00G = 1.00A = 0.00A = 0.00384031261700150446500G/—G = 0.54G = 0.500.13460.84— = 0.46— = 0.50228772162290150447090G/AG = 1.00G = 1.00A = 0.00A = 0.00687529362596150447396T/CT = 0.00T = 0.00C = 1.00C = 1.00380543464049150448849G/CG = 0.93G = 0.870.00090.51CC = 0.07C = 0.13208098266077150450877G/TG = 0.02G = 0.01T = 0.98T = 0.99208098366079150450879G/TG = 1.00G = 1.00T = 0.00T = 0.00228772266086150450886T/CT = 0.00T = 0.00C = 1.00C = 1.00223330166115150450915T/GT = 0.00T = 0.00G = 1.00G = 1.00223330066150150450950C/GC = 0.00C = 0.00G = 1.00G = 1.00495887666475150451275C/AC =C = 0.95A =A = 0.05223329969177150453977A/GA = 0.48A = 0.490.79171.03AG = 0.52G = 0.51223329869210150454010A/GA = 0.00A = 0.00G = 1.00G = 1.00228772369312150454112T/GT = 1.00T = 1.00G = 0.00G = 0.00216135970244150455044A/GA = 0.53A = 0.510.58130.94GG = 0.47G = 0.49773445670882150455682G/CG = 0.53G = 0.600.01881.32GC = 0.47C = 0.40429243971905150456705T/CT = 0.87T = 0.840.13430.77CC = 0.13C = 0.16495887872294150457094A/TA =A = 0.12T =T = 0.88686202472581150457381A/GA = 0.80A = 0.780.45120.89GG = 0.20G = 0.22383481972786150457589—/CA— = 0.00— = 0.00CA = 1.00CA = 1.00223329772950150457750G/AG = 0.04G = 0.050.32151.32GA = 0.96A = 0.95223329673106150457906G/AG = 1.00G = 1.00A = 0.00A = 0.00223329573162150457962T/CT = 0.00T = 0.00C = 1.00C = 1.00223329473273150458073G/TG = 0.24G = 0.230.70590.95TT = 0.76T = 0.77771302874131150458931G/AG = 0.9G = 0.850.02380.66AA = 0.1A = 0.15771322374406150459206T/CT = 0.93T = 0.880.00470.56CC = 0.07C = 0.12771356774665150459465C/TC = 0.61C = 0.630.41351.10CT = 0.39T = 0.3788898974740150459540T/CT = 0.90T = 0.860.03520.67CC = 0.10C = 0.14223329375382150460182A/GA = 0.00A = 0.00G = 1.00G = 1.00374965775400150460200G/TG = 1.00G = 1.00T = 0.00T = 0.00223329275460150460260G/AG =G = 1.00A =A = 0.00211263575863150460663C/TC = 0.35C = 0.360.73811.04CT = 0.65T = 0.6487126976098150460898T/CT = 0.47T = 0.420.07960.81CC = 0.53C = 0.58379279478432150463232A/GA = 0.21A = 0.10˜0.000010.41GG = 0.79G = 0.90657983778604150463404G/TG = 0.89G = 0.910.16301.33GT = 0.11T = 0.09380543379190150463990C/GC = 0.28C = 0.280.94840.99CG = 0.72G = 0.72587218679870150464670—/A— = 0.33— = 0.350.55261.08A = 0.67A = 0.65223329179928150464728G/CG = 1.00G = 1.00C = 0.00C = 0.00223329080213150465013G/CG = 0.14G = 0.130.87040.97CC = 0.86C = 0.87223328980227150465027C/TC = 1.00C = 0.99T = 0.00T = 0.010495843581994150466794T/GT = 0.68T = 0.630.05490.79GG = 0.32G = 0.37495888082187150466987C/AC = 0.75C = 0.840.00021.76CA = 0.25A = 0.16142267382698150467498T/CT = 0.45T = 0.32˜0.000010.59CC = 0.55C = 0.68204223482841150467641A/GA = 0.91A = 0.930.14851.37AG = 0.09G = 0.07380543283214150468014A/GA = 0.04A = 0.070.01881.93AG = 0.96G = 0.93380543183249150468049T/CT = 0.06T = 0.02C = 0.94C = 0.98223328883485150468285T/CT = 0.00T = 0.00C = 1.00C = 1.00223328783807150468607C/TC = 0.90C = 0.920.25551.32CT = 0.10T = 0.08381572083907150468707G/AG = 0.99G = 0.97A = 0.01A = 0.03379279284216150469016A/GA = 1.00A = 0.99G = 0.00G = 0.01379279184656150469456A/GA = 0.00A = 0.00G = 1.00G = 1.00230301885448150470248G/AG = 1.00G = 1.00A = 0.00A = 0.00379279085881150470681G/TG = 0.49G = 0.490.96861.00GT = 0.51T = 0.51495843686539150471339T/CT = 0.88T = 0.920.00831.76TC = 0.12C = 0.08223328686796150471596T/CT = 0.00T = 0.00C = 1.00C = 1.00223328587057150471857G/AG = 1.00C = 1.00A = 0.00A = 0.00773245187922150472722T/CT = 0.90T = 0.920.23491.29TC = 0.10C = 0.08223328488098150472898T/CT = 0.00T = 0.00C = 1.00C = 1.00142267489319150474119G/TG =G =T =T =379278989678150474478C/TC = 0.42C = 0.420.98731.00CT = 0.58T = 0.58456203290026150474826C/AC =C = 1.00A =A = 0.00686507790033150474833G/AG = 1.00G = 1.00A = 0.00A = 0.00155912690114150474914C/GC = 1.00C = 1.00G = 0.00G = 0.00379278890326150475126T/CT = 0.00T = 0.00C = 1.00C = 1.00155912790463150475263T/CT = 0.94T = 0.940.60801.14TC = 0.06C = 0.06379278690548150475348A/GA = 0.98A = 0.99G = 0.02G = 0.01688011090800150475600A/GA = 0.91A = 0.920.54331.14AG = 0.09G = 0.08686122790838150475638G/TG = 0.26G = 0.230.18430.83TT = 0.74T = 0.77380543091400150476200C/GC = 0.02C = 0.05G = 0.98G = 0.95186236492086150476886A/GA = 0.91A = 0.920.55751.13AG = 0.09G = 0.08495888193946150478746T/CT = 0.91T = 0.910.97011.01TC = 0.09C = 0.09379278595360150480160A/GA = 0.92A = 0.930.54481.16AG = 0.08G = 0.07686960596576150481376A/CA = 0.90A = 0.890.71890.93CC = 0.10C = 0.11687020596721150481521A/GA = 0.00A = 0.07G = 1.00G = 0.93424604798316150483116T/AT = 0.94T = 0.960.26131.37TA = 0.06A = 0.04495888298497150483297C/GC = 0.88C = 0.890.77231.06CG = 0.12G = 0.11379278499382150484182C/TC = 0.00C = 0.04T = 1.00T = 0.96379278399442150484242T/CT = 0.85T = 0.870.23911.22TC = 0.15C = 0.13587218899764150484565—/AG— = 0.90— = 0.910.59081.11AG = 0.10AG = 0.09


Allelotyping results were considered particularly significant with a calculated p-value of less than or equal to 0.05 for allelotype results. These values are indicated in bold. The allelotyping p-values were plotted in FIG. 4. The position of each SNP on the chromosome is presented on the x-axis. The y-axis gives the negative logarithm (base 10) of the p-value comparing the estimated allele in the case group to that of the control group. The minor allele frequency of the control group for each SNP designated by an X or other symbol on the graphs in FIG. 4 can be determined by consulting Table 27. For example, the left-most X on the left graph is at position 150385031. By proceeding down the Table from top to bottom and across the graphs from left to right the allele frequency associated with each symbol shown can be determined.


To aid the interpretation, multiple lines have been added to the graph. The broken horizontal lines are drawn at two common significance levels, 0.05 and 0.01. The vertical broken lines are drawn every 20 kb to assist in the interpretation of distances between SNPs. Two other lines are drawn to expose linear trends in the association of SNPs to the disease. The light gray line (or generally bottom-most curve) is a nonlinear smoother through the data points on the graph using a local polynomial regression method (W. S. Cleveland, E. Grosse and W. M. Shyu (1992) Local regression models. Chapter 8 of Statistical Models in S eds J. M. Chambers and T. J. Hastie, Wadsworth & Brooks/Cole.). The black line provides a local test for excess statistical significance to identify regions of association. This was created by use of a 10 kb sliding window with 1 kb step sizes. Within each window, a chi-square goodness of fit test was applied to compare the proportion of SNPs that were significant at a test wise level of 0.01, to the proportion that would be expected by chance alone (0.05 for the methods used here). Resulting p-values that were less than 104 were truncated at that value.


Finally, the exons and introns of the genes in the covered region are plotted below each graph at the appropriate chromosomal positions. The gene boundary is indicated by the broken horizontal line. The exon positions are shown as thick, unbroken bars. An arrow is place at the 3′ end of each gene to show the direction of transcription.


Example 10
In Vitro Production of Target Polypeptides

cDNA is cloned into a pIVEX 2.3-MCS vector (Roche Biochem) using a directional cloning method. A cDNA insert is prepared using PCR with forward and reverse primers having 5′ restriction site tags (in frame) and 5-6 additional nucleotides in addition to 3′ gene-specific portions, the latter of which is typically about twenty to about twenty-five base pairs in length. A Sal I restriction site is introduced by the forward primer and a Sma I restriction site is introduced by the reverse primer. The ends of PCR products are cut with the corresponding restriction enzymes (i.e., Sal I and Sma I) and the products are gel-purified. The pIVEX 2.3-MCS vector is linearized using the same restriction enzymes, and the fragment with the correct sized fragment is isolated by gel-purification. Purified PCR product is ligated into the linearized pIVEX 2.3-MCS vector and E. coli cells transformed for plasmid amplification. The newly constructed expression vector is verified by restriction mapping and used for protein production.



E. coli lysate is reconstituted with 0.25 ml of Reconstitution Buffer, the Reaction Mix is reconstituted with 0.8 ml of Reconstitution Buffer; the Feeding Mix is reconstituted with 10.5 ml of Reconstitution Buffer; and the Energy Mix is reconstituted with 0.6 ml of Reconstitution Buffer. 0.5 ml of the Energy Mix was added to the Feeding Mix to obtain the Feeding Solution. 0.75 ml of Reaction Mix, 50 μl of Energy Mix, and 10 μg of the template DNA is added to the E. coli lysate.


Using the reaction device (Roche Biochem), 1 ml of the Reaction Solution is loaded into the reaction compartment. The reaction device is turned upside-down and 10 ml of the Feeding Solution is loaded into the feeding compartment. All lids are closed and the reaction device is loaded into the RTS500 instrument. The instrument is run at 30° C. for 24 hours with a stir bar speed of 150 rpm. The pIVEX 2.3 MCS vector includes a nucleotide sequence that encodes six consecutive histidine amino acids on the C-terminal end of the target polypeptide for the purpose of protein purification. Target polypeptide is purified by contacting the contents of reaction device with resin modified with Ni2+ ions. Target polypeptide is eluted from the resin with a solution containing free Ni2+ ions.


Example 11
Cellular Production of Target Polypeptides

Nucleic acids are cloned into DNA plasmids having phage recombination cites and target polypeptides are expressed therefrom in a variety of host cells. Alpha phage genomic DNA contains short sequences known as attP sites, and E. coli genomic DNA contains unique, short sequences known as attB sites. These regions share homology, allowing for integration of phage DNA into E. coli via directional, site-specific recombination using the phage protein Int and the E. coli protein IHF. Integration produces two new aft sites, L and R, which flank the inserted prophage DNA. Phage excision from E. coli genomic DNA can also be accomplished using these two proteins with the addition of a second phage protein, Xis. DNA vectors have been produced where the integration/excision process is modified to allow for the directional integration or excision of a target DNA fragment into a backbone vector in a rapid in vitro reaction (Gateway™ Technology (Invitrogen, Inc.)).


A first step is to transfer the nucleic acid insert into a shuttle vector that contains attL sites surrounding the negative selection gene, ccdB (e.g. pENTER vector, Invitrogen, Inc.). This transfer process is accomplished by digesting the nucleic acid from a DNA vector used for sequencing, and to ligate it into the multicloning site of the shuttle vector, which will place it between the two attL sites while removing the negative selection gene ccdB. A second method is to amplify the nucleic acid by the polymerase chain reaction (PCR) with primers containing attB sites. The amplified fragment then is integrated into the shuttle vector using Int and IHF. A third method is to utilize a topoisomerase-mediated process, in which the nucleic acid is amplified via PCR using gene-specific primers with the 5′ upstream primer containing an additional CACC sequence (e.g., TOPO® expression kit (Invitrogen, Inc.)). In conjunction with Topoisomerase I, the PCR amplified fragment can be cloned into the shuttle vector via the attL sites in the correct orientation.


Once the nucleic acid is transferred into the shuttle vector, it can be cloned into an expression vector having attR sites. Several vectors containing attR sites for expression of target polypeptide as a native polypeptide, N-fusion polypeptide, and C-fusion polypeptides are commercially available (e.g., pDEST (Invitrogen, Inc.)), and any vector can be converted into an expression vector for receiving a nucleic acid from the shuttle vector by introducing an insert having an attR site flanked by an antibiotic resistant gene for selection using the standard methods described above. Transfer of the nucleic acid from the shuttle vector is accomplished by directional recombination using Int, IHF, and Xis (LR clonase). Then the desired sequence can be transferred to an expression vector by carrying out a one hour incubation at room temperature with Int, IHF, and Xis, a ten minute incubation at 37° C. with proteinase K, transforming bacteria and allowing expression for one hour, and then plating on selective media. Generally, 90% cloning efficiency is achieved by this method. Examples of expression vectors are pDEST 14 bacterial expression vector with att7 promoter, pDEST 15 bacterial expression vector with a T7 promoter and a N-terminal GST tag, pDEST 17 bacterial vector with a T7 promoter and a N-terminal polyhistidine affinity tag, and pDEST 12.2 mammalian expression vector with a CMV promoter and neo resistance gene. These expression vectors or others like them are transformed or transfected into cells for expression of the target polypeptide or polypeptide variants. These expression vectors are often transfected, for example, into murine-transformed a adipocyte cell line 3T3-L1, (ATCC), human embryonic kidney cell line 293, and rat cardiomyocyte cell line H9C2.


Representative Nucleotide and Amino Acid Sequences


Following is a genomic nucleotide sequence for a CTEP region. The genomic nucleotide sequence is set forth in SEQ ID NO: 1. The following nucleotide representations are used throughout: “A” or “a” is adenosine, adenine, or adenylic acid; “C” or “c” is cytidine, cytosine, or cytidylic acid; “G” or “g” is guanosine, guanine, or guanylic acid; “T” or “t” is thymidine, thymine, or thymidylic acid; and “I” or “i” is inosine, hypoxanthine, or inosinic acid. Exons are indicated in italicized lower case type, introns are depicted in normal text lower case type, and polymorphic sites are depicted in bold upper case type. SNPs are designated by the following convention: “R” represents A or G, “M” represents A or C; “W” represents A or T; “Y” represents C or T; “S” represents C or G; “K” represents G or T; “V” represents A, C or G; “H” represents A, C, or T; “D” represents A, G, or T; “B” represents C, G, or T; and “N” represents A, G, C, or T.

>16: 56742951-568412001tgtctaaaaa ttattatggc tgaaacatac ttatcatttgttttctgtag tagaaaatgg61cataatatga gaaggcctac tttgtaatag ttgtttgctttacttaatat ttttcaaatc121agccatctgt gtgaagactc aatatcaagt taggcctttaaaagggggaa aataattcaa181aaccactggc agctgtggtt ttccRgcctt ttctattggttgaactctgt aataaatgca241ggaccctaca tatacaaaag gtactgtttt ccaaattcacgtatgtatta gcatttacct301ttaaagttct catccgtcag aaaaacggtg aacacagcattcagtatatt tattttggtt361tagttacaca gtgtcaaaaa gttctgatgt atatggataagtagatgcac tttttgctgt421tttgtttgtt taaacagctt gctttaatta tctcaagctacttggcagga acacctttat481tccaggtttc gcataatcag ttattctggc aagagtagattaacacgtta gtgatctcca541atagacagat tatatgttaa tattatttga ggccattatttttaagtaca atttagacgg601agtttcaaat agattttaaa aatgagattt gtataaaagagtgtgcagtc cctatggtgt661taaaatcact gatatggagg agaagagggg ttggaattgtgacactgtgg cagcagatga721ccttggacaa gtcagttttt cagactttcc tcccttaaaatagggatact aaatctcaca781gggtggttgt gtataatgtc acccacacgc catctcctctataactgcat ttgtatgcca841ggaaattgtc tgtgaaggct tcagtttaga atagcttcatattattttgg ggcactgctg901ggtgattttg gttaaggctg gccttgggag ttctctgagttttctctgaa accaaactca961atttggttgt aggttccctg tttgctgttt gttgcttttagtaataggag tcagtcagtt1021tacctgggag ttaagtttgg actggagata atttgccattcttttttttt tttttttttt1081ttttttttga gatagggtct cactctgtcg cccaggctggagtgcagtga catgatcttg1141gctcactgca acctctgcct ccctggttca agcgattcccctgcctcagc ctcctgagta1201gtttgggtta caggcacaag ccaccacgcc cagctaatttttgcattttt agtagagatg1261gggtttcacc atgttggcca ggctggtctc gaacccctgacctcaggtga tctgcccgcc1321ttggcctccc acagtgcttg gattacaggc atgagccaccatgcccagcc gataatttgc1381cattctgtat ttatttgcgt gttagagacc agttaaagttaagacacttt ctaaatagaa1441gtcttgtata tggggctttt gagaaagtgt tttcccgtgatgctgggggg aaacacacat1501attcaaatta cttgtataaa acagtttatt ctgtgtttaggaacttgtag gggtgaaatg1561ctgacctgtg ttactctttc tttccatgat cagcRtccagaggaccagag gttaatttat1621tctgggaagc tgttgttgga tcaccaatgt ctcagggacttgcttccaaa ggtacatcac1681ttacacatta acttctgaat gtttttaagc actcaccaggttaggttcag gtccttaagt1741accttcgtat tacttttagc aggaaaaacg gcatgttttgcatctggtgt gcaatgtgaa1801gagtccttca aaaatgccag aaatcaacgc caaggtgtgtctgcctcttc atgatggtaa1861caatttgtat cattcagact ttcaggggag taataaaagaagttggataa aacgtttatt1921gagagactgt atggtgttat taccaagtaa tattttgtttctttcctagg aattagaaac1981tgtattatca acacaaagtg atgagttaat agtagcagattgttccgtta gtgctgtagt2041agaaaggtgg agttacatat tgcactatct tatgggatatgatttgatct atggttactg2101tgtatctaga ttactgaact aacactaatc gggtttttattgaatttagc acatagcaag2161tttcttcaaa ggagtcacta atttttataa agagtacaaaagtgaatata tttcctttgg2221aaattttcat tgtgattagt tggataggaa aagatcagagtttttatcaa gtgatcttta2281aagaattttt tttttttaaa aatggtctcg ctgtgtggcccaggcttttc tcaaactcct2341gagggcaagc gatcctccca cctcagcctc ctgagtagctgggactacag gcatgtgcca2401ctagacctgg ctctaaagac atatatgaca cacgaaaccatttatttttc atttcacaat2461gtttattcac atatatggta ttagtattct aatgtagtgatgcactctaa atttgcatta2521tatttcctag aacatctgaa cagagcatag gaaattccctattttgccat tatcagttct2581aacaaaaaac ttaaaagcac tttatcattt catttccctgcactgtaatt tttttaaatg2641atcaaaaacR gtatcatacc aaggcttact tatattggaatactatttta gaaagttgtg2701ggctgggttg tatttataaa tcttgttggt cagatgtctgcaatgagtaa atttagcacc2761attatcagga agctttctca ccaatgacaa cttcattggaagattttaat gaaagtgtag2821catactctag ggaaaaaata tgaatatttt agcatctatgtattgaaaat tatgttgaat2881aaatgtcaga ctatttttta cataacgttg cttctgtttaattttgtcac gttcagaggt2941ggggggtagg agatgtaagc ccttgacagc aaaataattccttttgcttg atttcagaca3001gttgcatcag ctcctttgtt ctgtgttcat gttacacttatttaggtggc tgaatccaca3061gaggagcctg ctggttctaa tcggggacag tatcctgaggattcctcaag tgatggttta3121aggcaaaggg aagttcttcg gaacctttct tcccctggatgggaaaacat ctcaaggtga3181gtgttataat aaagatcttg gcttatgcaa catgaatgttcctcgtttgc atcaatttaa3241gaataaggta tgtttacacg tatataatca gaacttttaaacatacagaa ttttgcttta3301taaatagctt cgctttaaag atctcttata tatttaacttttcttaatac acagcctttt3361agtacacaca aatttaaaaa gtaggtaatg catatattgaaaaaaaaaag aaaatgtagg3421cgttttatcc ttccattgtg ctgaccgctt ggttgccgtcatgataggaa attagtgctg3481ctgcaggaga aaacagctgt cgtaagcatt gtgcagctgctttgctgagt ggctttgtgc3541tttattgtaa caatgggtga caacaaggga gagactgtttaagaagtgtc cttccaaaga3601cttgggggta ctaggaaaat tggccaattt cttataactattaaagcttt tctttagagc3661aaaagtcaga actaaatgct ctgttatttg gatttttatagctcttggaa tacattgttt3721ttggggaaaa aftcattaac tgcaagttgc aattctgtaactctccaatt ctccgtcccc3781ctttttctag tactttttat acacaatatt ttataaagccaggtgtttta ggaatgagtt3841tttcttcctt ttccccctta atggaacttt caaatatacacaacagtggg gactggataa3901ttaatcccca caccatcacc caggcctaat aaataacaatcagagtttta ccatagctca3961tctattaccc tttccctttt ttttaaaaaa agagtatttaaaagtaattc ccaggcatca4021tgttatttca tccctatatt cttcagtata taactatgaaaaccttttag ttatcttgta4081tatctagaat gccattatca gatctaacag aaatcttaaaagcactttat cattttattt4141ccatgcactg taattttctt aaatgatcaa aaacagcatcataccaaagc ttacttgtat4201tggaatacta ttttagaaat actctgtgta tggaatttagttaaaagatt gtcagcatat4261aaattggata attattggat agaaaattat tggttagaaaaacttaaaac tacttccctt4321attctgattc aactattctt aacttgagaa ttgaggctcatatttgactc tctgaatctc4381accatattta aacttgattt cctttaacaa atatttattgaacagccagt acatacaact4441ttgcttaagg atatgagttg acctgcagga atgaccacataaccaatttc tgatctttgg4501gcaattctat tatggtttca attttgtgat gtgctactgaagaaattgac tgtgtaagaa4561gcacaaagcc aaagatgact cgcatacacc tgccctgtgaagttgagggc tgtgtggcct4621gattaaagaa gcatgcattt ggccgggcgc ggtggctcacacctgtaatc ccagcacttt4681gggaggccaa ggtgggcgga tcacgaggtc aggagattgagaccatcctg gctaacacgg4741tgaaaccccg tctgtactaa aagtacaaaa aattagccaggtgtggtggc gtgtgcccgt4801agtcccagct actggggagg ctgaggcagg agaatggtgtgaatccggga ggtggagctt4861gcagtgagcc gagattgcgc cattgcactc caggctgggcaacagagcga gactccatct4921caaaaaaaaa aaaaaagaag catgcatttg acatcagaccagctctgaaa tccagccctg4981ctacttacta gctcagtgac cttgtgcaaa gcccctgtcttccctgagct gtacttgggt5041tccccttgta aaatctcctt catgagattg ctgtggacccagcagcctgt acaggacccc5101cggtggtcag taagcatgca caggtgatac cacatgcacacttcactata gattcagatg5161gaggatggag gaagaagtgg atattgggag gatgggagagatttccttca ggaaagactg5221ggagaaatgt ggcttttgag ctgctctcta aaagatgaacagtgggttga gacctgcagt5281gagactcaac aagtcaaaac tgaggtggga tctacttaacccaaaaaggt tgtttatata5341tctgtgcact cagcaagcag gtggcaaggg ctgttgttttcctgtgggat gggactgtgg5401tagaagtgct gtgtcattta gtaccttctg tgcttgtggtacatgggtgc gtcatacagt5461catttaccat gtaactgccg taaattccat tcttcYgtctcttcgatttg aattcttgat5521tttaatttaa acttagtttt catttgttca tactcaacccactcaaaatg agtgtttttt5581caaatctatg tataggcctg aagctgccca gcaggcattccaaggcctgg gtcctggttt5641ctccggttac acaccctatg ggtggcttca gctttcctggttccagcaga tatatgcacg5701acagtactac atgcaatagt gagtccttcc cgccatgctgggtgtggcca gggctcccgg5761gaattgaagg gaattttatc cRtgttacct gtaaagttcagaatggaggg atgagtgtat5821tttcatcagt ctgcagagcc ctgctctgtt tggtctgtgggtagagtgta aatgacagct5881gctacctgat ttgtgtattg acacaagRgt gcttttgtctgatacatagt ttagtgactt5941tatttagaac atgttacttt cttttcaatt tgtgctatcttcaaagtttt gtgaggattt6001taatttgcta ctgtgccata atcttacagt gggcttgatgtttaatttca ggtgaaattc6061accttgtggc ttttcttaga aaaggcattt atagatatagttagtaagga agttcttcac6121taaattgaag aaaaatcaaa ggcatatcta cctacttgaaattcttaaca gtaaaagact6181gctgtgtaaa taagccacag acttcacggt gctttggtctcaacagtatc tgcctctgtc6241gtttttattt tagtttagca gccactgctg catcaggggcttttgttcca ccaccaagtg6301cacaagagat acctgtggtc tctgcacctg ctccagcccctattcacaac cagtttccag6361ctgaaaacca gcctgccaat cagaatgctg ctcctcaagtggttgttaat cctggagcca6421atcaaaattt gcggatgaat gcacaaggtg gccctattgtggaagaagat gatgaaataa6481atcgagattg gttggattgg acctattcag cagctacattttctgttttt ctcagtatcc6541tctacttcta ctcctccctg agcagattcc tcatggtcatgggggccacc gttgttatgt6601acctgtaagc agatggtttc tctaatataa attacactacactgtgttca cactaagcag6661attttgctct ttttgtttct tgtttttttt gagatggagtctcgctctgt cattcaggct6721ggagtacaat ggcacaatca ctgcaatctc cgcttcccaggttcaagcga ttctcctgcc6781tcagcctcct gggtagttgg gattacaggc gcccaccaccatgcctggct aatttttata6841tttctagtag agacggggtt tggtcatgtt ggccaggtggtctcgaactc ctgacctcaa6901gtgatctgcc caccttggcc tcccaaagtg ctggtattacaggcgtgagc caccactgcg6961cctggccaga ttttgctctt ttttgagcag tctcagttactgtagaagga gatgtgttta7021aatagtatat cactctgtgg ctgggcgcag tggctcacacctgtaatccc agcagtttgg7081gaggccgagg caggaggatc acatgaggcc aggagtttgagaccatcctg gccaatatgg7141tgaaaccccg tctctactaa aaatacaaaa aattagccgggtgtggtggc acgggcctgt7201aatttacttg ggtggctaag gcaggagaat tgcttgaactggggaggcag aggttgcagt7261gagccaagat cgcaccactg cactccagcc tgggtgacagagcaagaccc tgtcttagaa7321taaatacata ataaatagta tgtattctgg cactttcgatacaaggaatt catggcttgg7381ttgtatggtc ccaagaacat atcaatcctg tgttaatataagaatattat cttgtcctct7441agataagcta ccttaccttc caggctcaca aaccacaagtatgtagccat actgaggcat7501ggaacagaaa actgtatttg ttttgaatga gaacacatttgcctttatca gRccacagct7561gccttccagg gtaaagtcag gcactgactg ttagcatggccctgaaaggc aagggaacct7621tcacatacct gacatttggt tttagctgtg gcccgaagcagtagttctca actgggggtg7681gttttgtacc ctctctcccc aggggacatt tggcaatgtgtagatatttt tggttgtcac7741atctagggga agtggtcctg ctggcgtcta gttagtagaagcaagagtgc tgctgaattt7801tctacaatgc acaggacaac tcccacagta aatatttggctcaatatgtc actagtgcca7861aagctgagaa agcctggcct agagtgatgg gtcttcgtggttgaaactaa aagaagaaat7921tttcctgtat agtaaaaatg gatttttatt ttagcttttaaaaataaaaa aggaataatt7981agaatataat gaacactcaa atatccacaa ttagtcattgttaatatttt attatattta8041agacttggga tttaattggt ttcttcaaat aaaacgtttagttaatattt tctgtagtct8101ctagaatcat atatttaaaa gaccaaatgt aggttgtcattatgttatat ataattatag8161ctttgtaggt atatgcattc tccccgctct gttcaggttttcaagggtaa ggtttagttc8221gtcataagca tttattgagt gcatactatg tgccaggtgctgtttatatg gctgggtgtg8281caatgatgaa taaaacacag tccctgcctt caaggaccttacagactggt gagaatgtct8341gggagacagt gtgatcaaat gcctctgtag atgggtcttgcagtgagctt atcagggtgc8401tgctgtgatt agaggtgggg agccttggat tcttgagtaagtctcactgt gacatcagct8461aagatggact tttatgtgct tcctttgaag gcatcacgttgggtggtttc catttagacc8521gaggccggtt cagaacttcc caaatgatgg tcctcctcctgacgttgtaa atcaggaccc8581caacaataac ttacaggtat ggagcctccc acgaagcccaggcgagcttg acgtgatatg8641ccaggctctc caatcctcaa cctttagatt gccagcttgcggtttaccat tttattgggc8701taaatatttc atgatttgtt cacatttctt cttagagcagcagctatttt taaaacgtcg8761aatgtgccat cacattctat cacatatttt tgacgtggcaatttgcattt tggcttaagt8821aaataacatt tttttaaacc cactattttg agcgttcagtggtctgtaac agtgtgttat8881accataagaa ctggtatgaa gtggttaact actagtttaataatagttga agcctgggcg8941tggtggctca cgcctgtaat cccagcgctt tgggaggctgaggcaggtag atcacctgag9001gtcaggagtt taagaccagc ctggccaaca tggtgacaccccgtctctac taaaattaca9061aaaattagtt gggcgtgcct gtattctcag ctgctagggaggctgaggcg gaaggatggc9121ttgaccttgg gaggtggagg ttgcagtaag ccaagatcacaccactgcac tccagcctgg9181gtgacagagc Ragactctgt ctcaaaaata ataataatagttgcagatct agttgtttca9241tttgatattt gctgccagga gcagtcaaaa ctatgacaacatcaacacag ttgtgctgtg9301gaagcctgag aaacagccct atccagccta gggcatcattccctggggtc ctggctgcct9361gctgctgtgc ctatggggca gggggcaggg atttaccctgccctttccta acattatttg9421gtgttcatca tagccctaat tgttttctca ttgtttcattacctcattgt ttcattacct9481gtaggaaggc actgatcctg aaactgaaga ccccaaccacctccctccag acagggatgt9541actagatggc gagcagacca gcccctcctt tatgagcacagcatggcttg tcttcaagac9601tttctttgcc tctcttcttc cagaaggccc cccagccatcgcaaactgat ggtgtttgtg9661ctgtagctgt tggaggcttt gacaggaatg gactggatcacctgactcca gctagattgc9721ctctcctgga catggcaatg atgagttttt aaaaaacagtgtggatgatg atatgctttt9781gtgagcaagc aaaagcagaa acgtgaagcc gtgatacaaattggtgaaca aaaaatgccc9841aaggcttctc atgtctttat tctgaagagc tttaatatatactctatgta gtttaataag9901cactgtacgt agaaggcctt aggtgttgca tgtctatgcttgaggaactt ttccaaatgt9961gtgtgtctgc atgtgtgttt gtacatagaa gtcatagatgcagaagtggt tctgctggta10021cgatttgatt cctgttggaa tgtttaaatt acactaagtgtactacttta tataatcaat10081gaaattgcta gacatgtttt agcaggactt ttctaggaaagacttaYgta taattgcttt10141ttaaaatgca gtgctttact ttaaactaag gggaactttgcggaggtgaa aacctttgct10201gggttttctg ttcaataaag ttttactatg aatgaccctggcagagactc ctgtcatcct10261agcagtttac tctgcgtttg ttgtatctag acagtcaacaactgagttgt cggtgtttaa10321cctgaatgct tgtttttcag aagaRgactg tttgtgccggtaagaatgat caggtaaggc10381catgaaagtt tttgttggyg tttttgtttt tgagatggggtcttgctttg ttccttgggc10441cagagtacat tggctactca caagtgggct ggtagctggctacagcccca gactcctggc10501ttaagccacc tcctgcctca gccaccctgg cagctgggactacaggcatg cgccatcaca10561cttagcttga aagttttaat ttactaagaa tatacctgtgtttcccccca tttcctgatt10621taaacagtac tggcttatat aggaacccat caaagttaaattccccaaat ttaaatttag10681taaatttagt ggtttcacct tggcaaatct gcaatagtttcaccagctca aatttcatgc10741ttttgtaagc tgagcttatg tttgtgattt taatcctttaagtactactg tggtaactaa10801tcattttttt gttttttttg gtggtgtttt tgtttttgttttgagatgga gtctcactct10861gttgcccagg ctggagtgcc gtggcgcgat ctcggctcactgcaacctct acctcctgag10921ttcaagcgat tctcctgcct cagcctcccg aatagctgggattacaggtg cccaccacaa10981tgtctggcta attttttgta tttttagtag agacgaggtttcacccatgt tggccaggct11041ggtctcaaac ccctgacctc aggtgatctg cccgcctcggcctcccaaag tgctgggatt11101acagatgtga gccaccgcac ccagccaggg actaatctttaaagcaaagt tttatatatt11161tttacgtgag taatgttatg tgtaggtgtt ctatttggcaaaataaatca gccttttcta11221tcatgattgt ggtcatttaa attaatcctc atcggaaacattgtttacct aagataaaca11281ttcactaaac aactcatagc aagacgctgg gtaggtacaaagatgtctta tgtgtggtta11341tgctttcaaa gccaactgaa acccttttgt aaggagttaaatagcaaaaa gtttcaaata11401actgtgtgcc tctagaacag aactatcaga aggcaatgaatattcacaaa ttgtgaagag11461atagtttgct tcaaggaaga aatgacttgt aactagagtaggtatgaaat gatgggggaa11521aaatgatgag gtatgaaatg actcaccttc tctccagctcaaggtaagaa gggtggcagc11581aggagtaaaa gctcagccac aggacgtgct cttcctgccaaacagctgga ttctgcacat11641gcttgggaat gaggtcctgc tggtttagga aaacaaacattaagaattcc caaagtcttg11701ggtggaaaag cctgttgctt ttcagaggca aggccatcaccatttggcaa ggggcccaag11761gccccaggca gctgtggtac catctgtttc tgaaggagtggggattttac cccctgaaat11821gtcagtttgt ggcttaaact ctgggttcta caggcccaaaataaatagtg ccaggaaggt11881gcccctgaac agagctaacc agggttcaga ttggcaccccatccccactg gggcaagcag11941gactcttagc aattaaggcc taagacggct gacaggtgggacatggcaga aattcagtgc12001ttccaccaca gctactcaat gtgccacRat catgggccacacaccactct gaatacttag12061aaaattattg gtttgggcct ttattattaa gtagcaagtaaataactgaa aaagccccag12121atttcagctc tggctatagc agctttctaa gtctgtgtttttaaggtgca atttcttgaa12181tcctagttct gtagaagaaa cactctaccc ccccgccccccccacccccc ccccccaccc12241ctaaaaaatg agcttcatga tcaagtacat tttggaaccctcaggctgat ccaagttcat12301agatttcttc actgcaggcc ttctgggtcc tttaatatgcctgaagctgg ggctttccct12361tcctgagaat ggcccaggac tatccatgtg cctcattttgggaaatttag taatgagtta12421ctaaatcaac accacctttg gcattctaca tagcaaacatactttgttag atgtgacatt12481ttacacacta accaatggag ataaaatttt ttaaatttatttttggccag gcacggtggc12541tcatgcctgt aataccagca ctttgggagg ccgaggcaggcggatcactt gaggtcaaga12601gtttgagacc agcctggcca acgtggcgaa atcctttctctactaaaaat acaaaaatta12661gctgggcgtc gtcgtgggca cctgtaatcc cagctactcgggaggctgag ggaggagaat12721tgcttgaacc cgggaggggg aggttgcagt gagccaagaccacaccactg cactccagcc12781tgggcgtcag agtgagattc tgtctcaaaa aataaataaatgatttctta tttatttttt12841tttaccagtg ctctacatgt tcagagaaac ttctctggtaaccaaccaca gaaatgatcc12901ctgaaagtat agtcttagga gataaatatt ctttacatagccaggaggga gatgagaagc12961catacctgtc tacagtctga ctgacaaagg aggaggctccaggtcccctg gagaatccca13021ggttttatgt aataattact tggtcctttt caaagtacttggatgagtgt aggatagtct13081ctttgtctta tcagctagtc ctgcaatcta ggtgttctcccattttgtag aggcttgcag13141agatgagaga cctgtccaag gtctcaaacc cctaactggcagttctgaga ctagaaatac13201tccctctcag gagtggacct cctctacaat tttttttagcagtcctcatg tgccaaatat13261ggcgtggggg ccaggagaca gaatgaggca taggttgggcgtggcccctc ccctcttggg13321tcttgtagtc ggctgtgggt ggcaagtaca gcagYgatggcagacaggtg tgatgagttc13381aaggacaggg aaataacatc cacagcccca tcccagtactcctgtgcagc aatggaagtg13441tgccaccgac acaggggcta cagggtgagc aggagtgacaggcgaagaga ggaagagagc13501tctgcctgtg caaaggcgga gggaacatgg tgtgggaggaactgaagaga attccacata13561agtatgaaga gggtagggag attgagactg gagaaaaggggaagccgggg ctcccctttt13621gaccatgcaa cgcactggaa gcacagcact cccagcctcagggtcctcca tgattggaga13681ctgacaRtga attcagagga gcttgtggaa gtcacccagtcaggtccaga aatcctgcag13741tgcatccctt ccgttacccc tgtcataact gggagaagacaccacccaca tgacgcaggg13801gagagtgcay gcatgagcta gcacccatat tgtcccctgcatctgtcctt ggctatgttt13861tacacccccc accccttaga acattgtagt caaactaggatgtattaaat tggctggttg13921ctcccaacta cactggacaa agtggagaaa aaaaaaaaaggaggagctca aggtttcaaa13981ttcccagctc aagctctgca taaaaactgc tgtgacttccttagaagaga cccctatctc14041ctgtagctgc agggttgaga tttctgagct caagtgatctgcctgcctca ccctcccaaa14101gtgctgggat tacagttgtg agccaccctg cctggccagggctgagattt gtgaaaagga14161aacccaaagt ctcatcttgc atgtggctga attatgtcgcaaatccaatt cccaaattcc14221agccttgcag ggtgtcttca gttaaagtga ggacaacttgaaaatcggaa tgggaacata14281agggaagatt ccagtaaagc tggggacatt gaatccctaaattctgtYat gttccctgcc14341agtagaaaca gcccatctac ccctccctgg gtccagctgtgtggacacag attggcagcg14401agtgtgcagg tgttatttcc ctacccttgt aatcatcacactttcttttt ctttttcttt14461cttatttttt tgagtcagag tcttgtgctg ctgcccaggctggagtacag tggtgcaatc14521tcagctcact gcaacctccg cctcctgggt tcaagcaattctcctgcctc agcctcccga14581gtagctggga ctacaggcgc gcaccaccac acccagctaatttttttgta tttttagtag14641agacagggtt tcacccccaa tagccaggtt ggtctcgaactcctgacctc aagagattca14701cccacctcgg cctcccaaag tgctgggatt acaggcgtaagccacYgtgc ctgacctcat14761cacaatttct tagccctttg agaaaccctg tggccttccctgaggtagct gtcttgcggg14821gcacttctga ttcttcttgg atcctatgcc cttcccctctttgctggacc tgtaactaga14881ctcaagtccc accaggcccc agagagaaag gtacacactgtgacccatga agaggtgtgt14941tacacaccaa aagaactgca tgatttttcc aatttatacagacaaatcca agagaYatgt15001atgggagtag attttaaggt tgtgagatca cggaaggaccatagtgttgg atctggctga15061acgtaatgat atgggcccac taagcagaga ttcttaactcagtgctttag catgaggggt15121tagaaagggc tctaacttgg ttggttggtt gtttggttcgttggttggtt ggctggctga15181aacatggacc aaaaggtagg tggccgacac cgttccttattttgttatta atatatttgt15241atattcatat acaaacttgt atgctatgat atctaatacatattacagat ataaaacaaa15301tctttaggcc aggcatggtg gctcactcct gtaatcccagcacttcggga ggctgaagca15361ggtggatcac gaggtcagga gttcaagacc agcctggccaacagagtgaa atcccatatc15421tactaaaaat acaaaaatta gccggtcacg gtgtcaggcacctgtaatcc cagctactca15481agaggctgag gcaggagaat tgcttgaacc cggaaggtggaggttgcagt gagctgagac15541cccatcactg cactccagcc tgggtgacag agcaagactccgtctcaaaa aaaaaaaaaa15601tcttttgttt ctttcctctc tcattccttt atcacctaacataagatgga tcatcacagc15661attgaagtga caggatgtca agcagaagag taaacatcacccaaggacgt tgcagcctct15721ctggggaaag gattggcatg ttttctgttg tatgcaggatggttgagtca tgttaggtgg15781aagtatggct ttgttactgt ctttatctgg agattaagtgtggtttaagg agatgcatac15841aggtgccagg ttgacaaaga gagtactgta atgattagttttatgtgtga acttggctag15901gcccagttat gtaaacacga atctaggccg ggctttggtggctcacgcct gtaatcccag15961caatttggga ggctgaggca ggcggatcac ctgaggtcaggagtttgaga ccagcctggc16021aaacatggtg aaaccccatc tctaccaaaa atacaaaaattagcctggcg tggtggtgtg16081tgcctgtagt ctcagctact cgggaggctg aggcaggagaatcgcttgaa cctgggaggt16141ggatgctgca gtgagtggag atcatgccac tgcactccagcctgggcaac agagtgagac16201tgtatcgcaa aaaaacataa aagaaaaaac aacaaaaaccccgtgaatct aggtgttact16261atgaaggtat tttgcagatg tgattaacct gcatgggcctcatctaatta tctgaaagac16321cttaattgca aaactcaggg ttccccaagg acagagcaattaagtctatg gcctgcagcc16381tcagcttccg cctgagtttc cagcccacca tcctaccctacagcttcaga cgcgtctagc16441cagcccctac aactgtgtag gacaatttct agaagttagttaatgaatac gctattggat16501ctgtttctct ggaggaaccc tgactgacac aggggccggctctggaggtt gtggggtcca16561gttccttatc cctgtgtagt gtattggcca gttggggtgggaattgcttc caggcaggct16621gtgtcatttg ttcaggcagg gtcccctccc cttggctctgcctgagagca aaggcaggtg16681ggggtggccc tggggagggc ctgaagcttt gctctgtgcctcctaaagct ttcccactcc16741agggaccagg ccaggcaggc tggcaggaag aggcaggcttcatctggaag gatgtctcca16801gggtggaaat gatgagattt aaatggtgta gggacccggagggtggggtg ggacagcacc16861actgacccag ctgcagagtt ggaccctctg aagcccattgtgtacatgag aatctgtgtg16921cctgattgcg taggtgccta tacatggata ggctgcgaatctgtgtgcac acagctggct16981ggagagcaca tgagtaggta tatgtaccac attgtcagcactcacccatt agctcctggg17041gactcacttg ctgcaggtga tccctgtcct cgtgggctctacaccctggc aggtcaacac17101agactacaaa gaaacaagcg gacataaaat gacaagggctaggacaaaaa gcatggaaag17161gagaggggat aacgtggcag gggacatttt agaatgcagtggtttcgaca ccaggaggag17221gagtggttag acagtggtcg gggagggcct ctgaagaggtgacacctgaa tgatgagatg17281gagcaaacca agcaaagatt ggaggaagag cctccaagcagaaagaactg caaggacaaa17341ggccctgggg caggagcggg tacgtgtgtc ctgtatgtgtgtgtcctgca cggtggcagg17401tgtctgaagc tgagcccaga ggagctgtgg agatcaggcccagaagtgga gccacagcac17461gtagggccag agacctgcag taagaaatgg gatgtggtcgagatgggatg ggagccaccg17521cagcaccatg gggcgggagc agcagagtct gatgttgtgtacttcaggga gctggagttc17581tatgaaggaa gagcgaggag gcatgtggga ggaagaacagccccactgag gcctgcaggg17641aaggcagcag accccaggtc agagcatgaa ggtagaggggaggttccaag aagtgggttg17701gggaataagc actggatggc tgatgacaga gggcagggtggaggatgcgg ggccagggag17761ggctgcacag agtcctggga gggtgagcgg tggccctggctggctaggag gcgccacctt17821gaggtgctac tggaggatac gccgcaggga aggtggatggtctcttctga tgacaacctt17881cttgctggca ttagactgaa aggggaggtg atttgtagggatgaggccag aggggttgtc17941cccagggaag ggcaccagat gtggggcagg agagctggtgtgagttgcag ccgtggggcc18001tagaggaagt cacagcaccc cactgaattc tcacttcctcatcataacag accctgtgac18061atataaaacc tgctctgccc accgcacagg gatcacaaggctggagtgaa ataatggagc18121acttccccag agtggcacac gggacccagg gacgggtgtgcaaaaccgtt ctaggtggaa18181gaacactttt tttttctttt tctttttctt tcttttcctttttttttttt ttttttttga18241gatggagtct ccgtctgttg cccaggctgg agtgcagtggtgcaatcttg gcccactgta18301gtccctggct cccaggttca agtaattctc ctgcctcagccttctgagta gctgggacta18361caggcaccca ccacaacatc tagctaattt ttgtatttttagtagagaca gggttttacc18421atgttgacca gactggtctt gaactcctga cgtcaagggatccatctgcc ttggcctacc18481aaagtagctg ggattacaag catgagccac cgtgcaaagccaaaaacact tgattataat18541agcatgctat ttttcaatgt attagataaa tgtattttccatttaaagtg gggatataaa18601gctccccttt aaaatccaca taagtaaaaa agtcagtctgtttaaaaggt taagtaaata18661acagtctagg gcagatgcac aaaagacagc atcatgaccgtggttcctga aggattaagg18721ttgcaggaaa cactgaatgc taaaagcttt gtgaatgtatagtccatgaa aatgtctttt18781aaaaaatgag gtgcatacca agatgtttga gtgtgtgtatttggggtagg tgctgtgggc18841atacgggtgt acctgtgtgt gtctcacaag caggtgtagctgggtgcttg tgtgtatgtg18901gtgtgtgtgt atctgtgcac acgtgcatat ctgtgcccacatatccatgc acacgtcctc18961ataaggctct ctgcggccag gtgcggtggc tcacgcctgtaatcccaaca ctttgggagg19021ccgaggcggg gggatcacga agtctgaagt tcgagaccagcctggccaag atggtgaaac19081cccatctcta ctgaaaatac aaaaaattaa gacagtgagtgttgatcgtg aagaagggaa19141gatgaatgtg gggattaggt gggaggaatg gggtgctgtcaagatgaaaa taaacttagg19201gtggagaggc tggggcaaaa gagaggccca acagtatgatttgccccagt gcggggactt19261tgtgcctggt gatttgaggt ggcagggctt ctacccaggcctgatgggag ctgggattaa19321aagcagctgt gacctaaggc aggccattgc tctgtggcctRctcccctaa ctcttttgca19381gaaagtccca ggctaagaga tgggggatgg ttgtaatgacccctcccaga aatcctggct19441ctgtcctgca gaggtggggc ccggggatca agacgcctctaggttcaaga gagaggcaga19501atgaggggtc agccagctgg ggcaggaagg cttcactctaggctgcaagg agagaccttt19561cgccttgact ggaaggacgt gaggagcctg tggcctcctgtttgcaacca agggctgagg19621aaggggccgg gcattcctgc tgtaggtcaa tgacctggagaaacacatgc ttgaggacag19681agctcagatc attgtcccag cgcaaacctt ggtgggatgtaaggtttgga gcttcttaag19741ttccaagagg cagtctcatg cagttcaagg agggctggagaagcctggtc tgctcatggg19801agtcaattgt taaattttca ggaattttgt gagccaattattgaacacag ctattattaa19861aaacaaaatt ataggctggg cgtgatggct catgtctgtaatcccagcac tttgggaggc19921caaggcggtg gatcacttga ggtcaggagt tcaagaccagcctagccaac atagcaaaat19981cctgtctcta ctaaaaatac aaaaacatta gtcgggtgtggtggctcaca tctgtaactc20041cagctacttg tgaggctgag gcatgagaat tgcttgagcccaggaggcag aggttgcaat20101gggctgagac cacgccattg cactccagcc tgggcaacagagggagattg tgtctttcaa20161aataataaaa taaaataaaa taaaataata ggctgggtgccgtgactcac gcttgtaatc20221tcagcacttt gggagaccaa ggctggaaga tcgcttgagcccagaagttg gagatcagcc20281tggggaacac agggagaccc tggtctgtac aaaaaataaaaacaaaatta gccaggcatg20341gtggcacatc cctgtggtcc cagttactta ggaggctgaggtgaacaaag ttaacactca20401aaactcatca cttgtgaatt actttgctac agtgcactattattattatt tatttatttt20461tactgggcag cctcttgagc ctaagtaggc ccagagactgtccagcatac tattattgat20521gctttgtggt tattgatatt gattggatcc gtatagtggaaatggctata ctgtagaatt20581gtgtgctact gtgtatttct taccaattct gcattcagtggcatcacatt catagcttga20641agttggccat ggtgggaggt aaatatgtgt ggtataaattggcaaagact acagattggg20701gttcctgtct ggccccccaa gagctggttg ttaaacttttaccagcacac cactgagttg20761gagtctggaa agcaggcttc gtccaggttc tgccctgctagctcaactgg ctctcaaagc20821tttgctccac caactggcct atggctgctt ccactcaccaattctccctt ttgccctcta20881aggccacctc ttccaggaag tttcccctga tttctttgcctggacttcta aaattctttc20941tttgccaggc gtggtggctc acacctgtaa tcccagcactttgggaggac gaggtgggca21001gatcacttga ggtcaggaga tagagaccag cctggccaacacggcgaaac cccgtctcta21061ctaaaaatac aaagattagc tggacatggt gacgcgcacctgtaatccca gctactcagg21121tggctgaggc aggagaatca cttgaacccg ggaggcagaggttgcagtga gccaagatca21181caccattgca ctccagcctg ggcaacagag ggagactccatctcaaaata aataaataat21241taattctttc ttacctcttc cgttcatatt catacagaataatctccaca tctcgaaatt21301cttaactgat tagctagttc ttgctattaa ttaaatacgtgatgcatatg gccaagcttg21361gatggatgga atccctgtat tggtaaggtg ggaatttttcttttcttttt tttttttttg21421agaccaagtc tcactctgtc acccatgctg gagtgcaatggtgtgatctt ggctcaccac21481aacctctgcc tcccaggttc aagccattct cctgcctcagccttcctagt agctgggatt21541acaggcacac accaccaagc ccagctaatt tttgtatttttagtagtgac agggttttgc21601catgttcgcc aggctggtct ggaactcctg gcctcaagtgatctgcccac ctcagcctcc21661caaagtgctg ggatcacagg tgtgagccac cacgcccacctagggtggga attttccacc21721tgggttctgg gctcagctct gccacagatt cctctctctgggcttatcct ctgaRggcga21781gattttggca tgactgagtg gatggaggaa gaacttggggtcagcgggct gtcaccctgc21841tctgccgtgg aaccgactca acaacagggc cacaacaggccttgttggac atggaagcaa21901atgagaaaat tagtaatact gattcagtgt ttacttaaggttctgatact ttgtccatta21961tagacctttt gcattaattt tgatttttta ttatataaaatatatatata acataaaatt22021gatcatttta gccattcgaa gtgtacagtt ttgtggcgtttaatacattc acattattat22081acaacccatc tccagaactc ttttcacctt gaaaaactgaaactctattt ccattaaata22141tgaactcact ccccgttctc tcttcctcca gcctctggtgacctccattc tattattatt22201attattatta ttattattag agagagtgtc cctctgttgtccatgctgga gtgcagtgat22261gcaatcacag ctcactgtag cctcaaactc ctgggctcaagggatcttcc cacttcagcc22321tcctgagtag ctgagattat aggcatacgc caccacactctgctaattca cttatttttt22381ggaaagatgg ggtcttgctg catggtccaa gccagacttacattcctggg ctcaagcgat22441cctcccacct caacctccca aaacattgag attacaggtctgagccaccg caccctgccc22501attctacttc ctggctctta aatatgacta ctctagatacctcatataag tggaatcata22561cagtatttgt ctttgtaact ggttcatttt acttggcataatgtcctgaa ggttcatcct22621catcgtagtg tgtgtcagaa tgcccttcct tttaaaggatgaataatatt cccttgtgtg22681gatatatcac atgttgttta tccactcatc attgatggatgcctgtgttg cttccacttt22741tggctgctat ggaaaatgct gctatgaata cgggtgtgcaaatattcatt tgagtccata22801attttgattg ttttttcttt ttgagacaga gtctcacactgctgtccagg ctacagttca22861gtggcgcaat cttggctcat tgcaacctcc acttcccgggttgaagtcat tctcctgcct22921tagcctcccg agtagctggg attacaggta tccgccatcacacctggcca atttttgtat22981ttttagtaga gacagggttt caccatgttg gagactggtctcaaattcct ggcctcaaat23041gatccaccca cctcggtctc ccaaagtgct gggattacagtgagccacca tgccgagtcc23101ataattttga tttttaaatg gtggctacta agtttttctggcacccctta aattttgtca23161ggcacttgcc ttaccctagt cctggcccca gtttgggttgtcacagcaag gtggaagtgt23221actgaaaagc tcgtgtttta tctttatacR tttacatggggccccaaaaa gggggaaaac23281ccactttgat agggatatga cacagggacg caggagccaaccgaaagagc ccccagtggc23341caaagatsga gcaacttgag caacaaaata aataaagtaagcatcaaatt atagcccaaa23401gtataaaata agtgtctatg agtctatact cacatagatgatttaataca ttcatattaa23461taaatgggag agcactttga gaggccaagg tgggcagatcacttgagccc aggagtctga23521gaccagatta ggcactgtga tgaaaccctg tctctaccaaaaacacaaaa attagctggg23581catggtgggg catgcctata gttccagtta cttgggaggctggggaggga ggattgcttg23641agcctgggag acggaggttg cagtgagctg tgatctcaccactgcactcc agcctgggca23701acagagtgag gccctgtctc aaaataaata aatatataaataagataaat atataaataa23761aaataaaaat aaacgggaaa gaagagacaa atcttctgtgcaggagaatY ccaaatgaat23821tctgtagatt ctccacccta caggagggca cacacaactccaggctgcct tagtgacctt23881cttccaaaga gtacagtacg ggaaggggga gcggggagaattaacttcac agtggagaaa23941tctgacaaat acgacctccg ccaagtgatc gaggtcacatcagctgtcat gaattatgtt24001gatagtgggc atcctggata tgatgggatg aaatggcactttacctccac gacccttttc24061acaacagccc gtaatgccag tataaggaaa acatcagaccaggagtggtg gctcacgctt24121gtaatccgag cactttggga ggccaaggtg ggtggatcacaggtcaggag tttgagacca24181gcctggacaa catggtgaaa tcctgtctct actaaaaatacacaaactag ccaggcacgg24241tggcgggtgc ctgtaatccc agctacttgg gaggctgaggcagaagaacc gcttgaaccc24301gggaggcgga ggttgcagtg agctgagatc gcgccactgcactccagcca ggttgacaga24361gtgagactcc atctcaaaaa aaaaaaaaaa aaaagaaaagaaaagaaaaa gagaaaagaa24421aaacatcaga cagatcccaa cagaagggca tcctacagtatacRtgacca ctgctcctca24481aacctgtcaa gactatcaga aacaagagaa actgtcacagctacaaggag atgtgacaat24541taattgtgat tttttttttt gagatgtggt ctcgctttgtcacccaggct gcagtacagt24601ggcacaatca cagctcactg cagcctcgaa ctctggggctcaagtgatcc tcccatccat24661ctcagcctcc caagtagctg gggctatatg cgtgcaccaccacacccagc taatttttgt24721atttttttag agacggtatt tcgccatgtt gcccaggctggtctcgaact cctggattca24781agcaatccac ctaacttggc ctcccaaagt gctgggattacaggcatgag ccaccatgcc24841ttgccaaatg tgatgtattc ttgatgggat cctggaagaggaaaaagata ttaggtaaaa24901actaaggaca tctgaataac catggatttc agtaatgtatccacactgat tcattaattg24961taacaaatat accgtatgaa tgcaagatgt tcataatgaggccggggcgg tggctcatgc25021ctgtaattcc agcactttgg gaggctgagg cggaaggatctcttgagctc aggagttcga25081gaccagcctg ggtaacacag tgagatcccc atctctacaaaaaatttttt gaaattagcc25141aggtgtggtg gtggcacatg cctgtagccc cagctactcagaagactgag acaggaggat25201tgcttgagcc gggaggttga ggctgcagta agccaggatcacgccactac actgcagtct25261gagcaacaga gcgacaccct gtctcaatga taataataacaataataata ataatggaaa25321ctcagtatgg gttgtatatg ggaaacttgc tcagtttctctgaaaatcta aaattcttct25381gaaaatcaaa gtctgcttaa aaattcacat ggggtttgcattctcctcca tgacaaggtt25441ttgcaggtta tgattacaga ggctggagag ggtgcaggttatcccgcccc tccctgtccc25501agggattccc ttccccagga gctgtgtctc ccctgtgagagagggtgagc ttccatgacc25561ccaagcctct tgccctctga ctccggtatt cttagaagctgggaccagca ctgagcccaa25621attcccgaag cgctcaaata ctggctttct gtccctatgtgacctggagc ttgtagttta25681acttctctct gcctcactgt ttgacctata aagcagggcaatcaaggcat cccgggggtg25741gctatgaaga gtgaatgaga tagcagacaa cccagatgcctaccgacagg tgaagggacc25801aacacagtgc ggtataggcg tataagggaa tggagtatggacacagccta caacacagac25861aaaccttgaa gacattcctc taagggacat aggccaggcatggtggctca cacctgtaat25921cctagcattc tgggaggccg aggcgggcag atcacttgaggtcaggagtt gagaccagcc25981tggccaacat ggcaaaatcc cgcctctact aaaaatacaaacattagctg ggtgtggtgg26041taggtacctg taatcctgga tactcgggag actgaggcaagagagttgct ggaacccggg26101aggtggaggt tgcagtgagc cgagattgtg ccactgcacttcagcctggg cgacagagcg26161agactctgtc gaaagaaaga aagggaggaa ggaaggaagaaagaaaggga agggaaggga26221agggagggga ggggagggga ggggagggaa gggagagagaaagaagaaag agaaagaaag26281gaagaaagaa aaagaaggaa agaaagaaag aaagaaagaaagaaagaaag aaagaaagaa26341agaaagaaag aaagaaagaa agaaaagagt gaacccaggaacgaaagatc acacacactg26401tatgactcta tttacatgaa atgttcagag taggcaaatccatagagaca gaaagcacat26461ttatggttgc caggagctgg gaaagggcag gatggggaatgactgtttat tggatgtggg26521gctctatttt ggggtgatga gaatgttctg gaattaaattcatggctgca taacactgtg26581aacatactaa atgcccctga attgtacact ttaaaatggttaaagtggca agttttcact26641aagcagtaaa ttaaattcta ctacaatttt aaaaagactaaaaaataatt taaaaaagat26701taaatgagat aacgcaaaaa agcattatct cgaaaatacagctgatatta gtataattct26761tactaagttt taagagtcta aggtgcagga ttctaagtttaaagggatag gctcttttgg26821ttttttggtt tagttatttg gttttttttt ttaatccattatccccaccc ttgggaggcc26881cccagcaccc agtctgcact agaggatggg gcccacctcccttttctctc caggcccagc26941cactgaccac cagtaccctg gccaggggca ccctcggtcattgccctccg tggcccaagg27001aagggaacag aaacaacagc caagaagaca atagccgccgggaagtcctc acatttctgg27061agaaatagag cccattaatg aatgaagttc ctccagcctgatcggaggac ggggtgctgg27121ggaggcctgg gctaaagggc tcacctccag cccccaccctggcagggccg atggtacatg27181ctcactcagt gagggggctc cagaggtctg tgggtacgaacccaagggct ggtgcccagg27241ggcaatcagc ttatgtctct gagccttggg aaacagtgagggtcagcccg gctccccacg27301tgcttctggg cagctttggt attggagcag gtgcaaactcRggactaggg caggaccccc27361tgagaggcga ctgagcaagg ccatcccgac tcatgtttccttggccctgc ccggggcaca27421gcatcctgcc cacatccctg cagccctggc tccttcctaggggctctgag gaggcagcac27481ttggtcatct ggtcacagtt gctgcagggc agttcttggccccagctgta ggtaaagtac27541tgtatgttgt aattttttga aagataacac gttcacacaactcagaattg aaatgccaca27601gacattcccc ctgctccgcc cctttccccc ggatacccagtttctcccgg aggcagccaa27661tgatctcaga ggctgtatac ccccccagag ttattttatgcatatcaagg aaagtctaca27721tagaggactg tttctggggt acccagatgc agcgtcaaatgccatggaat actacagtga27781ggacattatc ctttcaagct ttcaaatcag agcaagggaaaggtcgatgc tagagtttct27841ctagcaccca tgaagccctc tccctttttc tactgagttttactttacag gcaacagcag27901gcttcaagct tggggtcatt gtcgggcaac agtatctggcaagaattcaa tgtctttttc27961tcatagtcat tgtattttgg cctctttcta tttatggcaactgagagaga aagcttattc28021ctagatatat gtatttaagt aaaaaataaa tgaattcatggaaacatatt aagcaattat28081ccagataaca taagggatgg caaaaatggt gcagatggtggaggggagac aagtagaagt28141tggggtgctc ttgttgaatg tctggctctg aactctagaggaggccgcag gggctgggca28201ggaaggaggt gaatctctgg ggccaggaag accctgctgcccggaagagc ctcatgttcc28261gtgggggctg ggcggacata catatacggg ctccaggctgaacggctcgg gccacttaca28321caccactgcc tgataaccat gctggctgcc acagtcctgaccctggccct gctgggcaat28381gcccatgcct gctccaaagg cacctcgcac gaggcaggcatcgtgtgccg catcaccaag28441cctgccctcc tggtgtgtaa gtatcagtgc atctgtctgccctgccaggg gtcttttcat28501ggacacccac tatgccagga gcctccctgg cctgaagccagccctgaagc cggctgccac28561actagcccag agagaggagt gccctgggag ggagatgggctgagYggagc tgtcatcacc28621ccctcctgac ctcgccttca aggtcaagtt ctttggtRagaaggtcctag ctgcattgca28681aacagccagg tatagggatt tgtgtttgtc tgagacccagaatcactggg gttcRagtta28741gggttcagat ctgagccagg ttagggggtt gagtcagggggtaaagatta ggaggttggt28801gtatatttgg tgttgggggt cactctatgg ccaaagtcaggggttgccat gagctcaggt28861gacggaggct ccatcactga ctgttgtgtg actttggccagctcccctgc cctctctggg28921cctcagtctc ttgctcaata taataagggt atagggaggctaaatgatac aatttctaaa28981atagagtatc gccaagttca aaagccagaa ttatagacccccaggactac agacagtgtc29041acagcatcgt ctgggtgagg ctagggttag tgtgcggctgggctcagggc tgccccattt29101gctaggatcg tggggttccc atgtgtcagg atccagaggctagggtatga tcaggatctc29161tagctggggt cagggtcaga gctctctgtg tcccctagaattgccatcaa ccttaaaccc29221agagggaggc ccagtccaac ccctcagctt taagacctgctgggagcctc atctcagaga29281ggctgagtca tggccaaggc cagttggggg tgggagcagggggcttggtg tgggcctgca29341gcccctcatc cactgccctc ccctctagtg aaccacgagactgccaaggt gatccagacc29401gccttccagc gagccagcta cccagatatc acgggcgagaaggccatgat gctccttggc29461caagtcaagt atgggttgca caagtgagtc gggcctcgggtgtgaccagg ctgggggtag29521ggaggcggga ggaacagcct ggggcttgcc cccagcccacagggaggaaa ggcagcagct29581gggggactca ggtctctccc cttgatttgg aaccagagcctgacaccttc cctaccccca29641ccctccatac cctggtgccc tggggggatt tattggagtRtatcaacctc tccaacagcc29701cctctaagag tcaggcttca aagggtcctt tcccactgccctgggaagat ggaggtctta29761tttcggggtg aatggggggt agggtagaaa aatctcaacaaaataagtat tttttaaaaa29821aatgtataaa tgttgttttc ttatagtaca gacaggtcttgctatgttgg ccaggttggt29881cttgaactct tggcttagcc agtcccccac cccaagcctaaaattagtat cttgacttta29941tttgggatga tggtaacagt caagggtcgg ttgtgggccaggtgctttta caaacaaYat30001cctcaccttt agcatatatt tttttctttc ttgtttttcattttttgaga cagagtctcc30061ctctgtcact taggctggag tgcagtggca caatctcagctcgttgcaac ctccgtctct30121gggttcaagg aattttcgtg cctcagcctc cagagtagctggaattacag gcacacgtca30181ccacatccgc gtaatttttg tatttttagt agagatggggtttcatcatg ttggccagac30241tggtctccaa ctcctgacct caagtgatcc gcccacctcagtctcccgaa gtgctggggt30301tacaggcgtg agccaccacg cctggccctt tatctatcttaatctttatt ttatttattt30361atttatttat ttatttattt atttatttat ttatttatttattgagatgg agtctctcac30421tgtcacccag gctggagtgc agtggcacga tctcagctcactgcaacctc cacctcccgg30481gttcaagacg ttctcctgcc tcagcctccc tagtagctgggattacaggt gcccaccacc30541acgcccggct aatttttgta ttcttagtag agacggggtttcaccatgtt gacctggttg30601gtcttaaact cctgacctca agtgatccac ccgcctcggcctcccaaagt cctgggattg30661caggcgtgag ccacagcgtc cggcctatct taatctttatcatatatttt agcctcttct30721gtaaaagagg ataatgccat cgcccggatg accctgcttaacaaacacgg aaacaggagc30781cgatagaggt ttagcagcct ggcggagctc atgtgcaaactcagctcagt atcggaaact30841cagccacctt catggcacct caggctgccc tggagcctgggtcccggtct gtgtgtcggt30901ctgaggcccc aagggtgggg cagacattgt tcagggaccttgtctttgtc ttaaagccaa30961tctcctcctc ctccccggcc ctgctaaaca cgctccccaggggtggtctc tgctacccgc31021gcacattggg ccttgagtct tggtaaatgt ttctgagccaccagggggcg ccagcggtgc31081tggatgccac ttcgcctttt gcaggaaaac tcccgccgctagcgggtgct gtggggcgtc31141ccaggtctcg cgcagccacg ccctctgtgt gaccttgggcttcagtttag gcttctgtaa31201aagagaataa tgggcaaggt ccagtggctc atgcctgtgatcccagcact ttgggaggcc31261gaggtaggag gattacctca gccagggttc aagaccacctgtctctataa aaaatttaaa31321aattagctgg gcatggtggt gcgtgcctgc agtcccagctactcaggagg ccaggggagg31381tcaaggctgc ggtgagctat gattgcatca ctgcattccagcctgggtga cagagcaaga31441ctctgttgct aaaaaataaa agaggataat gctatcctagacctatgtgt tgcaagaggt31501cagacatggc aaaagcgttg agaagttaaa gaaatagtatccttaataaa tcagcaataa31561ttcagtaaga ccagactgcc atagactaga tgtcatagtcattaatatat aactgttatc31621ccaaacgtat atgagtgggg tagaaataaa atatgattggccataactat gattggtcat31681gattaatgtt agatgaagtt ggataatggg taagatgagaattcttcaca ctattctctc31741taaagcgaat ggaataaaat agaacagaac agaccgggaaagccagatat atgtggattc31801tccttgctgg gcacagtgtg tcatagtggc ttataatatgggatttggag tgggatggac31861ccaggatcaa attcccttct actgaggttt tctgaagccacataagctgt ctgagccatt31921tctgtctcag ttcagtgggt acagcaatag tgactacctcgtgggtagct gtgaggatta31981aaccaggaaa tgtgtataaa ctctaagcac agtgcctgccacacagcatg tgtttggtac32041gtgatggccg cttctattgt gtcatattcc atgtgctcaagccgggccct gggggagagt32101tcagcaaggg tagagggata tgagagtgaa tgtggcccactggcctccct gcctgcagtc32161tctcctctct gatccttgct tcctaagggt cttcactgagccccacctct gaccaagtcc32221ccggcggcac aggcagcaca gatcctctgc tgtacctacaccaagacccc agggccaacg32281cttctcccat tgtgcagctc cacctctgcc cccggggcctagctgaggcc tcctccaagc32341tgagccacct actatcttcc aaactcccac cctccatctggtgtcacctc ctcccagaag32401ccctctgtat cagtttcctg ttttctgcca taaaaaaaatcactccaagt ttagtggctt32461aacatgacac aagtttacca ttttacagtt taaaaggctagaagtccacc atggccctcc32521Ytgagctaag atcaagctgt cagcagaacc agattccttctgggggctat aggggagaat32581taattccctc gctttctgca gcttctagag gcttcccccattccttggct tccctccatc32641tacttttatt tagggcgagg gaagcttcct gctctgactttctcatttat ggtattctcc32701cctgctttcc agcagctgtg attgtcccaa gtcctgtcctctggttctct aggccagaaa32761aactatgatc taccagagct caagaacttg aaagggccttttcccactgt cccttctcac32821agtgagagcc ggagcccagc ttcgtgctag aatctgtgaaaatggagaaa tgcaccctgt32881gctgttctct tcctccaccc ggcatctccc ctgcagcccggctgggtttt tttgtttgtt32941tgtttgtggg tttttttgtt tttttgtttg tttttgagacagagttttgc acttgtcgcc33001caggctggag tgcaatggca cgatctcgac tcactgcaacttctgcctcc tgggttcaag33061cgattctcct gcctcaacct cccgagcagc tggaaccacaagcatatgcc accactcccg33121gctaatcttt tttttttttt tttatgcatt tttagtagagatggggtttc accatgctgg33181ccaggctggt ctcgaactcc tgacctcaga tgatccacctgcctcggcct tccaaagtgc33241tgggattata ggcgtgagcc acggcctggc ccagtctgactgttttcact tactctctaa33301tgtctcaggt agtgtttatt gtattctgtg cggaggtcaagaatttagtc atccaaggag33361gttagtgtat taggagctta cgcagctatt accagaagagactccactca aaaatttggt33421acgtggctgg gcgcagtggc tcaaacctat aatcccagcactttgggagg ccgaggcggg33481cagatcacct gaggtcagga gttcaagacc agcctggccaacatggtgaa accctatctc33541tattaaaagt acaaaattag ctgggcatga tggtgcatgcccataatctc agctacttgg33601gaggccaagg caggagaatc actgaaccca ggaggtggagactgcagtga gctgagattg33661cccgctgcac tccagcctgg gcagcaagag caaaattctgtcacacaaac aaacaaacaa33721acaaaaaaaa cgggttgggc atggtggctc atgcctgtaaccccaacact ttgggaggct33781gaggtggggg aatcacctga ggtcaggagt tcaagaccagcctggcaaca tggtgaaacc33841ccctctctac taaaagtaca aaaattagct ggatgtcgtggcgggagcct gtaatttcag33901ctactaggga ggctgaggca ggagaatcac ttgaacccaggaggcagagg ttgcagtgag33961ccgagatcgt gccactgcac tccagcctga gcaacagagccagactcagt ctcaaaaaaa34021aaaaaaaaaa caatggtatg agctttaaat ttctgtagaactgaaagagg attggagatt34081gtagtagggt ctaattctaa attagagcat ttagaataatgtggagtctg gtcaacatag34141tgagaccccc ccaatctgca caaaaaagac aaaaattagccaggcagtgt tggtgcatgc34201ctgtggtccc agctattcca gaggctgagg caggaagatcgttggaattc gaggctgcag34261tgaactgtga ttacacaact gcactctggc ctgggcaacagagagccacc ctatctcaaa34321caagaaagaa caaactaaaa aaaaaaaaag aagaagaagaatttggagca atctagttgt34381ttcctatacc agaagtcttt gccaatctat ttttttttaattttattttt aatttttgtg34441agtacatagt aggagtatat atttatgggg tacatgagagtacatagtag gagtatatat34501ttatggggta catgagatgt tttgatatag acctgcaacgttttgtcaat ctattttttt34561tttggcgaca gtcttgctct gttgcccagg ctggagtgtaatggcgcgat ctcagctcac34621tgcaacttcc gcctcgtggg ctcaggctat tctcctgccttagcctccaa actagctggg34681actacagacg cccaccatca tgcccggtta atttttttgtatttttgtgg agacgagatt34741tcaccatgtt ggccaggctg gtcatgaact cctgacctcaggtgatctgc cctcctcggc34801ctcccaaagt gctaggatta caggtgtgag ccaccacgctggcccaccaa cctatttttg34861atctaacttt acctctggtg gtgtattgat actcttccgaatcaattttc acccttcttc34921atataccatt tacatttcta agaatttgtc catttcatttcatctagtta acctcatttg34981ttgacataca attgttcgta gtattctctc ataattccttttatttctgt aagactggta35041ataatggcct tgcttttatt tctgttttta gtaatttgagtcttcttctt tttttttttt35101tttgccagtc tagctaaagg tttgttgatt ttgttgatcttttggaaaaa ccagctattg35161ttttcaccga ttgttgtttt tgttctatta tttcattcataggcactaag atcctgatta35221cttccttcct tctgctagct ttgggcttag tttgcccttatttttcaagt tccataaggt35281ggaaagtttg attattgagt tgagatcttt ctcttttttaaagataggca tttctagata35341taaatctccc tgtgagcacg gttccctcca tcttcagcacaccagggttg actctctccg35401ggcgttcttc cctggtcacc tctccccttc ctctcctcttctgcctcctc ttccactttt35461cggtaccctg tgattgtatt gggaccaccc agataacctaggatcatctc cccacctacc35521ccaaggtcct taacttaacc atactttcat atgggtaacacgagttgagt gtggtaccca35581gggtttgaca tgttgggtaa catatttgca ggttctgtggattaggagga cattttgggg35641gccatgattc tatcttccac cctcgcctag acaaaattggaggctcactc cttgggctcc35701ctggatgacc cccaacatcc ttcctcactt ccattccttcccagcatcca gatcagccac35761ttgtccatcg ccagcagcca ggtggagctg gtggaagccaagtccattga tgtctccatt35821cagaacgtgt ctgtggtctt caaggggacc ctgaagtatggctacaccac tgcctggtgg35881taagcattcc tgtcagctga tgccccatgc cctggccctctctgggctgg agggctgaat35941gagggtcctg ggtccttggc tctttccagg ctgggtattgatcagtccat tgacttcgag36001atcgactctg ccattgacct ccagatcaac acacagctgagtatgtgtca agcgtcctct36061ggggaagtgg gagctggact ccagggcttg gcctcagcagagggggaggt tgtgcaggca36121gagggttctg gggccaccaa aggaggccca gcctgggaagtttgcagggK tggggacccc36181agagctggcc aagctcttga ctggcctggg cagcatgtggataccatctg atagcggagg36241ctgccctgag gtcatgtcgg gtctccctgc agcctgtgactctggtagag tgcggaccga36301tgcccctgac tgctacctgt ctttccataa gctgctcctgcatctccaag gggagcgaga36361gtaagtacac caccctgtgg cccccattcc tgctcgtgcccatcctgtta gtgtgtccac36421ggctccYtcc aggctcaacc ccacacaggg catgcttgtgggtggccaaa cctgagggca36481gcaatacctt cagtggggtc acttcctacc ccctcccatcaatacaccct caaaggctgg36541aaacaacaat aaccaacagc tagtaactaa cagctattaagaacttgctg tgtgcaaagc36601actattccaa gcccttttca tgaattaatt gattttgtccttaaaaccaa ccctaggata36661tagattctgt tatcatcccc tttttacata tgggtaaactgagtcacaga gaggttagaa36721aggaaaagct catatctacg gagtgcatcc tgcattccaagcaccacact aactcagaga36781taaaactcta gccaagctaa gtaacttgct gaggacacacaactcgccac taagggatgg36841gagtaggatt tgaacccagc attctctgac cccagaagctgagttcctag atactttact36901ctcctgcttc ccagggtggg gctttttgtc ttggccaacaccctctgtca aggagctgtg36961ggtaacccca ttgcacagag gaagataaca aggtttggagagtccctagt catgttacca37021atgccaaacc tggaaggcag aagggaactg gtgggtggggtctggagagg agccctctat37081tcaggccatt ttctgactct ggagcagacg gatacatgtatgaatttgga ctctagacac37141gttctcgtgt gtgtgacagg tgtgagcgtc acaggagctgggccctcccg aggaattctg37201ggatggtgcc acagttaatt cttgggtctg aggctccgtgttctcagctg caaaatggga37261gtgataattc ttacttcctg agctacaaga gtcagggccaacagagccat gaacggtgcc37321tggtacacac taggcRctcc atggatgcac aggactggtcaggggctcat tgtggtgctt37381gctgccttca ggcctgggtg gatcaagcag ctgttcacaaatttcatctc cttcaccctg37441aagctggtcc tgaagggaca ggtgagtgag gctggctgactccctgtggt ccagggccat37501gcccaggagg ctggatccct ttcctccctg cctttccctgagaaggtgcc actcccacct37561tctccatgtg gccagtcccc tgtgccggtc cccagcactgccaccaccac gcagctggaa37621ggaggcactg cctctggcct cctttcctgc ctggaaagcacctgctctgt ctgccccaga37681tctgcaaaga gatcaacgtc atctctaaca tcatggcYgattttgtccag acaagggctg37741gtgagtgYgt ttctgtctgc atgcctcaga agacagcagtgggagccaga aagccacctg37801ctgcactatg tggccttggg actgtcactc ttcctgtctaggtcccatgg gctctatctg37861gctctgacac ttgatgatta gttatgagca tactttggcaaatctctgcc cctttgggct37921gcagcMtcac aagctgtgtg gcgttgggca agtctatagaactcaggaca aatgggtgat37981taagtccaag aggactccaa gattctcctg gaagtagattaggaaaaaag ataattagat38041tgctcacatg gctgggcact catccatgta ctgtactctcctatgcagta cagagcagag38101ctgggtttca gcccaagtct tggactctgc tctgaaccaaccttctagaa gggctctacc38161tacccagaca gacagacttg ggaaaagaga gaatgaaaaagtgccacacc cctccccgca38221cacccaggtc ccactttaca gaggggaaca ctgaggctggagggttgggt agctgtgtgg38281atgcagggga gcggtgactc agggcaattc ccccatcctgaggccctgcg ttgatctttt38341cctcctgcag ccagcatcct ttcagatgga gacattggggtggacatttc cctgacaggt38401gatcccgtca tcacagcctc ctacctggag tcccatcacaaggtaggagt tgtgggaggg38461tggggcaggg cccagcttcc ccaggggagt tggtccttttttgtgctctg acaaccccgt38521cccccagctt caaccttatg gcagccaaga gtcctggggcgctcctcctc attcctgatg38581ctcctccgca ttcctgatgc tgcgaggagg gcaggccacagcgacgtgcc cctgacccct38641ctctgcaggc accagggctg cccactacaa ggatcccagcaaagcaccag ctccttccta38701gagggcttat tcggcttctg tcatcctcta cagcagtggattgtggcccc cYcccagggg38761gtactgacaa aagctttgga ccctctatta cttaggatatagatttctgt aacaaagaaa38821tccgaaataa tagctgctta aacacaataa acagttatttccctctgttg cgttctgagc38881atctgcagcc ccgcgggatc aggaggctgc agggtgtcaggcacgcaggc cccttccacg38941tgttctcagc cagccccagg catgacctca tcccagggtcctggctgact ggcctgacca39001ccacacccac tctgctcaca gcccgttggc ctgaacYtgatcgcaggacc ccaccctagc39061tgcaagggaa actgaggaat ttatttcagc taaatattgagaccagctaa aagttaagtg39121gtacagaatg gagggagaga ttggagaaga ctttagggcggacccagcca tctttgtaac39181agagcctctc cctggaaaac tggacagaag gatcatttcagaggttcatg gccactcctg39241aagcctgttc acaacccatg ggctggatga tctagtggggcgggggactg ggcagcagct39301tgttttcctg attttggcct ccaggagccg atggtcaatggactgccctc tgcaggggca39361gggctggtgg tcagctgggg cggggtggga gctggaggtccgtggtcacc agctgccctg39421actaatgtcg ttacttgaat ataaccctgt gaaggcaggaaccacgtctg tctggttcac39481ttcccacggt ggttgagaca tagtgggcac tccggaagtatttgttgaat gagtgaaagc39541cccgctgggg gaaactgggt acagctcttt cctcagtttccccatctgca ctctgggctg39601aatgctgggg ctcctcccaa tctccctgaa gctggacctgagcccagtag ggacacacag39661ggtccagcca gcgtcctggc ttcctccagg gtcatttcatctacaagaat gtctcagagg39721acctccccct ccccaccttc tcgcccacac tgctgggggactcccgcatg ctgtacttct39781ggttctctga gcgagtcttY cactcgctgg ccaaggtagctttccaggat ggccgcctca39841tgctcagcct gatgggagac gagttcaagg tgagtgggtggggctgggct gctagggRat39901ccagatggca tgtggtatgt gtgtgtgtgc acacgcatggggaggaggga ggaaactcgg39961aaacttggtg gtgggcaaaa gaactaagct ggagcaatagcagtgaagtc cagactgggc40021acagtggctc acacctgtaa tcccaatcct ttgggaggctgagatgtagc aggacgaacc40081gcagacaaaa ctcctcagac actgagttaa agaaggaaagagtttattca gccgggagca40141tgggtaagac tcctgtctca agagcggagc tctccgagtgagcaattcct gtccctttta40201agggctcaca actctaaggg ggtctgcatg agagggtcgtgatctattga gcaagtagca40261ggtacgtgac tgggggctgc atgcaccggt aatcagaacgaaacagaaca ggacagggat40321ttttacaatg ctctttcatg caatgtctgg aatctatagataacataact ggttaggtca40381ggggtccatc tttaactacc aggcttaggt caggtaggcccaggcctggt ttcgggtctg40441gttccttggt ttcgggtctg gtctctaggc gttgggctacctgcctttag tttcgcttct40501ctttcttttt ctgagtataa aacaatataa aacaatatgagagggtctgt ctctcttctc40561tcagagacag gagggtccct ggaggccagg agttcaagaccagcctgggc aacatgggga40621gacccctgtc tctacaaaaa taaaaataag tttaaaaatcagctgtgcac ggcRgtgcat40681acctatagtc ccaactactc aggtggctga ggagggaggatcacttgagc ccaagaggtt40741gaggctgcag tgagctatga tggcaccact gcactccagtgtgggtgaca gagtaggact40801ccatctcaag aaaaaaatac agtccagcat ttattggagtcaactatgtg ttgccagata40861gatagatgga tagatagaca gagtgatcaa tagatttaggtatagatata acttggcacg40921tagtaactgt gcattaaata taagttgata ttagacttacatttattgca gttatatttg40981ctacactttg ttttgttgca ctcatcctgt gaaataagtactgttacctc tgttttgcaa41041acaaaaaaac cacaaagctc agagaaggta ggtgacttactgaagatcac acagcctgta41101agaggtggcc ccaaagcctg tactcttcac ctatactgtactagaaatgc ttaggtagtt41161tccaggctgt gcttgtcatt gaactcatga ggaaactgaggcccacagag gggaagagac41221ttgtgcgagg tcacacagca tgtgtggggc acagtggggagcagaagcca ggcctccagc41281cgggacaggg gttccctgtt ccacaccctg cccagagcatctcacatgtt gtctgggagg41341ttgggagttg cgtctgagga ggggtccagt ccttgaaactgcccttggtc cctgcgaagt41401tttcttctga ggagtggact ttactccacc caccctccaacttcctcatt tcttttcagg41461cagtgctgga gacctggggc ttcaacacca accaggaaatcttccaagag gtaactgccc41521cctgcccctg tgtggggttt atctcacgta ccccaatcctgctctggctt caagagcccc41581cacacagcca ataacaccac caatggcaac aattataacagcgaacacag ctcctactcg41641gttgttcggc atggagtgaa gcacttagtg tgtgtgacttccttcagtgc tcacaccgac41701cctatgagtg gggcggtcaa actgtcccca ttttacacacagggaaactt agtgaatggc41761aaggctgggt ttgagcccag ctctattgcc cccaaagataaggctccatt ccctgctcca41821tttcccaggc atagRgactt gtagggggct ggaaccccaggatcaactct gggctcagag41881ggccccagca ataagtgact gttgattact cctgatcccaaagctgactt caggcaagct41941ccttggaggt cgcagcccct tcttgctatg cccagtggcaatgatgttca taatcccact42001cctcagtgca gggttccact aagaacccat gatctcctacctcaaatgga cctcatgctt42061tctgagtaag cctccctcag ctttctggtc acctcactccccccacccac tgcaatgact42121tcttcaggcc ttccctgcca tcctcaaatc tccagctgccccctcctgtc taccttccac42181ttccctctcc acacacaacc tgcttaccag agagctgagcagagccacca acagaacttc42241ccccccacgt cgctgctccc agtcgcaacc cactcacccacacctgcgcc ttcctgcggc42301cgttctcctg ttctaacaga ggacRgtccc tcttcccttctgaactcagg ccgtccagcc42361ttccccggct ctgtgatgYc tctctccYtg cacatacacaactcacaata ttgggcaggc42421ccctgaccgg cYcttctccc ttagcccctt gtctgagtcctgttcctttg atgtcctatt42481tctagtcttt ccatttctct ctgtctctac ctcctccccaggctaccatt atctctagtg42541gggacccatc tgtagctccc ggtgggtctc cctgtgtcctgataccctcc aataatctgt42601tccccacagc agccagaaca atcttttcaa gaaataaaactggtcattca cctgcctgct42661taaagccggt gtaggataca ggctaaacgc tctcccatggcctccagggc cctgcatttt42721ctcatcctgt ctacttcttc atctagttgt ttcccacccagcgtaattgt aactgtttag42781ttgaaagttg acgaggtctt ttgtcagctc tagaaatttcttttcttttc tttctttttt42841ttttttttaa gacagagtct tgctctgtgg cccaggctggagtgcagtag cacaatctca42901actcactgca acctccacct tccgggttca agcaattctcctgcctcagt gctgaaatta42961caggtgtgag ccacagcacc cagcccatca gctctggaaatttcttcatc actctctctt43021ccatgattgc cccatcccta ttttctccat gcctacctcctggaatttcc atgagacaca43081cgttgggcca tctcattcca ttttccgtgt ctcttagttgctctgtcgtg ttttccatct43141cttttatctc tatcctaaat tctggatagt ttcttcaagtatctttttag ttcattaatt43201ctttttacag ctgtgtctta tttgtttact tacccactgagattttcatt ttattttatt43261taattaatta atttatttat ttttgagaca gagtctcgctcttgttcccc aggctggagt43321gcagtggcgc aatctcagct cactgcaacc tacgcctcctgtgttcaagc aattctcgtg43381cctcagcctc ccgattggct ggggttacag gggtgcaccactgtgcccag ctcatttttt43441tgtattttta gtagagacgg ggtttcacca tgttggccaggctggtcttg acctcctgac43501ctcaaatgat cctcctgcct cagcctccca aagtgccgggattacaggtg tgagctcccg43561caccccgccg gccctttctt tcttttgagc tgagctatgtatttaatgaa accttttctt43621gtgtatccag cRgttcagtg gtttcttggg gcatgtgatctccttgagcc cagtcccaca43681ggctgtaatc gaaggtcctc aggccacact ccccagccccgctggctgcc tgcgcattcc43741ttatcttggc catgttcctt ccacagggct cttgtccacactgtcccctc tgccagaatg43801gtttgccctc ccccatgcca cctgctcctc ctcctgccacctcagggaag gcctctccca43861cctccctgac taggtcaggt cccctcgtgc cacagcctRgtgtgtctctc ctttaaatac43921tcctcagctg cagttttacg ttctgttctg ggatgccctggaaaatgctg ggctcctgca43981gatatggccc gcagctcctg cgctctctgc tctatccccacccctagccc agctgctaca44041gcagcttccc tcggagggtt accatgcagt aggtcctgttctaagctctt tccacagatt44101atctcattcc atcctcagga caaccctatg aggtaggatctatgattatc cccattttac44161agatgaggaa agtgaggccc agaaggctaa gtgaaggcatcctcagcaca tcctgagaga44221ggagttcagg gtaggaatag cttcactagc acacagatgagaaactgagg ccYagagagg44281acaagagtcc taatttgcac agcctggggc ctgggcactaccccgagcta cttccttttc44341cccagccctg gggcccggag ccagctttgt ccttcccatctccgagggca tggactgctg44401ctgccctgat gggcccctgt cctggccatg ggacccctgtcttccacagg ttgtcggcRg44461cttccccagc caggcccaag tcaccgtcca ctgcctcaagatgcccaaga tctcctgcca44521aaacaaggga gtcgtggtca attcttcagt gatggtgaaattcctctttc cacgcccaga44581ccagcaacat tctgtagctt acacatttga agaggtgaggcgggtgcagg gagaggtggt44641ggtgggggaa cctgactcac atatgggccg cagagggcaggggcctgggg gtctctgaag44701cctccagatc cttctcacca cctctgctgg cactggttgtctcttgcaca tggctcctta44761caatcaaaat cacatcatgc aagtaacgag ggggtacacacgtggtttcc acagcttagg44821taatattttc tctcttttct tatttttatt ttttttagagacagggtctc actctgtcat44881ccaggctgga gtgcagcctc acactcatag ctcactgcagcctcgaatcc tgggctcgag44941tgatcctccc acctcagccc tcctgagtag ctgggaccacagacaaacac caccacacct45001ggctaattta aaaaaaaaaa tttccttaga ggcggggtcttgttatgttg tccaggctgt45061tctcaaactc ctggcctcaa gcaattctcc tgccttggcctcctaagttg ctggggttat45121aggcatgagc caccatgcca agcatatgtt ctttcattcttatttttatt tattatttat45181ttatttactt atttattttt ttgacacaga gtctcactgtgttgcccagg ctggagtgcg45241gtggcacaat ctcggctcac tacaacctct gcctcccaggttccagcgat tctcatgcct45301cagcctccca ggtagctggg attacaggca tgcgctaccacgcctgacta attttttgta45361tttttagtag agacagggtt tcgctatgtg ggcccagctggtctgagact cctggtttca45421agtgatctgc ccgcctcagc ctcccaaagt gctgggattacaggcatgag ccaccacgcc45481cagccaatat tctcctcctt aagctgagca gtggacaatggtgtttatta cccgagtcca45541caacccttta ttcattaggg ccacaagggt ttccaaattcagaacttctg tgaatttgta45601aaagtagtat agtgtataga cactggatat attgcagaacaccccaatag ggtgtggggt45661ggcaccccac aatcaattct cctcaaatgc ctcaattggcatttctcctc atatgaagca45721agataaatac catacatagc ttcctagaca atggccaggttttgccaaca aaacttaaga45781aaaaacttgt agttttcaga tcctgtttga ttttataattacaaataagg aattaagaat45841cagtattatc tttaatgctc cttagaatat cttcaatttttttttttgag acagagtctc45901actctgtcac ccaggctgga gtgcagtggt gcaatctcggctcactgcaa cctccacctt45961cctggttcaa gcgattcgcg tgcctcagcc tccccagtagctagctggca ctacaggcgc46021gtgccaccac gcccagctaa tttttagtag aggcggggtttcaccaggtt ggccaggcca46081gtttcaaagt cctgacctcc agtgatccac ctgcctcagcctccaaaagt gctgggatta46141caggcatgag ccactgtgct cggccaatat ttcttaatacattaagaact aaagacaaga46201gcgatacaat cacattgtgg aaaatataga aaaatagaaagaagaaaacc actgtcacca46261taaccccctt ctccaggggc cttcgatgtg gtgactgggtgcatttcctt ctggtgcttt46321gttattttta aataaatttt ttatcttgga gtaactttatatttgaataa aagttgcaaa46381atacagagtg ttcccatata tcccccaccc acttcccgctttgtccacat cttacataac46441catgctacag tgtcatagcg gagagattaa cattggtgcatgactgttaa ccaaactcta46501aactttattt gaatctcccc agtttttcca ctgatgataccctttttctt ttccaagatc46561tgatccagga tagcacattg tatttagccg ttcttttttgttgttgtttg tttgtttgtt46621tgtctgtttg tttctgccca ggctggagtg cagcggtgatcctcccacct cagcttctcg46681actagagatg tgcactacca cgtatttttt tgtagagacagggttttgcc acattgccca46741agctggtctc aaatccctgg gctcaagtga tcctcccaccttggcctccc aaagtgttgg46801gattataggc atgagccact gtgcccagtt tatttagccttttaaatatc tctttaattt46861ttgtattact ttccttttca tttttctgtt ttattccttttggctttctc atgtggatgt46921agacatatta ttttatttac ttattttttt gttgttaagaatctgaaaca ttgagcattt46981gttaaaaaaa agaattattc sgccgggcac ggtggctcacgcctgtaatc ccagcacttt47041gagaggctga ggtgggtgga tcacatggtc aggagttcaagaccagcctg gccaatatga47101tgaaacccca tctctactaa aaatacaaaa attagccggacatggtggca catgcctgta47161gtcctagcta cttgggaggc tgaggtagga caatcgcttgaacctgggac gtggaggttg47221cagtgagctg agatcgtgcc actgccctcc agcctgggcaacagagtgag actgtctcaa47281aaacaaaaaa agaaaagaaa agaaaaagaa agtgacttctcaggtcctaa ccccaaagcc47341acaggtgctg gggaactttc ctcggttttc agaagagcagtagctaagcc tggttcccgt47401gtcatccttg cctctccagt ccctcagtgg aaagaatcaggggccctgag ctaggagggt47461tgctctctgc ttcgggaaga gccctggctc acagcaaatttggtttctct ccccaggata47521tcgtgactac cgtccagScc tcctattcta agaaaaagctcttcttaagc ctcttggatt47581tccagtatgt gctgcagaga agagaggggg cggtcaactccgcaaacctc tccctggccc47641cttggagtca ggcacagggc ggggtgttgg tggggaaatgtggccccttt cYtctggggc47701atatgggctg actgcaggga gataagaccc tgcctagatagaatcttcgt ggggaagaag47761gggctccagg aagaatggag ggctgccagg aagaagggcctggcaggagg agagcgctgc47821ccgagcaaag gcctggccgc cagaatagca aatctcaagggaatagcaaa tctcaagaga47881gtgccccaaa gggcctgagc tatgagacag aagcactggctgctattctt agagtttctt47941tcccagggga tgttacagga gggggcccaa tggagggtcaaattatcatc gcttttttat48001ttcaggatta caccaaagac tgtttccaac ttgactgaggtaggtagtct tggatagact48061gggggaaata agtcctgtgg gacctcctgc cttaaagaaagcaggcggag ggccctaaag48121gaaatcaggc aaccagacca aaagaatgtg gaccaggtggtccatgctgt gtctcttgtg48181acccttcttc tccctgccat gtcttttggg agagcccttgtgttgcaaaa atgagagtgt48241ggtggtatgg attggggttt aggcagaaca gtactggccaagcagcgcct ccctggacct48301caattttccc tctgtggaat gggctagcaa tcctgggcctccccagggcg aaggaaagac48361cactcaggaa gggcaccgtc tggggcagga aaacggagtgggttggatgt atttttttca48421cggatgggca tgaggatgaa tgcttgtcca ggccgtgcagcatctgcctt gtgggtcact48481tctgtgctcc agggaggact caccatgggc atttgattggcagagcagct ccgagtccRt48541ccagagcttc ctgcagtcaa tgatcaccgc tgtgggcatccctgaggtca tgtctcgtaa48601gtgtgggctg gaggggaaac tgggtgccga ggctgacagagcttcccatt tcaccttgtg48661ggcccttccc aggcagagct tcaggtgccc ctcttcccagtcattgatac ttagcggtcc48721tggccccctt tcctctccct gctggtggYa ttgcacgccaatgactcggc cagatgccca48781gacccctgtt cttggtttac ctgcagaata ttatctttgccaccccgcgg gatggctcaa48841cccactttca ggatgcaggt ctcctaatag caacctgatatagcagaaag acccctgggc48901tgggagtctg agacctagtt ctagcccagc cctgaacctcagtttccctt tctgtgaaac48961aagaatgttg aacttgatga ttcccaattt tccttttgaccttgaaatgg tagaatattt49021atccctttga ggtgactcgg atggtagact ctcagacaccatagcacacg tgtgctgggg49081gtattttgga ccaggctctg ctgagagctt tctgctcccttccccacaga gtatgttgag49141ctgactgtgc tttccttttg aacatctgct tgtccacatggcttaggtag gagaggaagg49201gcgtggaaac tggaatgatc ctagtggggt gtcttggcatctcttggcct cattttcccc49261atctgaacca tgaagctaaa actaggggat gtggattaaatggttcctac aactacttgc49321aaggagacca ctctgtgtgg ttgcaaagaa cactttgagaagctgtgtgg gaaagtttcc49381ttcctagcag ggtagactca gctaactgca ggtcatgtggccattgtgga tgggttggga49441gctcaagttt ggggcagaag ggaatttttt ttggcagcagagtggcaagc cctgccgcca49501ggcaaactct gctcttcctc atcctcagaa gcacttgctcactctgctaa atcaaagtga49561aacgcatgtt tacagaatat tggtccaaaa gggtctcagcatctcccact acccagggtg49621gcagagcctc gggccggcct tgctccccaa gaagggctgactggggctct gtcccctgcc49681ccagggctcg aggtagtgtt tacagccctc atgaacagcaaaggcgtgag cctcttcgac49741atcatcaacc ctgagattat cactcgagat gtgagtacaaagcccccctc accagcccct49801gttcctgggg agagaggccc agacaggatt cctggggtgactgggggctg ttggggagac49861agacagaggg gcctctacca gcttggctcc ctcctggtggcctgggagtc agcccagctc49921Rcccctctct cctactgccc ctcccttcag ggcttcctgctgctgcagat ggactttggc49981ttccctgagc acctgctggt ggatttcctc cagagcttgagctagaagtc tccaaggagg50041tcgggatggg gcttgtagca gaaggcaagc accaggctcacagctggaac cctggtgtct50101cctccagcRt ggtggaagtt gggttaggag tacggagatggagattggct cccaactcct50161ccctatccta aaggcccact ggcattaaag tgctgtatccaagagctgSg gagtccttct50221tctgtggctg gcgggtagag ggRgggggaa gggattgtctcaccagtgcc gtccacctct50281tttcagccct tccaaggcag ctgcccccaa accctccaagcttcatgatg actggaggaa50341gaaatccaaa cttctctcct tgggactcac gatcctccctgatcaggtcc ctggatacct50401tccaaattta tcccctttaa cccagcactc tccttgtctgaccagcttcc tgcaggagct50461gtcacacact ctctgtccct tggggttcca gtgctggacagaaagtgagg gaggaccagg50521gcttcagatc ctgaggatgg tgggagggga aggggccctcagaggtctgg tttctggtag50581aaatggagga agacagagcc tttaaaaagg caaacgactttattccagaa gataaactgc50641tcacgagcct gagcttattt ccagctcacc tttttttttttttttttttt tgagacggag50701tctctctgtg acccaggctg gcatgcagtg gcacaatcccagctcactgc aacctccact50761tcccaggttc aagcaattct cctgcctcag cctctcaagtatttaggatt acaggcaccc50821gccaccacac ctagctagtt tttgtatttt tagtagagacggggtttcac catgttggcc50881aggctggtct cgaactcctg acctgcagtg atccacctgcctcaaccccc caaagtgctc50941atgttaaata tggtgaaccc caagtttttc ttcaaagaatcagtatgtct gtatgttcag51001ctctcttatt ctttgattct ccattttaaa gtttaacttcctggttctct tcgccccctt51061gcttctaatt tcagtaaaca accttttcca tcagttttattcagtagttc acacctgttc51121ccctggtcac ttgctccatc ctgactcatc ccagtcacctgctttgacct gagtcacccc51181tggtcacctg ctctgatgta agtcaccttt agttacccgttcctaactgt ccttcctgcc51241aaactactca cctcgccact ctggctcata cctctgctctctttaaaata gccaatcgga51301attagattag accgtgcggt ccaaccttag ccaacaggggaacaacatag cagcagggat51361tacctgggtc aggaataaga accccttccc ctcccttgttcaactgtgct ctcaccattg51421ttccatctat gaggagcacc ctttctacag aaactaaaaattgcttgctg agaaaattaa51481atttatgttt gagtgctatt tctttgcagc agtggagaacaagcattcct aacactggga51541ttgcaggcat aagccaccgt gcccagcttc cagctcaccttcttatgctc aaattgtgtc51601ttctccttcc caccctcaag ctacaataca aaaagtttcttccaaccctc tcagtcttgg51661aaggtagcag gctctatttt ctctgggtgt gtaaagaaaatgcctctccc acattagcca51721attgagacgg gaggaagcgc agcaagatgc tggctagtgcaaggtccctg gggtagaaag51781aatcatgatg gattcaagaa cagtcaagag ggctggtgtggccctgaaag caaagaacta51841ggggcgagag atgaggccca accagcaggc agggtcacataacaaaggtg ataaaagggc51901ttggccttta tttcagcagc caggagagac agccaggaggctggggctgt ggggagctca51961gaagtaagat gccccttcca gtctgggaat atgtgaggggagggcaccat cttctgagcc52021aggtttcttc ccagcccttc cctgcccttc caagtgctttctgaggcctg tttctcttcc52081tcccctgggg cctaatgcaa gtgtctgact cactaagcaggagcatcatg ggcgggatgg52141gcggctctta aagggccctg gcagaaggag tcagtgtgatctcgccagtc cctgagtcca52201acgtgggaat tctgggtctt gggatattgg cctttgaggtggtgacacca gttaggagcc52261acatcccacc caagaatgtc cccttgaaga ggctgggaaggcccaaggcc cccaccttga52321tgctacaatg acagaatcag gataacttgg cagccctaaggcagctcttc cttgaatgga52381aacttttatc tgcatgaggg gcagacagag aagtcacttggagtcttaac ccttgtagac52441cccagcctga ctgggactcc agaaggtccc agggctctgctccagaaaga agggtagggg52501catgccccca gcttccttca gtgaccttgg agaggtctccccagggctga gctgggaggc52561acttccatgt cactgtctca tccaaggagt gcgattagcaggagatatgg agtccagagg52621gtgagaggct taccaaaatg ggactgacct cYgagcccctctcccaaatt ccagcccctc52681catccaagcc tagaagctct gacctagtcc tattgaagtcctcctggcct gggtgtgtgt52741tggggggaat cctggctcca acccagttag gatcatttccataaagaagg ccacacctgc52801tgcttcctct ggggaaaaac aagtgctccc caaggccagcaccaggcaga agcacatcct52861gccacctggg ctgctgacct tgggcaggat ggggcccgggtgtttggcaa ataggaaggg52921tagagggaag gcctggcttt cagacctggg tctaatcccagctcccccca accccagtta52981ctaattctgc catcctgggg cccctctgtg cctccatttcctcttctatt caatgggatg53041ataatacttt ccatgtagga ttctggcaag ggctgggttagcccagagga ggagcccatg53101gtggccaaga gcaggggctg cagagctggc ctgcctgggtccacccttct gctcctctgc53161ttctgtgtga tcttggccaa attatttagc ctctctgtgcctcccttttc tcatctgtaa53221aaagaaagat aacagttgcc atgaagagta aaggagaggccgggcatggt ggctcagacc53281tgtaattcca gcactttggg aggctgaggc aggggtatctcaggagttca agaccagcct53341ggccaacatg gtgacccccc ccatctctac taaaaatacaaaaaaattag ctgaatatgg53401tggtgtacac ctgtagtccc agctactctg gaggctgtggcaggagaact gcttgaacct53461gggaagtgga ggttgcagtg agctgatatt gtgccactgcactgcagcct gggcgacaga53521gtgagactgt cttaaaaaca aacaaacaaa aagattaaaggagagagcgg ctgcattttg53581ggaggccaag gcgggctgat tgcctgagct caggagttggagaccagcct gggcaacatg53641gtgaaacccg gtctctacta aaatatgttt ttaaaaaaaattagctgggc atgcacctgt53701agtcccagct actcgggagg ctgaggcagg agaattgcttgaaccggaga ggtggaggtt53761gcagtgagct gagatcatgc caatgcactc cagcgtgggtgacagagcaa gactccatct53821caaaaaaaag gagagagcac agtgtctggt atatcctaagtgctccacga gtgccagaca53881ttggttatac ttcatggagg tgaggtacac agaggtgtctaggtcatgcg gactcactcc53941atcctccagt taaccatgac tccctcccca cccacctcctgagttctctc tgctgtcaaa54001ctttcctctc atatctccag tttcccaccc aaaagtccaaacactcaaga ttccttctca54061tctccaaccc ataaaatctg atcggcttct ccacactcaagtgtaaatga ctgatggcca54121tttgattgac actggagggg ctggcacatt tttagcacatttttagccaa aggtatgatg54181tgctgatagc ggactctcag gccacaagcc agtctgaggacagggaaagt ttgaggaggt54241cactcttcca gaaccctttg gtgataacct ttctggcaggcctggtaccc ccagagtgaa54301aagggctcca gggtcaagac ccagctctgc ccctcattgctgtgtgacct tcagcaactc54361acttgattta tctggacctc agcttcttca tctgtctaatgggataataa tctttgtcct54421gccctcctca cagggctgtt cagaattaaa tgcatctgaaaatgatctgc atttgtgtct54481tggactgtgg ttatttgttc aagtgtctgt ctaccctgcctgcacaggga gcgggtcagg54541gtcttccctg ggacttcatg cacaggtctt tcctgggacttcatgtagga ccagccatcc54601cgtcagtgct cagtgaacat gagctgcttc cctgtgggatgtctgggagg tgagtggaag54661gccttcctag caggcacata ctggaacata atcaatccctcccatgcata cagctcacac54721ccacattctt atccattccc accatgcccc tcagtggcctggggagacta ggaatacccc54781acttgacaga taaggaagct gaggccaggg gaggtcaaggcatttgtctg aggttgcaca54841accaggagtg gtgaagctgg gagtcacaca caaggaatcactgcaaagtc tgtgtccttc54901ccactctgag taggacttga accagggatg tccgatgctgatgcttgtgt cctgaccact54961accttgcagc gtcctcaccc acacccaccc caggcctgggaggcagggga gcaccagcgg55021tctgggagtg aaagttgctt ccctgtggga tgtctgggaggtgggtagaa ggccttccta55081gcaggcacag ctgcccaccg gatgagtatg tccagggggagaggagcccc ctgtcccagg55141atgtgggcaa aaacctggag aagctgaagc tggactttgaggatggcccc tgacYccatc55201ctgggacagc cacctcccct tccttctgcc ccctccagtccctcctctcc ttccctgctc55261tccctcctac ctctttccat ctcccccttt ctgcctgtgattcctcctgt gactggggca55321agatccttca cctctgtcct ccctgagcct cagtggctcacctggaacat agggtgatgc55381ctgcagaagt attttagggt tactttatga gataaattggtagactgttt ttcccgggtc55441agccagccag gggttcggtg aataggagcg aacgctgctgccattccctt ctcccctagt55501tcatcctgga ggctctccgc tctccccctg gttctaagtcccctcctcct gcaccgtatc55561ccccctccca tccaacccag tccccactga ggcactgagacagggtcttg gcccagggtc55621cccacccacc tgagctccgc atgtgagccg accttcacccgcctgcctca gtttcccgtc55681cacgaaaggg gtgagcgccc ccacgtctcc tgggactgtccttgggtccg atgcggggat55741gtggggaggt gccagggtgt gggcgcagca gggagcgggtgtgttaggcc cccgcccatc55801ccgcgcccga gccccatctg gctcgggctg gcacctcgaatccacgtgat ttctcggcag55861cagccgccag ttccatgcac tggcggagca gctctaggcggcggcttcta ctttcagttt55921cgtgcagagc gcggaggagc cgcgagcgct gagggtgagtgccgggagct ctgagggtga55981gtgccgggcg tgccgcgggg ctgcgggacc cgggctggggcgagcggaag ggagaggatc56041ggggttcgaa ttctgcacgg agaggggtgg aggggatgtcagaggccctg gagcgggagg56101tgcgggtggc cgggtggctg gccgatggat agctgggtaagcggacaggg cgccagtggc56161ccggcagcgc gcacagcatg cgccccggca gtttggaggaagagttgccg gcccgcagag56221gatggcagat gagggtcgcc tggatggggg gacacagtaagcggctgtgc tcccctccct56281gcgcagctcc tgtcacctac cggatccacc cactctctctgtcttttact ttgcaacttt56341tcattgattt taaaacaatt acggaagtta cactgttcattgtaYgcaat ttagactttt56401tggcctaaac aactttttat tgtggaaaat tccaaacatatacaatagta gaaggaatag56461aattaggttg agccttctgc acctgcgggt tttcatataatgaagcccca cctatccacg56521ttcagcttgg acagtcacga ccccaaggcc acctactcacgaccccaagg ccacctaggt56581agcccaatct ccaccgctgg ttattttgaa acaaatggcagacagcatag catctcaact56641gaggtatttc agaatgtact aaaagataag gcatcttttaaaaacaaaac cacagtacca56701ccagcatact acaaacattt taatagttat tccttaatgtcaaatctcca gattatttct56761aaggaacatt taacctcata agtgataggt gaatacgtgggtgttgtttt gttacttgct56821ttctgcattc ccatgtggtt ttcggtcact attctcacccagaaagccag gacctgaaac56881tggctggggt gatcattcga ggaggtcgga agaggctcctaccttcagtg ccgtttgcgt56941ccattttata agttggagtt cttatgtttc cttttttaaaaggttgaagt ttctgcagac57001ctaaaaagca gtttgaaaac tggcagttcc cagcctctaaaacccggggg tagcaggagg57061cagagagtac cccggggcca gatcctggag cctcattgtcccttcaaaYc accttccgtt57121tctctaaggg agaaataaac cttgaaaagc catgggcttttcagatgtat ctagatgtat57181ctgatgcttt tcaggtgtat ctagactccc atccagcgtgctttctgcaa aacttactga57241accatagccc agaatggcca tccatgatgc ccacccgccttgtctcctga agcacattgc57301caggtggacc tgcacatggt gtggacggca gacagactggggctctcaac aactggtatt57361tgctggatga ccatgaacta accattcaat ttctcgaaactttggtttct cgtctgtaaa57421atgaacatat gcaaatctat cctacaaagt gtgttttgtggattgaatga gatgatacac57481gcccacccag tgccttgatc aaccttaaaa tgctgcacaagtgtgagggg agatggatcc57541ttgaagaaga cagacaagca gaggggaaag atcttggaagagtttcacaa tatgctgaac57601tttattcctg gatcagaYac agagctgtcc gggtgtccacagggccgggt cagcctcctc57661agaccccaac acacataccc tcttcccctc tgaggaaaattcagcaaaac ttcttttgct57721gttgttgttc tttattcctt tttttttttt ttttttttttgacgaagtct cactctgttg57781ctcaggctgg agtgtagtgg cacgatcttg gctcactgcaacctccatct cctgggttca57841agcgattctc ctgcctcagc ctcccgagta gctgggattataggcgcccg ccgctacacc57901cagctaattt ttgtattttt agtagagatg gggtttcactatgttcgcca ggctggtgtc57961aaactcccaa cctcagatga tccacccgcc tcggcctcctgtgggattat aggcgtgagc58021catcttgccc ggactccttt tttttttttt ttttttttttaatagacatg aggtctcaaa58081ctcctggcct caagtgatca gtctgcctct gcctcccaaagtgttgagat tatgggcgtg58141agccaccaca cccagccata acttcttagc atgacttttcccatttgtta tgagttcaat58201tgtgcctccc cacaaaagat atgctgaagg cctaaccctcggcgcctcct aacgtgacct58261tatttggaaa tagggctgtt gcagatataa ctggtgaagatgaggtcata ctggagtagg58321atgggccttg aatccaatag gaccggtgtc cttataagagaggagatgga cacatgaaga58381cagagacata cggggatcag acaatcatgg acggaggaggaagagagtgc ggcgatgcat58441ctaggagcca caggacacct agaatggcca gcagccggtgggaaccagga gaggcaagga58501cggatcctct cctccagcct tcagagggag cccggccctgaccacacctc gatctcagac58561tctgacctcc agaactgcga gagaagaaat ctcagttgttttaatgtacg cagcttgtgg58621cactttgtga cagcagatac agcagtactg tgacaacactaggaaacgaa tacaccatcc58681cagcatctct gctctgtttt ccatacagaa ttgaactaaggaccaggcaa gctaatgcaa58741Rtccaaacac tgtaaaaact ttggaggcaa tctaaggatgtgagccagat ttgtttgcca58801gatctttttt attttattta tttatttatt ttattttatttttttttttt agtgagaggg58861agtctcactc tgttgcctag gctggagtgc agtgatatgatctcggctca cagcaacctc58921cacctcccag gtttaagtga ttctcctgcc tcagcttcctgagtagctgg gattataggc58981acctgccccc atgcccagct agtttttgta tttttagtacagacaggatt tcaccatgtt59041ggccaggctg gtcttgaact cctgacctca ggtgatccacctgccttggc ctcccaaaat59101gctaggatta caggcatgag ccaccaacac ccagcccatatattcatatt tttaatggac59161ttatacatga aaatggtatc tcacttttaa aaataaatgatatggaatta tgcgttaaag59221gRaaattaaa tcttattata tcatgtttta aaatttttaatttttcatag ctaatacatt59281tatgtagttt taaaaatgta aaacatttgg aaagatataatgaaaaataa gtctccttcc59341atctcctgtc tcccagccac ccaattgccc tccccgaagacaaccaatgt tatcaggttc59401ttgtgtctcc ttccaaagac agtctaagtg tgtttttacaaacatggata tatacatata59461tatatacacg tatatatgtg tatatatata tacacacacacacacacaca catatacaca59521tatatagaca cacacacaca tgtgtacttt tcccttctcacaaatggcag tgtactatat59581gtagtgttct ctaacttggg tttttttttt ttaaacttagtgcaatttgg aaatctttct59641acatcaaaat tttaaaatct gccctttccc tctttctttttaacagctgc ctagtatttc59701accgtatgac tgctctgtaa ttgatctaac agttgtagaacacttaggtt atttcctgtc59761ttttgctatt tcaacagtgc tgtaatgaat atccttggtcaggcatcatt tttcatacgt59821gggagtgaat ctttaagaaa accaggagtg gatttgcaaggtcaagggga atatgcagtt59881tgaacttgga taaataaggc aaattatccc cccttaaatgttgtactaat ttttgctccc59941accagctgga gggggagggg ccaaatttcc atatttgcaaatctgggaga cgaacaatgg60001tgtgtttttt atgcctctta ttacgaatga gtttgaacatcttttcaaat atttaagagt60061cacctgtagc tcattttcca taaactgtca gttcatatcctttgcccact tttttattgg60121cttttggtct ttttcctgtt gagttgtaaa agcacttttcatgttaaggg aatttgctct60181ttgtctatta tatggttata ctgtcattta aaatggtggcatagttgctt atagaatgtc60241tgaaccatat gcgtcattgt tagatattta tattgggtctcattttcttg tattatatat60301gggatgtttt ccctgttttt tgtaaaaaaa aaaaaaaaagcaagatatga cattttaatt60361cttccaatag ttctcaccat aatggtgaag gaaaggaaatacgtttggga aaatacttcg60421ataggatttg gggtggctgg aacctgtgtg caaaatggccaacagggacc aggaccattt60481tgggtgggaa gagagtgctt tgcatggtgt atgtgtatggggcggagggg ctgtatttgc60541tcctgaaaga aaagggggtg gagggagggg agaagaaaggaaggagagaa ggtggaggga60601ggttagccac agagggagat gactcccaga aacttcttaggggaaggatg gcaaaagggc60661attttcggtg agtccaggaa tgccctctgc tccgtgtgaggcaggtacca gcactgcaga60721caccggctct ggctcaccac ctgccatcat gagtgcattcagcttctcca Ytgagcttcc60781acacaccagg ccctgctcta ggcactgggc tacagccgggaacacaacca actccctgcc60841ttgtggagct gatgaggcag tagaaacaga caaacaagtaaacaaagatg tgcatgtcat60901atgaggtcag gtggaagtga ctgcagtgaa gaaggcaaggcaggcgaggg tggagcatgc60961tRgatagaga ggcagatgta gccttcttgt agggatgttgggacatttga gagagaactt61021gaagggagcg tggcagggaa ccatgggcca tggcatctggaggaagaggg aaccagtcag61081aggggatggc aagaaacaaa aaagtgggga gaagaagaaagcagagaaga ggagaggagg61141gagaagagga gaaaatgctg cttaaagtct gcttttgtgctcccagatgc tcattgtgaa61201tgacattttt gcaatttttg caattttgtt ttgtaatttaataatgggct gggctgggcg61261cagtggctca cgcctgtaat tccagcactt tgggaggctgagatgggcag atcacttgag61321gtctgcagtt tgagaccagc ctggccaaca tggagaagccccgtctctcc taaaaataca61381aaaatagcca ggtgtggtgg cacgtgactg taatctcagctactctggag gctgaggcag61441gagaatcgct tgaacctgag aggtggaggt tgtagtgagttgagatcgtg ccatgctctc61501cagcctgagt tacagaggga gactcggtct caaaaaaagcaacaaactgc ttgaattaaa61561gcaggagccc tcagctagag gagtgcccac ccacctcctccccaggaatc gcagagctcc61621caggagaggc catagcctcc tataggtcat ggcattgcaggtgggttggt gtcccagctg61681gctgtttctg tctcaagaaa ggaagggctg ctcccgctgacatccaggcg taagcaacgc61741cctggtgaac atcctcgtag ctagagcttt gctcacattctggatggctt ccttaggctc61801aatcctcaaa gtggactcct aaagggatat atgaacttttattttttaaa tgtttgaaac61861cgtgttgtca aatttctctc ctaaaagatt gtgccaatgtagagaggctg ccgaccgctg61921gaagcttccc aatcccccag cacctatccc ttgtgggtgggatggatcct gtaccatcgc61981cagaccctca agaacccctt gtcctgcaYg gtcccttctgtccctcctgg tgaaatggaa62041ggagcatgca tgccttggga agctggtgct ttgaggcattcagatcttac cgtggcatca62101tgtttgaaga gagaaatagc ttgctgtttt gtgtgtctctcaatagtctt attcactgag62161ttcttgaagg tgtcctgtgt gtttctggac tgcagaatccttttattgaa atggacaggt62221cagtgttttc ccagagaaag acctatccag taggagttcacaagaggatt ttaggaggta62281tgtggagagg gcatccgatt ccattgaatc gtaaagtgacaaatttgttc ccttttcagt62341tctttttcat tcttccagac tagtgaaaga gaaagcctcagtcaggtgct aacgcatctg62401taaacctctc acactcttga tattttcagc aaggggaggccaggcctccg gtcagagccc62461tgggtctgca gcaataccca gctacagttc aacagcatcatagtgttttt tgttttcctt62521ggctttcttt ctttcttttt ttttctagac aaggtctcactctgtcaccc aggctggagt62581gcactggttg cacagctccg tgcatagttt cctgcagcctctatttccca ggctcaatcg62641atcctcctgc ctcagcctcc caagtagatg ggactacaggtgcgcaccac cacacctggc62701taattgtttt ttgtttttat ttttgataga gacgaggtctcattacgttg cccaggctga62761tctcaaactc ctgagctcaa gcagttttcc tgccttagcctcccaaagtg ctgggattac62821aggtgtgagc ctccatgccc cacccttgag tttcttttcgatgatacctt cagttcgtgg62881caagtggtac ttcaaaaaat aaagttaaaa gtgacatggtttctagaaaa gctttaagga62941aatggtgttc tggctttcag ataagtcaaa aaaaatctcaaacatgagta aagagttttg63001gaaattatac acttacccct agagggtgag tttgtgggggaaatttcata atgtatactt63061ccagaatatt tagaactttc caaatgagta caggttatgttcgtaaacag gaaaaataat63121aaagacataa taaaatgata atttagtttt aaaagacgaccatttgttga aagcagtatt63181atatttcagt taggaaatgg cctctggaat cagcatagattttattgttt tatttatttt63241gtttttgaga cagtgtctca ctctgttgcc cacactggagtgcagtagtg tgatcacagc63301ccactgcagc ctcaacttcc tgggctcagg tgatccttctgcctcagcct cccaaatagc63361tgggactata ggtgcacacc actatgccag gctaatttttttgcattttt tgtaaagaca63421gattttcacc atgttgccct ggctggtctc gaacttccaggttcaagcaa tctgcctgtc63481tcggcctccc aaagtgttgg aattacaggt gtgagccactgtgcccggcc agcatagatt63541ttaaatccac cttttgttgc ttgacttctt ggagcctgtttcttcatcta tgaaatgcag63601gaaacgtgcc tggaaatatt gcttgagatt ctaatggggaggtgcaggtg gaatactgta63661gcctgatgcc cagcctatgc cgggaactca gtacataacagccaatgagc attggctgcg63721gactggacat gtcccctcct tgtgctgtag tattaatgtctccaaccctc acagtgatcc63781tgtgaagtaa atgtaaaatc accacccaga tgaggaaaacagtggcacag agaggttaag63841aaaactgtcc aaggttgcac agcactaaaa tgttgaaatcaggatttaaa cccagccctc63901ctgaccccag aggatctttt ttcaaaaatt atgttcttttattttatttc gagatggggg63961tctttcacag tcacccaggc tggagtgcag tcacaatatcacggcttact gcgcctcaac64021ctcccaggct caagtgatcc tcccacctct gtcccccaacccccagttgc ttaggagcac64081aggcacacga caccatgcct ggctaatttt tgtactttttgtagagatgg ggtttctcca64141tgttgcccag gctggtctca aactactggg ctcaagcgatcctcctgctt cagcctccca64201aagtactggg atcacaggtg tgagccacta tgcccagcattagaggctct tttaacagct64261ccacaattcc ctgtgagatg ggctgcatac aaagcattactcctgcttga catatacaca64321aaccatggcc caaagggagc tgggacttgt ccggatgtcagcctctaagt cagttttggg64381tcagtgagac ccaaaaccaa ggctctagcc gtctagcccctccaaccttt cttctgcccc64441agttttatgg gtttggcaat gtctgccagg atgggagggagcagttcaga tgatccagtc64501tggaggcaaa attctgctaa attcaaaggg cccagcctcaagtcactgat gtcttttttt64561tttttttttt actttaaaaa aatgtattMa ttctaaaccacacaagtaag acacgaatca64621gtcttccttg cagaaagtta aactttttat acataaagctgatatctatt ttactcactg64681cttccagccc catgcctytc ccctctcctg cagtaacccctatttgatat gtttccagaa64741ctttatctaa accttcacat aataaaaata attcttatatagggcttact aacttccaag64801cactgcttta agagctttac atatttaagc cccacaataactctgtgagg taggtgctgc64861tcttatcccc attttacaga tgagaacatt gaggcccagagaggctatgt aactggcctg64921gcgtcaccca gcctgcagtt ggtggaaagg tcagtcccaaatctaggcag ccttgctccg64981aaattcatgc tcttagcctc taagttataa aacatgctattatcgacctg tgggaagaaa65041cagtattgct gtttgttgat gtgtattttg agacaagtgatatcatgttg tgcatatcat65101tatacaatgt gtcttgttta ttccatgata catcttgaagatacagccac gtcaacaaaa65161aataagtccc tttcctgtac ataatcccac agcgtggttacaccaaactt tattatggct65221gtctagggtg tttaaagacc gctgctggaa tttctttatccaagactctg tgtgtcttag65281cccattgggg ctgctgtaac aaagtgccag agactggctggattctaaac aatagaaatt65341tatttctcac agttctggag actaaagtct gagatcagagtgccagcatg gtcgggttct65401ggcaagagcc cttttccggg ttgccgatgg cggacttttcattgtatcct cacatggtgc65461aaagcaggct agagcattct cttgggtctc ttttataagggcatcaatcc cattcactac65521ggctcctccc tcctgaccta attacctccc ccagaccccagctcctaata ccctcctatt65581aggggttaga gtttcaacat gtgaatttca ggggagcacaaatattcagt cgatcacatt65641gtgtattctg ggccccaagg ctgtccattt tgctttctgctgagaagttt agtggtaagg65701tcaaagggta gaagcgcagt aagatctaga agtcactgctgatttgccct acaagatggg65761caaaccactt cccagcctgc agctctgagc cctggatccaggccttctct cctttatgtc65821tcgagcttac tctgtcccct gccttactta ccaaaccaaagcaagactcc tctgggacat65881tcctgccagg ccccatggca aggttggagc tgaggaggggacttccaaac cttggtttta65941ttttcacttt ggcttgggtg tgccaagccc tggcagagccacagagttgg ggcacgaggt66001gccaagaaac agctcccagt ctgaggaagg tgctctgccctgggaagggg ataRagctga66061gtgttggtta tggggagaca tcctcaaggt ctccatctaaatatggtcaa cttggtggcc66121ttcctgtccc cagggccttt ggRgctctca gaggacaagaatcactcagc tctgatttgc66181tggagaagca gagccccagg tgggaggtag cgaggagcctgtctctcccc actgggagtg66241gagagctggg tgccacagcc tcaaacagtt gttcccagacatcggcacat ggggaacccc66301ccgggagctt ccaaaagtgc cagtgcctgc gttctacctcctgggatggt gctgtgatgg66361gtctggagtg tggcccattg ggatttttta aagaccctcttcccaggtga tgccgtcgtg66421cagacaagca tgggaaccac tggcctggaa gccccagggagaggcctctg gggcccggga66481cacgcaagcg ggagccttct cctagcagcc ttgctagccacccacccctt cctgtgggtg66541ctagacccaa actgccaggg ctgagcagga gaagcaaggccaccagctgg ccacctgctg66601tcccagccag gctcaggctg gcagtagggc accccagtcctggaggaggg tgcatctgga66661aagcttgggg gctcttggtg gaaagttcaa gcctttagcataggaaggtg gctggggtga66721aggaggcagt ttaaagacta gtgatgtggg ctgggacccagattgctggg tttccaatga66781ccagaagaag atggccttgt tggactgggg acagggaccacccaggctca ggcctgaggc66841tgggagtgca ggcatgaatt tgagtgcagg ctcaggaacatccccagggc cgccaggcag66901ggagacacct cttcaactcc tggctcctcg actctagctggtgacctagg caggtccctt66961tcccactgtg agcctcaatt tcctcatgtg taaagcatcatgactgtgtg ttttaagtcc67021tttagggccc tatctttgtg agggacaaca gagacgatggttttcacagg caacagtcac67081ccctgcatca tcactgactc acagaaatgg atatgccctataaggacatc tcttgcttgc67141cctgccagca tttgtgggcg ggggaggaaa tggccactaaccattcctga aggcacctcc67201caagggaccc ctgaaaggag ggtgacgcct cccagaaagagaccagtggc ccagcccagc67261cctgctctta gttttgtttc ctctgctttg aatgccagcaaggcctttcc ctcccagggc67321ctcagtttcc ccatctttac aatgggcaca gcatagaccccatcactggg gctctttctg67381ctctgccacc ctgtgcatcc aggctcaggt gttatccgaagccctgacat catcagccat67441tcccgggggg aaggcagagg cgctgggttc tctgtgtccccctggtaggg cttggtgtag67501gattcaggga ggattggagg gcctctgtgg cctcaggtcctcccccaggg tccccaggcc67561ctgacctgtc cacctggacc taaagaacca acaacagcagcactttctgt ttctttgagg67621tatttctgtc caaatgtctg tagtcatgac tggggtgcctggctatcacc ccacaaactg67681catcctttct gatctgcaca gatgagaaaa ctgaggtcttgtttcccctc catcccaaga67741cctaatggga cctcctcctt aatctaatcc tcaagaggcagaaacaggat ggaaagcaaa67801ggaatggcag ccagaagtct gYggctccac tcctgtcctctctgcatccc tcacttcctt67861ccttacacca ggcgtcaggg gctggagaga cggaagaagcgatagcaacg acaaccacac67921tagtggtaat catagcttgt gtggattgaa ccttttttttatttttcatt tttaattttt67981gtgggtacat agtaggtgta tatatttatg ggttacatgagatgttttga tataggcgtc68041cagtgtgtaa tcacatcagg gtaaatgggg tttccatcacctcaagcatt tatcctttgt68101gttgcaaaca attcaattat actttttgtt atttttaaatgtacagttaa attattactg68161actatagtta ccctcttgtg ctattgaata ctaggttttattcattctaa ctattttttg68221tacccactaa ccatccccac ctcccccacc ctggcctcctactatacttc ccatcctctg68281gtaaccatcc ttctactctc tatctccatg acttaaattgttttgatttt tagatcccac68341aaataagtga gaacaagtga tgtgtgtctt tctgtacctggcttatttca cttaacataa68401tggcctccag tgccatccat gtccttgcaa atgatgggatctcattcttt ttgatggctg68461aatagtactc cattttgtat gtgtgccaca ttttcttttactcttttatt cttttctttc68521tttcgagatg gactcttgct ctgtcaccca ggctggagtgcagtggcacg atcttggctc68581actgcaacct ctgcttccca ggttcaagca attctcctgcctcagcctcc caagtagctg68641ggattacagg catgccccac catgccctgt taatttttgtacttttagta gaggaggggt68701tttgccatgt tagccaggtt ggtctccaat gcctgacctcaggtgatcca cctgcctcag68761cctcccacag tgctggaatt acaggcgtga gctgccgtgcccagstgcca cattttctct68821gttcattcat ctgtcgatga acacttagat taattccaaatcttggctat tgtaaacagt68881gctgtcataa acatagtagt gcagatatct ctttgagacactgattcctt tcttttgggt68941atatacctag cagtgggatt gctggatcat atggtagctctaaatttagt ttagtttttt69001tttgtttttt tttttttttt gagacagagt ctcactctgtctcaaggctg gagtgcagtg69061cgtgatctca gttcactgca acctctgcct cctgggttcaagcgattctc ctgcctcagc69121ctcccaagta gctgggacta caggcatggg gcgccactacgcccagctaa tttttgtatt69181tttagtagag acagggtttc accatgttgg cgaggatggtctcaatctct tgacctcatg69241atctgcccac ctcggcctcc caaagtgctg ggattataggtgtgagcctc cgtgcccagc69301cctattttta gttttttgag gtacctccga actgtcctgtagtggctgta ctaatttaca69361ttcccaccag tgtatgaggt ctcccttttc tccacatagattgaggtgtt tgtttgtttg69421tttgtttgtt tgtttggaga tgaagtctcg ctctgtcgcccagactggag tgcagtggcg69481tgatctcagc tcactgccgc ctccgtctct tgggttcaagctattctccc acctcagcct69541gggattacag gcgcctgcca ccacgcctgg ctaattttttttattttaag tagagacgag69601gtttcctcat gttgcccagg ctgctctcaa actccggacctcaggtgatc tgcctgcctc69661agccttccaa agtgctggga ttacaggctt gagccaccatgcccagcctg gattgagttt69721gtatcatgtg ccaggttcca tgtcagggat tccacatgccccatcccaca accatcttgc69781caggtgggca ttatgatgac cccccatagc agacactgtcagagctcccc caaccccatc69841tctgcccgga tgcccccact cactgtgggt gacacctgcatccttcttcc ggggtcgcct69901ttgcctggtg ggcattgcct tgctcagaga tgcctgggcagtcatgcctc cctcccccgc69961ccaatggggg tgcagtgacg tgaagtgtga ccgaccacccagaccccttg cacatgcgca70021ggatggacct cttctatcat cacgctccag ttctcccatgtggcaggctg aagcRaggct70081tttgaaacca tatctttgct cagctgcctc tgctaccctatctttcttcc accaccccct70141caataaacaa cttccacagg aacccccttg ggctctgcttctagggacct gacctagaag70201atcctcattt tacagatgag gacgctgagg tacgaagaggctgcgtaacc taccagggtc70261acacagcttt ggtgtggagt agggactcaa atccagggccctggtacgga ggcatttgcc70321ctcaccaaga ttcaggcact gagagaagcY gacgggcctagagaatggca agacttgaga70381tagcagaagg aaggagagag ggtgagaaat ggatccccgtgctgaggtct ggtctggaag70441gagaagtctg caaggtagga aaaagaggaa aggggacgtgaggtagggaa gcaggatgtg70501caaggcgggg acttgtgaaa gagaatgccg gggggtggtgagcagcatct catgggcagg70561tcagcaggtg caggagaggc ctaggagggc cggggactggatgatgaaag ggcatttgtt70621tatttatcct ttgtttttgt tttttgttgt ttaaattgagaccagctctc acaatgttgc70681ccaggctcgt ctcgccaact gtctgcccac tcctggcctcaaacgatctt cctgcctcag70741cctccaaaag tgttgggatt acaggcataa gccaatgtttattcgtcctg agccttccct70801ggacacctga tatgtagctg ctttgtggtg gtcacagttccatggtgtga ctttatcctg70861gaggcagtgg gatgctgata gcaagttcag acaggcatgaggccagacca gagctgagtt70921ttcaagataa ctccagccag aggtatgcgt gcatgtgcacatgtgggtac atgtatgtgt70981gtgcacgtgc atgtgtgtat gagtgtggac tagagatggaatggctttct gagcaaaggg71041aacagccaag gcaaaggcct gtgggctgca gggagagaacaaggtttgat ctctgcactc71101cctcctctaa gctctgtgtc aacagcattt tcaggacagcaggaaggatt cccaaagagc71161acagcagcga gggcagttgg agggaggcgt ctgctgggacactgaaacca gggYggggta71221aactcccctc gcacctcctc agactcagag cccccataaatcttccaggt gcaccccagc71281ccttttccct ctctctgtct gaactggggt ggcatgatcccaggactgca actccacgtg71341tctggattcc ccttactgac tgcgtgaccc tggccattttccctccacct ttctctcagc71401gcccccattt gattactcgg cctcaggggt gcactggggattcttagagg taacacttcg71461aacggaaagc cagaggtcct ggtgccaaaa tgcaaatgtgagggcttgaa agttcatcgg71521gttttatttt ctctgttccg tttgcagtag ctcttctttcttgttttcta tagaacagta71581aaaaacttta tgcatttgaa tatcgtgaac cttgtaattcatatgcaata taaaaactac71641tagctatgca tggagaaatc aattgaagaa cagtggcttagcatgtcttt ctcattcttt71701gatggctacc tcaaatcaaa tcaatatgaa cttggggtcaggcatggtgg ctcacacctg71761taatcccaac acttggggag gccaaggcag gaggatcacttgagcgcagg aatttgagac71821tagcttgggc aacatagcgg gacctcatct taatattaaaaaaaaaaaaa agagaaagaa71881aaaaagtgaa cttgggaggt ttgaatgaca actcgtatagctgaagtaat agatatattc71941aacttttaaa acttaatttt cattagataa cacatgcatatggtataaca ttctaggcca72001ggtgcagtgg ctcacatctg taatcccagc actttgggaggccaaggtgg gcagattgct72061tgagcccagg agttgaagtc tagcttgggc aagatggcaaaaccccatct ctgcaaaaaa72121cacaaaaaat tagctaggtg tggtggtgtg cacttgtagtcccagctact caggaagctg72181aggtcgggga atcatataag cccaggaggt ggagactgcagtgagccacg accacaccac72241tgcactccag cctgggtgac agagcaatac cctgtctcaaaaaaaaaagg aaaaaaaatt72301cctttcactg gggacaatta cctttatgaa tttcttccagaaatattaat gtatttgtat72361acacattttt ttttgagaca gggtctcact ctgtcacccaggctggagtg cagggatgca72421atcttggctc actgcagcct ggataccccc aggctcaagcaatcctccca cctcaacctt72481gcgggtagct tggacaacat gtgtgcacca ccactcctggctaatttttg tattttttgt72541caagatgggg ttttgccatg ttacccaggc tcgtctcaaactcctgacct caagtgatct72601gcccgccttt gcccctcaaa gtgctgggat tacaggcatgagccaccata tttatttttt72661ctttacacaa aggaagcata ttctacaccc tgttttgccccggctctctt ttaaaaaaca72721gtgtatcttg gataccattc catatcattc cataaagttcatcttcatcc tctttttttt72781tttttttttt tttttgagac agggtttcac tctgtcgcccaggctggggt gcagtggcac72841tatctcagct tacctcaacc tcccgggctc aagtgatcctcccacctcag cctcctgagt72901ggctggatgc tgcttctttc tttttgatgg ctgcaaagaattccattgta tagatgtgcc72961ataatttaat cataatatgt cctctttgat catttaggtttttccaatct tttgctatta73021caagcaaggc cacgttaaat atccctgggc atattattttgcacattatg aagatatctg73081taggctaaat acctgtgtat ggaattgctc agtgtgattacatggcattt accactttgg73141tagataaagg ttgtatcctg ttacatgtcc acggatgaatttcttccaga aatattcatg73201tatttgtata cacatttttt gagacagggt cacaaaaccgttaacacatt attattatta73261ttattattat tattatttca cattatttag ggaagtttcatttttttgtg agctatcact73321gataatttct tatttactca tcatcttgta tttctcttccttgcacattg gggaaatgtc73381tattctagtt tttaatgtaa atgttcttgt ggcttttttagaaaaaatca aaatgtgcac73441attaaaaagt ttgaatggtt caaaaggtcc taaaaagggtccacagtgga aaaggctctc73501ctttcccagc aggcccagat ccctcctcag acacaagcctgtcgtcagtt tcctgtgtag73561cttcccagag ttggtcacta tgtatgcaaa tacacacacatttaaaatat acacactcca73621cgtccacgtg gaatgatgca aagcatctaa gtgcccgttaattcacaacc ttgccaactc73681agtaatatcc ttgcgaatct aatagctaga aaatggtgtatctttttagt tctaatgtat73741tatatttatt ctattttctg tgagcttgaa catcttttcatatatttaaa agtcattggg73801gccaggggtg gtggctcatg cctgtaaccc cagcactttgggaggccgag gcaggtagat73861cacctgaggt cagaagttcg agaccagcct ggtcaacatggtgaaactca gtctctatta73921aaaatacaaa aaaaaaaaat taatcaggca tggtggctcgtgcctgtaat cccagctatt73981gggaggctga ggcagaagaa ttgcttgaac tggggaggtggaagttgcag tgagtggaga74041tcgtgccact gtactccagc ctgggcaaca gagtgagactctgtctcaaa aaaaaatttt74101taaatgtcat tggtgtttcc cttttttgta aaccttttatgttctttgcc tagttttcta74161tgaggtcatt ggctttttca gtgttggttt ttagtaactctcgatttatt aaaacattta74221tacatttata gctttgttta tgatgtatac atttataaccttgtctgtga tgcagatatt74281tttccaattt gtcatctggc ttttgacctt atctgtggtattctttgaca atacaaaaat74341tttaatttat atctgatcag tttcatccag ttgtttttttcttttttcat gatttctgag74401ttttgtgtca tgcttagcaa gatgctctct actctgaaattattttctgt aaaatatttt74461tttcagccag gcatagtggc tcacacctgc aatcccagaactttgggagg tagaggtgga74521aggattattt gagtccagga gttcaaggcc agcctgggcaacagagcaag accccgcctc74581tattttttaa aagagaaatt tttttaaaat actttttcccatgttttgtt tgagcactta74641cattttctta acttttttgt cgtgaaacat aacacatagaaaaatgtaat gtaagtgtac74701aacttcatga attgttataa attgaacata tagctttctggtactttcat ggtttaactt74761cttacattta aattttggtt tcatctagac tttattttgatataattgtg aaatagaaat74821ccatttttat tctaaaagaa cactttttaa atgttcatgaaatgttttaa aatttattat74881ataccaagca agaaaaaatc tcaacatagt cctcaaagcagaaattgcac aggacttatt74941ctttgtacag tgtaatgcac aaaaactaat aagaaagccttaaaaacaac cctttattaa75001attactccat tccaaattat aatttcaatc tacttagcacataagtattg atatacattt75061atcgaaattg gccaaaagtg ttttattatt ttttaaaagaaaaagcctag caatggctta75121agcaataaag tttttaattt taaagaataa caaacagcctcactaaatca gaggaaagaa75181ataaaaagat aaaagcaaaa attacagaac tagaaaagggaccattccag caaaattgat75241aaatgaaaac aaaaatttgt ttttcaaaca taagagttaccaacggctgg tgaatctaaa75301aagaagaaaa aacaaagtaa actaaattaa atgtgaagccatgaagagat ttaaaattat75361aagaaaatag gccgtgcacg gtggctcacg cctgtaatcccagcactttg ggaggccgag75421gtgggtggat catgaggtca ggagcttgag acccgcctggccaacatggt gaaaccccgt75481ctctaccaaa aatacaaaaa ttagctggct gtggtagcatgagcctgtag tcccagctac75541ttaggaggct gaggcgggag aatcacttga acccaagaggtggaggttgc agtgagccga75601gaccttgcca ttgctctcca gcctgggtgg cagagtgagattccgtctca aaaaataaat75661aaataaataa agctgggcgc agtggctcat gcctctaatcacagcacttt gggaggccga75721ggtgggcgga tcacaaggtt aggagatcga gaccatcctggctgacatgg tgaaaccccg75781tctctactaa aaatacaaaa aatgagctgg gcatggtggcgtgtgcctgt ggtcccagct75841actcgggagg ctgaggaaag agaatggcgt gaacctgggaggtggaggtt gcagtgagct75901gagatcacgc cactgcactc cagcctgggc gacagagtgagactccattt caaaaaaaaa75961aatacaagaa catattatat acaactgtga gctacaccatgtttgaacat cttgacaaaa76021tgagcaactt tctcaaaact aaattgccaa atgttcatttttaaaaagcc aaaaataacc76081aaccaacaca atgaggataa atttaaagtg atcaagtttgatttttttaa aaaactgttc76141aaacatcttg gtagtgctgg gcaggaagtt ggctttcattctgggtgaga tgagaaggct76201ctaaggggca taggacctga tgtcatggga cctgatgcaggctctgtctt aatagctgac76261tcctgcgtgg agtaggttat tgggggatgg gtggacagagaccagggagg aggctggtgc76321aggaatccca gtgagaaatg atggtgtcca ggctaggccatagcagtaga ggaagcaaga76381ttctggaatg cacttggaaa atgaagccat ctttgggcttgagctcaagg aagcatgaag76441ctgcccctaa ctgaagtggg gaaggtggtc tggggagcagtttaggagga gagatcagga76501gctcagtttc ggacttggaa attttgaaac gcacatgaggcatccaggtg gagttgggag76561aattaaataa tgctgaaagg tactcacttg gcaagtagcaaatattcgct atattgtctg76621ttcaactttg tcaactgctt ttccagtaga aatgtagtgtccttatcaca catgcataaa76681tgttaaactc aaaagtaaaa tgaaatattt tctcagtagatatgaataac tttttaattt76741ttttgttttt tgacatgcgg tctcactctg ttgcccaggctggagtgggg tggcgagatc76801atagctcact gcagcctcaa actcctgggc tcaagcaatcctctgccaca gcctcccgat76861tagctgggac tacaggcaca caccaccacg cccagctaatcttttatttt ttgtagagac76921tgagttgcac aatgtagccc aagctggtct ccaactcctgagctcaagct atcctcccac76981ctcggcctcc caaagtgttg ggattacagg cgtgagccactgcacctggc tgctttttaa77041ttgtaatatt catcctccat ccatcatact tagtgcaaatatttttcccc acctattgcc77101ttcctatttc tcttttattt cacgtcattt agggaagtttcatttttttg tgagctatca77161ctgataattt cttatttact catcatcttg tatttctcttccttacacat tggggaaatg77221tctattctag tttttaatgt aaatgttctt gtggctttttttaaaaaaaa atcaaaatgt77281gcacattaaa aagtttgaat ggttcaaagg gtcctaaaaagggtccacag tgggaaaggc77341tctcctgtcc cagcaggccc agacccctcc tcagacacaagcctgtcatc agtttcctgt77401gtagcttccc agagttggtc tctatgtatg caaatacacacacatttaaa atatacacat77461gccacagctt tttaaaattt gaatttatgg gccatgtgcagtggctcacg cctgtaaccc77521caacactttg ggaggccgag gcaggtggat cacctgaggtcaggagttcg agaccaacct77581gaccaatatg gtgaaacccc gtctctacta aaaatacaaaaattagctgg gcatggtggt77641gggtgcctat aatcccagct tctcaggagg ttgagacaggagaatcgctt ggacccagga77701ggcagaggtt gcagtgagct gagatcgtgc cactacactcaagtctaggc gacagaggga77761gactccgtct caaaaaaaaa aaaaaaaatt gaatttagactcaggtgcag aggctcacgc77821ctgtaatccc agcacttacg gaggctgatg aggggagaatcacttgagtc cagtagttca77881agaccagcct gggcaacaca gggaaactat gtctctacaaaaaaattaaa attagcctgg77941catggtggag tgtgcctgtt gtctcaccta ctcaggagggtgaggcaggg gaatcacttg78001aactcaggag taggaggctg catgagctat gattgcaccactgcactcca gcctgggtga78061cagagcaaga ccctgtgtca aaaaaaaaaa aaaagaaaagaaaattagac taccatcata78121gatggtacaa acacttccca gtttgttgct ttcgttttgtttgttgccat ttttactata78181cagaaaaaaa aggcaataaa gaatacatta ttataatatgttaatttcta ctgcattatt78241tttaacaact tcattgaggt gtaatttaca taccgtaaaatctatccatt ttaggtgtag78301gattcagtga tttctggtaa atttactgag ttatgtgaccatcaccacaa tctggttttg78361ggacattttc attactgcca taatattcct caaacccatttagaatcatt cctatttctg78421ctcccaggcc caggcaacca gtaatctact tgctgtttcaatagatttgc cttttctgga78481tgttttacat aaatagaatc atacaatacg tgatctttagtgatcttttt tcacatggca78541taaacttggt tcctttttat gttgaataat attccattgtatagatatgt cacagtttgt78601ttctccattc atgagctttt gggtatttgg gttgatttcactttttgact gttatggata78661atgctggtac aaacattcat atacaagttt ttgtgtagatgtatattttc atttctcttg78721gaatagacct aggcgtggaa ttgctggatt agatggtaattctattgttt tacattctaa78781ggcaggggtc cccaaccccc aggctacaga tcagtgtcggttcatggcct gttaggaact78841gggccgcaca gcaggtggtg agcggccatc gggcgagtattactgcctga gctctgcctc78901ctgtcggatc agcggtgcca ttagattctc ataggagcacaaacccagtt gtgaaatgcg78961catgtgaggg atctaggttg cgagtttctg atgagaatctaatgataaat gtaatgagct79021tgaatcatcc cgaatccatc ccccaacccc aacccccgtccggggaaaaa atgatctctc79081atgaaatcag tccctaggcc aaaaagtctg gggactgctgttctaaggaa ctgccaaaac79141tgccaaactg tttttcagag tggctggacc attttacattcccaccggca atatatacgg79201tgtcctgttt ctttacatcc tcatcaacat gtgtctttttcattacagcc attctatgtg79261ggtgtgaaat gctatgtggc tgtgtttttc atttccatgcagaaattttt aatttaattg79321cttagttaaa aataattctt taaatttaaa acactcatattgccatatgt atatttttat79381actacaaagt gatacaattt ttgttaattt tcttgccttgattactcttt acctgtatag79441tatttaaatc tttacataag atcacaatta tagtgaatagtaatttattc aactcaaaat79501cttcatagga tttagaaaat ttaagtcctt taccaaagggattgacttYt aacttcatta79561aaggttgcga acagtatcaa atccttggta aagccacattcaatctttgg cactccagga79621ttttgagcta taactgtagt gatcactaat atgtcatttctaagctgacg gtcataatga79681ctaaaacctc tcatagattt taaaatactt ccttcaaagtcagtaaacat tccaagttac79741taagctgttg aacaatttct tattttgaag attttttctgataagttcca aagtgtttct79801gatgaaggaa ataaaagctg tccagagaaa tctgagtcattgaggtgagc acagattcca79861ttggctgctt gtgctttcat cattacagta caattaacttcagaagtcga gagatgctgc79921agaattttaa gtacccaaag tttctcaaca agttgattttcaagcaaggt cattaactgg79981gccattgttt ttgccaatcc tccaacttca gccatttgaatcttgtatga tgaactcact80041tgctggtaac ctggaatatg ctcctttggt ggttgtgcctgataaaagtc aacaatacgt80101ttacaatttt ttatcctcaa ttcagaactt ggtattttcattaagtcacc cagaagcgca80161actgaactag cagtatctcc agcataagtt atttcatccgatactttctt tttcaaaaat80221ggcaagccac actattttat gatatcatat gcagattctacaaaatgcgg ctggttttca80281atttttactg cacacagatt cagaatttca aatgtctgtactaaatccct taagggaagt80341tcattctgat aacactgtac cagtttcttg acagatttaagttgcttttc ttctaagcct80401tctttagcag tctcttcaaa aagtttgatg acaccattaaggtccacagg cttcaaaaca80461ccagttccac atggcgaggg aggccttggg aaacatcatcatgatggaag gcaaagggga80521agtaaagacc ttcttcatgg tggcaggaaa gagacagcatattgctatgt attttaacac80581cacttatttc cccccttttt tctttcaata tcatggattaaatagtgtat tttaaatgag80641tgtgaggctc acttggactc tattccatcc ctttggccaatttttttcca tttttaatcc80701aagaatctta aagtttgaat gatsgtcacc ttgttatatattttattatg tttggaagct80761tttttgctat tgtctgatcc tcccaacaaa tagccttttgatagaattgc ctttattcgt80821ttctttatat ctaattctaa cttaagatta gacttaaaagtaacttcagc ggttttatta80881tgaaatattt aaggcatata aatactgcct cttttctctaaatgactgct aatataattt80941taccaagttc tgttaaagta tcctgttgta cataaagtgctgttgttttt tatctgcctg81001ttaacttaga gtgggtttta ttttctttca ctttctgtggtcgaaggcaa gtatgtctta81061gtcagtttgg gctgttataa tgaaacactg tagactgggtggcttaaaca acagaaactt81121gtttctcacg ttctgaaagc cgggaagtcc ccaatcagggagccagcagg cctggtgtct81181ggagaggatg cgcttcctgg tttgcagacg gcaccttctcattgtgtcct cacagggcag81241agagcaaaaa gaaagggcaa gcgctctcca gcctcttcctttttcctttt tttttttgtt81301tgtttgagat ggagtcttgc tctgttgccc agactggagtgcggtggcat gatcttggct81361caatgcaacc tctgcctcct ggcttcaagt gattctcctgcctcagcctc ctgagtagct81421gggactacag gtgcctgcca ccatgcctga ctaatttttatgtttttatt agagatgggg81481tttcatcatg ttggccagac tggttttaga ctcctgacctcaagtgatct acctaccttg81541gcctcccaaa gtgctgggat tacaggcgtg aaccaccgcacccggcctcc agcctcttct81601tgtgagggca gtaatcccat cataaggggt ccaccctcttgacctaatca cttcgcaaag81661gtcccacttc caaataccat cacactgggt atttaggcttcaccaggtga attggtgggg81721gaggtgggac acaaacattc agtccacggc aagtttttatctcaatttgc taaagcctct81781ctttatttct cctgttacag tgtgataatg ttttttaaaatatcatttag ctggctgtgg81841tgacccatgc ctgcagtccc agctactcag gaggctaaggcaaaaggatc acatgaacct81901aggagtttga atccagcctg ggcaacatag aaagaccctgtctcttaaaa aaataaataa81961ataaataaat aaataaataa ataaataaat aaataaaggaaagaggctgg gcacagtggc82021tcatgcctat aatcccagca ctttgggagg ccgaggcgggcagatcacct gaagtcggga82081gttcaagacc agcctgacca acatggagaa accccttctctactaaaaat acaaaattag82141ccgggtgtag tggcacatgc ctgtaatccc actacttgggaggctgaggc aagagaattg82201cttgaaccag aaggtggagg ttgtggtgag ccgagatcatgccattgcac tccagcctgg82261gcaacaagaa Igaaactcca tctcaaaaaa aaaaaaaaaaaaaaaaagaa agaaaagaaa82321agaagcactt aaagaggctg aggcaggcag atcacttgaagtcaggagtt caagaccagc82381ctggccaaca tggtgaaacc tagtctctac taaaaatactagaattagcc agacgtggtg82441gcacatgcct gtaatcccag ctactcggga ggctgaggcatgagacttgc ttgaacctag82501gaggtggagg ttgcagtgag ctgagaacat gccattgcactccagcctgg gcaacagagc82561aagactccat ctcaagaaaa aagaaagaga gagaaagagaaatatagaca tatgttatta82621gtcccccagg acctcttcaa aagatctctc ttttcctttcttatttctaa ttaccatact82681acataccaca tccattatgt cagaatgtgc cctatttacgtggatttgtc taaagtcatg82741gaactctgag ttacattccY cgtatttcac agagacacaatcagagcaca cgctgatctt82801ccgcctctct tcatttcctc catgtactct gtagctacctgttctcttct ttgttcgtag82861gaagatctct gttgcgtggt gtgggagttt gtgccagctcatctttttat tgtgctttct82921gtgagcagct atcaatgcct ccaggtcttc tctttaagaagaatgtttac tctcaattgt82981ttaaaaaact aactaaatag gaagaagatt gcaaatcctaacctttttgg ggttttatat83041tgggggcaaa agttggcatc tgcagtaagg attatttcattttcatctga ataaatgagc83101agtaataact ttgctgactt gcagggctca ttgtgatgccaaaggacatt gtaaggtgca83161tatctgaatt ggaggaggaa gaggggcatc ctctgagccaggtgtggcag gaggtgacat83221caaggagggt taggctgcgt aaacccaggg acacaaggagctgcagtcgg ggaagaacaa83281ggtctagcgg atggagttgg ggggactgtg tctggagccaatgttctcag atgtgtctcc83341ggcaggcagg ggcaagggct ggtgcctggt ttacagcattccttttggag tctggaatag83401tggggaaaac tccctgtctt ctctcccctt aggagtctgcactatggaaa caacctgtca83461atccagctca aggcacacat agcccagaca cccatgagaccctctccgtg gggaccctag83521agcacctatc atgaacgagg agaccaagta ggtgatttttctctcccctt cacctcctct83581tttcccctcc tatctacttc gtcacttttc tcctactgccaagactggtc cctacccaaa83641tctgccttac tgggctgccc ccaacacaac aaacctgcccttgaccatca ttcagcatga83701gaatgtaatg atcagacaca gaaaatcagg aagagttttgagacagcatc taatctaccc83761attttagaga tggtatgact gaggcttata taggaaaaaggcttgctcaa ggtcacacta83821tgagtgtatc agctaggata ggccaggtta cactgtagtacatgcaccct ccaaagtccc83881agtgactcat ggcaacaaaa gtttatttcc tgctcttgcttcctgtctcg tgtggattga83941ctgggattgc tcctccacat catcctgtct cccacactcaggctaacagg gtagccatga84001tttgcaatat ttctggtccc tggagtagaa aaaaagaaaaagtactgtca attacacctt84061ggttcttaaa acaactacag gcatgacatg agtcttttttagcatgtttc attgaccaaa84121gcaagtttca tggctgtgcc caatttcaag gaggcagagaagtgtaatcc caccaaaggc84181ctagaaagag gagaaagagt atctgtgaac agccctaatgcctaccacag agaattagta84241acagagctgg gccatggatc tttcaaccat cgtcctctgtctccaagatt attccccatg84301gaaatctcaa tgactgataa tgatgccatg tgctttttctcctgaggatg gttagcctta84361aagagatttg tgtcatatcc taaggggata gaacactaatgatggaaaca aaggtattgt84421gttagactgg ctggaggaga aatttgagga tgagaaacatcaccagaaat cacaccatcc84481agycactact tacttccatc tggtgccatg ctgccctggaccatttcttc atgggtagca84541tggatgctgg acaccatagc ctggaaaaga agttatgccctaggctatgg ccacatcctt84601ttgccgagat cacacaaaat ccagggactt agccttgtctggtgccatct aggcctccaa84661ggccttggaa atttactggc ctgggaggca agaaacctcagttctcctcc tgcctctgtc84721atsgacttgc tgtgtgactg tgggcacacc ctttgcccttccttggccat ggtctttccg84781tctgcttagt ggaggtggtg atccctgcct gaggatcatggtgtgagcat gtttcataaa84841ttctaagact ctctgcctga gtgaggacct attgctattagcccagttga ggagaaatga84901ccagtggggc tgacagtaca tccaagtatg tctctactgcatgcccaggg agcagctggg84961ctctaaaccc caggacgcat agtactggcc tcagcctctgggaattggga aggctggctt85021ctgggtggac ctcctactct tttcagagtt agaggtggactctctggagt tgtgaggata85081aaataaggta tataaagcac ttagacagtg cctaatacacagtgagtgct ttccaagtgt85141gtactgctat gaggaaggac atagtaccag aaagtacatccggaaatgtg atagcatagt85201ccactagatg atggaccacc atttagttgg ccaatccccaactgttggac atttaggttg85261tttccaattt ttaataatta taaataatct tgcagtgagcatctttgcaa ttaaatattg85321tatatacgtt catgatcgtt tgccaaggtt agagtcctagaaatggaatt actgaatcaa85381aggaactgca cattatttag gcttttgctg tgtaaatgccccgtgccctc tattggtact85441tctagaagga ggtggtttaa gagttccagt tcggccatcatgatggctca cacctgtaat85501cccagcactt tgggaggccg aggtgggcag atcaccctgaggtcaggagt ttgagcccag85561cctggccaac atggtgaaac cccatctgta ctaaaaattacaaaaattag ctgggcattg85621tggtgtgcac ctgtaatccc agctactcgg gaggctgaggcagaagaatc gcttgaaccc85681gggaggcgga ggctgcagtg agccgagatt gcaccattgcactccagcct gggtgacaga85741gcgagactct gtctcaaaaa aaaaagagtt ccagttcagaagggaagaat ttgcttagca85801aaagaggtga tggtctgtgt tagctaggat tagagttcactgtgagtagc agaaagcact85861aaacaacagt ggcttaacca gaatggaagt gtatttccctgccatgtaac agaagtccaa85921agtcagtgag cacagggcag atgggcagct ttaccttccaccttcctcag tatgggttcc85981acctcatgat tcaatatggc tgcccaagat ccagccatcccatcaacaat ccagacaaca86041ggaaggagca aagaagaata gacaacattt ctacttacattccactggcc aaattacatg86101gctacatata actgcaaggg agactgggat ataataatctattctagatg accagagaat86161atttagtagt tctaatactg aggaagaagg gaagaacagattttgggaga caactagttg86221tctctgccat gaggttagct cagactgaga gcagcataaatggttcatgg aaataagaat86281gagtaatgca tcctcacggg actgtccaca ggggatgaacaagaccattc cagagagcca86341gggtgcaggc acaaatggag tagggagggg gtgcagaagaaacagactga tctctggagc86401tgatccctgg gcagagacat caagactcca tggagaggccacttccctgc ctattttatg86461tcKctcaaat gtagggactg gttcttgact gcttgacttccctagaaact cccttatccc86521ccaactcacc ttScccagat caccttcccc ctagttcatctgtaccccac tcacctgccc86581tcaggtcacc tgccccacaa ctcacctgtt ctccatctaatcttcctccc agctcccctg86641tcccccaaat cacctgcccc caatttgctt gtcctccagctcaccggttc cccagctcat86701cttccttcca gttcccctgt cccccagctc acctgcctgccctcagttca cctgtccccc86761agttcatctt cctcctagct cccctgtccc ctagctcacctgtgccccag ctcccctgtc86821ccccagttcc cctgtccccc agctcacctc cccctcagctctcctgtccc ccagctcatc86881tgcccccagt ttacctgtcc cctagctcac ctcccccccagtttacctgt cccccagctc86941acctcccccc agtttgcctg tcccccagct caactccccccaagttcccc tgtccctcag87001ctcatctgcc cccagtttRc ctgtccccct caactcacctatcttccctg tccctccagg87061gctggctcct catggacccc gttggcctcc agctcggcaacaagaacctg tggagctgtc87121ttgtgaggct gctcaccaaa gacccagaat ggctgaacgccaagatgaag ttcttcctcc87181ccaacacgga cctggattcc aggaacgaga ccttggaccctgaacagaga gtcatcctgc87241aactcaacaa gctgcatgtc cagggttcgg acacctggcagtctttcatt cattgtgtgt87301gcatgcagct ggaggtgcct ctggacctgg aggtgctgctgctgagtact tttggctatg87361atgatggtaa gggcaggtgt gagagacgca aagcagccgggccagtacct gcgtcatggg87421gagccgggag gagcccaggg acccacctaa gtcagagagagggtgtagcc cagccacgat87481ctcaactcta tatttctgga cacttcccag aacaaatttcctaatgcgcc caaatctgct87541ggggcctgga ggacccctcc ttctacctgg cttcactcgaattgctcgaa ttgctgagtg87601actgcttcca gccacaaaat cccacatagc ccataatgcccgagagattt atttcttctt87661ttttggcggg ggtggggggg tgttttttgt ttgttgttgctcttgttggg ttttgtttgt87721ttgtttttta tttttgagac aaggtcttgc tctgttgcctaggctggagt gcagtggcac87781aatcatagct cactacagca tccaactcca ggactcaggtgatccttccc acttcagcct87841cccaagtagc tgagactaca gtagaactat aggtgcatgccaccacatta ggctaatttt87901tcattctttt gtagagacag gacatcactg tgttgcccaggctggtcttg aactcctggc87961cttaagtgat cctcctccct tggcctccca aagtgctgggattatagatg tgagccatca88021cacctggcta gaggtgtttt tgtttgtttg tttgttttgcaacatggtca gaaacagtga88081cggggagcgc cttctgccct ctactgatcc gtggggatttcttgggcacc ttctgtttgc88141acagcactga ggggaaacac aggacattga ggggcaacagcgtttttgga gagaaaatgg88201gaactcactt aagaacccta cttcaaggca gagtgtgggaattgcggggg gcggggcggc88261gcatgcacat atgtgcagac atatgcagat acacacagtgcatatacatg tgggtatgtg88321cgtaaaccca tgtacacatg catgcaagtg tgcccacatgcataacacat gcatgcctgt88381gcacacacat acataaactt gcatgcactt gcatatacacacatttctgc ccagcactgc88441cttcaaagct caccaccaca ttttctccac aacagataactgagtgttcc atttagttct88501cccttgctgg gtatctccct gtgagatgag ccctgagccaggcgccaggc cagagctggt88561ccccagcatc cctcgacagc cccataccac attatactctcccctctctt gcagggttca88621ccagccagct gggagctgag gggaaaagcc aacctgaatctcagctccac catggtgagg88681actggagttg gggggtggga agggggtggt gagcactgtgaagtccccac ttccaagctg88741gaggaggctg tggaggctgt ggtggctggt cacagccatttctcataggc catgctcttc88801gtctgtccct gacccatttg caagtgtgtc aagcccctaactgtgtctcc cagccccacc88861tcctcctgca gtgactttca aggctttagc ttgtcccgttaccaattctM aagggtctaa88921cctggaaccc ctcaggaagc ctgttctcac tttaYtgcccgcaacccgca gggcctcatc88981tcccagcccc aaagtgtcag gcttcatggg gaagccctaaYcaccccctc ccgacttgta89041caccttggac ttgacRctca cccacagctg ctgtcttcagcgggggagcc tttggctgat89101tttctgaagg agctcggaag ggccagtgat taaataatgaccacctactg attcgtgggt89161cacactttca tctcagcacc ttgatttcta cagaagcattgactttactt atcgctgtgc89221atggcagtaa tgccaacaga aaacccaccc tataacctcagctccccagt gaatcaaaac89281tgtccaagtc cctggtccaa taggcccgca tcactgagctggcatcatta tctcatggct89341gtaaccagat ctgattgata tttggccagt gagtccctttttaatatagg atttgttaag89401atattgaagt gctctcgaac tggttccagc ctcctagctggacaaggagc ccagggccct89461gctccagggg ctgttcctat tggtcactta gcttagctgtaggaggaccc tgcttgactt89521cttaaaattc tttcctgagt cctctttcct ttctccctcccttcctttct gggtcccctt89581ccttcttgtt ttccttcttc ctttctcaaa ctcttccagaaaggcattaa agtgattgtt89641gaaaatccat acaatgagac aagactccag aaactattaagggaagtgag gaaatgtggg89701tgataagaaa tcgggatgat aaaaccctaa cagaggagggaggttgcagg cctggccaaa89761ctcactggga acttcactta tatgaccacc ggcggcttccatagagcttg gtccttccct89821gatggacaga tggccattta gtgcttggag ctgagtgtttctRggggctg ctggctgtYg89881gccctgcttc ctgcatcctg gactgcaaga ctgccaggcccagaacatcc accttccaat89941gggggtgcct agaagtccac tctgcaaata gaagctggtgttgacccagc ctctgcctgc90001tgcctgcctt tccagtccct gcatgtgggt gtacttggctgcctgccacc tgtctgtgga90061ctggaKttcc ccaaaggttc tgggtaaccc ctcagcccagRtccccagac cccactcctc90121caccccttcc tttgcttttt caggcctgaa gcgcccacatcagagctgtg ggtcctcacc90181ccgccggaag cagtgcaaga agcagcagct aggtgggtaccagtgtgggg aggaacataa90241acagagagat ggggttgcct gggggccaag acccggaccctggaccttgt cccctgccaa90301taagcctcca gaggcccagt gactcttgtc tcgcaagtttccaggagaaa aggactggag90361gtcttgcaca ggcagaggag aggcctgggc tggcagcgaaggggctcccc acccatctgg90421ctgcatgggg acttctctga agagggctcc gctgaaggagctggaagcac catacaggtc90481tcagcttcgc tgtccaggct tttccaggga caccctatgtcctcagtgtt gaaggagacc90541cagggaggag accagtttgg gggtgagcag ggatggggaggggtgaggag gcctgggaga90601aaccttcaag acagaggccc tgggggccca tggggagacatggagctgct tagggcaggc90661caggccagtg agagaagaaa ggggacttct ctcattcttgaccagttctc agaatggtcc90721tcgttctcca cgagttgtcc cactaactag agccttctctgcccccactg ctgccaacca90781tggctataac cagaggattc acatccgctc aaaatagttcactaccttgg cctttcccca90841tagggttccc ccaaaagcag ccccagccct ttccctgggtcacctgagac ctctcaatga90901cccaggaatt aaaaggttaa catctggcac tgtaggggcccagctcccac agttccgatc90961ggtaatgcct aggcctacag gttgttagtg ctcacccctgggcattgcag aactgaaata91021ttgggaagRg gcactgggga tccagatatt acagaaagaggttgtttcaa taagatattg91081caaagtagct gggcgcggtg gctcacacct gtaatcccagcactttggag ggctgaggca91141ggtggatcag ttgagcccag gaattcaata ctagcctggccaacgtgaca aaaccttgtc91201tctactaaaa atacaaaaat tagctgggtg tggtggtgtgcacctgtagt cccagctact91261caggaggctg aggcaggagg atcacttgag accaggagtttgcggctaca gtaagctagg91321atcgtgccac tgcactggag cctgggcaag actgagactctgtctctggg aaaaaagaaa91381aaaaagagat gttgcaaagg aggtgcccta ttcccctccccccatcttac tgaMccctta91441caccacgtgt actattgcag aatggataga accgtgacccacacttcccc attcccacct91501gcctgtttaa atagctaccg gagagcctat gctcccttagaactgattcc ttctggaagt91561tggggtggca cagatccccc tatggtgctc ttgacacccccaccctcacc ccatcataca91621tacacatctg gggctacagg ctcccaacag cccaatactggggcaagaag acatgagcag91681agggccgggg ggtcctctcc tcatgccatg tccctgccccttgcagagtt ggccaagaag91741tacctgcagc tcctgcggac ctctgcccag cagcgctacaggagccaaat ccctgggtca91801gggcagcccc acgccttcca ccaggtctat gtccctccaatcctgcgccg ggccacagca91861tccttagaca ctccggaggg ggccattatg ggggacgtcaaggtggaaga tggtgctgac91921gtgagcatct cggacctctt caacaccagg gttaacaagggcccgagggt gaccgtgctt91981ttggggaagg ctggcatggg caagaccacg ctggcccaccggctctgcca gaagtgggca92041gagggccatc tgaactgttt ccaggccctg ttcctttttgaattccgcca gctcaacttg92101atcacgaggt tcctgacacc gtccgagctc ctttttgatctgtacctgag ccctgaatcg92161gaccacgaca ctgtcttcca gtacctggag aagaacgctgaccaagtcct gctgatcttt92221gatgggctag atgaggccct ccagcctatg ggtcctgatggcccaggccc agtcctcacc92281cttttctccc atctctgcaa tgggaccctc ctgcctggctgccgggtgat ggctacctcc92341cgtccaggga agctgcctgc ctgcctgcct gcagaggcagccatggtcca catgttgggc92401tttgatgggc cacgggtgga agaatatgtg aatcacttcttcagcgccca gccatcgcgg92461gagggggccc tggtggagtt acagacaaat ggacgtctccgaagcctgtg tgcggtgccc92521gcactgtgcc aagtcgcctg tctctgcctc caccatctgcttcctgacca cgccccaggc92581cagtctgtgg ccctcctgcc caacatgact cagctctatatgcagatggt gctcgccctc92641agcccccctg ggcacttgcc cacctcgtcc ctactggacctgggggaggt ggccctgagg92701ggcctggaga cagggaaggt tatcttctat gcaaaagatattgctccacc cttgatagct92761tttggggcca ctcacagcct gctgacttcc ttctgcgtctgcacaggccc tgggcaccag92821cagacaggct atgctttcac ccacctcagc ctgcaggagtttcttgctgc cctgcacctg92881atggccagcc ccaaggtgaa caaagacaca cttacccagtatgttaccct ccattcccgc92941tgggtacagc ggaccaaagc tagactgggc ctctcagaccacctccccac cttcctggcg93001ggcctggcat cctgcacctg ccgccccttc cttagccacctggcgcaggg caatgaggac93061tgtgtgggtg ccaagcaggc tgctgtagtg caggtgttgaagaagttggc cacccgcaag93121ctcacagggc caaaggttgt agagctgtgt cactgtgtggatgagacaca ggagcctgag93181ctgyccagtc tcaccgcaca aagcctcccc tatcaactgcccttccacaa tttcccactg93241acctgcaccg acctggccac cctgaccaac atcctagagcacayggaggc ccccatccac93301ctggattttg atggctgtcc cctggagccc cactgccctgaggctctggt aggctgtggg93361cagatagaga atctcaggtg agtaagagtg gaggaggaccggggagggga ttgggctttt93421gggggagcag aggccaacca gtctagcaaa cctctgccaagaggactgga taagaatctt93481gaatatcaga acataatggc ctgcaatgca agagaggaagctccatacct tgacaggacc93541tctggagtcc aaatggatcc tcctcttgtc tgtggtttctggactctcag tctctctgtc93601aatcatgggc tgaaaccaca gatccaggct gtctaYagaggctggtggac tttgggcaag93661tatatggagc acacacatgc acactgtcta ggccagagtttcttcgttcc taaaacgaat93721ctgtaacaat agccaactca tatggtcatt gcaagaatgagatgggatgg tgcatgaaaa93781acattttgta gcacagtgcc tagcacagag caaaggctcagtgtgcatat tagctagaga93841aaaggctagg ctgcagtaac agagaaacct cctccccaaatacagtaggt taaataatgt93901agaattttat ttctctctca tggaagagtc agaggtaggtggtccaggtc agtggaatgg93961ctcagctcca cgcagtcatg caggtaccca ggtccctcccattttgctcc attatcccct94021tgggaatcct atctgcacag tcaaagctac gtcatgggtatatctgtgct ctggcttggg94081aacaaggaaa gagcatggag gaacatgtaa atgcattaaagttcagtcct gaaactagga94141tacatccctt ccactcacat tccattggtg agaacatagtcacctggcca cactgagctg94201caagggaggc tgggaaatgt gatctctggc tgggaaaccatgttcctcat gatagctcta94261ttgctgtaga tgaagtggag aatgggcttt ggtggacgattagaagtctc ggccataata94321tgtatttgtt agtactactg tattaagccc catctctctgaggggatggc gatgacttct94381cagctctgcc cagcactgat cctctgacac ttcgcttcttcttatggcag ctttaagagc94441aggaagtgtg gggatgcctt tgcagaagcc ctctccaggagcttgccgac aatggggagg94501ctgcagatgc tggggtgagc caggccttgg agctgagaagggtcttcagc tggggatgcc94561tggtactctc ctccctctcc ttaatcctac acaaggcagattcctggccc cgcccttttc94621ccctcctcgt tcctccccac catctttgct tactctgtaggttagcagga agtaaaatca94681ctgcccgagg catcagccac ctggtgaaag ctttgcctctctgtccacag ctgaaagaag94741tcaggtgagt gatctccagg agggctcact gactggggagatgagccact gcccaggtcc94801cagagtcccc ctggggcctg catgttcctc caagtctgaccagtagtttt tcagtgagac94861ccagagaggg aaggcatcag tccaagtact cagtagggctgagtccaaac ccaaggctcc94921cagagtcccc agagcaaggc ttccttcatc taatattttagactgtcttg gaggagcatg94981agtgttaagg ctccctccct ctttctgaaa tcccaggagaagggatagca gtgcgtaggc95041aggaatcagg cactgtgggt acacataact acatgaagcaccacacacct tcacatttgt95101tcacacatgt ctacacttgc acagaagtac acaggcatatgcaagaatat gcacccacac95161atgcccactc ataggtgtgc acatgtatgc agcgcacacatgcaccttta actacatgta95221cacattttga tgccagcaca ctctaactaa ctaagcttgtatgcacaaat atactcctgc95281cctgtgtctg ggactcagta ccatggggag gagtgggaccagtgaccctc ctccctggca95341gaacgctgct agtttatatg gcacctttat gacatttagagaaggcacca cttcatccac95401acagatgcag cctgtcacta aggttcagca cttgttgagtgaaaataata agttggacca95461cagtccctat tgtcgtctcg gctgggcatc tgtgaaccgtgattaagcca aggttcagaa95521gtactgaact tgttgacatt tttcttccct ggctattgaaagtgacttta attttgtctt95581tcatcaccca ccattgttct taatcaccct cactcccctcaactcatctg tctccccagc95641taggaaccca ggcaaggctg gcttgtgaac aggtggggaaagtgaggtca gagaggaatg95701cgcttggctc agggctctgg gtgagtcagg gccacagccgaggctggaag cgatgtctgc95761agcgtcccag tctagacttt actcattgcc tggggggcctatcccaggca catcccaggc95821ataagccctg ggagcagggt gctaggtctc ctcattgtgcctcatgaaga ggccgtcagt95881ctgtcttcta gatcccttga gccgccaggc aaaaacttccccataggaac agaatagacc95941cagaattgag gccagcagag ggtctttcct cctagccgtgcctgctggaa tccggcgagc96001aggccatcag ctctttctgg gcccctgtct tatgtctcccacatgagggt ggccatcctg96061tcacttgcta actggggctt gcaagtgccc caaccccagggcaaagggac tgggccttgg96121tctcctcgca gttttcggga caaccagctc agtgaccaggtggtgctgaa cattgtggag96181gttctccctc acctaccacg gctccggaag cttgagtaagtgatctttcc actgcctctg96241cagcccagtc cctctctata cctgattcac cccactcccttgcaaggcaa ggaaggtctg96301gggcccctgg ggtaggggat tccactcctg acacctttgccacaatcttg cagcctgagc96361agcaacagca tctgcgtgtc aaccctactc tgcttggcaagggtggcagt cacgtgtcct96421accgtcagga tgcttcaggc caggtgagca gaaggaaagggatcttggcc ttatgggcct96481tgagaaaaga ggaggggaaa gtgggatggg aaatggaggaggcccctcgt ctgcaggata96541aatctgtgca taccctactg ttttactcac agctttaccttcagaaccta gctcaggctt96601ggcacctggt acttggtata tattgaatta atggatggatgaaaagatgg atgtatggat96661ggatggctga aaagatggat gggtggatga aaagatggatggatgaatgg atggctgaaa96721agatggatgg gtggatgaaa agatggatgg atggatggatggatggatgg ctgaaaagat96781ggatgggtgg atgaaaagat ggatggatgg atggatggatggatgaaaag atggatgggt96841ggatgaaaag atggatggat ggatggatgg atggaaagattgatgggtgg atgaaaagat96901gaatggatgg atggatagat gaatggatgg atggatagatggctagctga aaagatggat96961aggtgtgtga aaagatggat ggatggatgg atggatggatggatggatgg atggatggat97021ggatgaagga atgagtcaac aagtctacga agcacaggcatagccaaagg aataattagc97081tgtgtgttgc cctccatggt gctgaaccaa tatagccagttttgatcatg gggtaggtta97141ggtgtcattt ttcttactca taaaaatttc tattaaaaaaaattcagccg ggctcagtgg97201ctcatgcctg taattccaac actttggaag gccaaggcaagaggattact tgagctcagg97261agttcgagac caacctgggc aacatagtct ctacaaaaaatgaacaaaat taatggggca97321tggtggtgca tgcctgtggt tccagctatt tgggaggctgaggtgggaag attgcttgag97381ccgtggaggt tgaggctgca gtgaggtgtg aacacaccactgcactccag cctgagtagc97441agagtgagat ctccatctca aatttaaaaa gaaaggaaaaaaaaaaactc acaacattct97501taatttttat tatatttctt gtgaaaattg tttttctgactttttaaaac actcttgcag97561gattcatcaa gcaaagacat aatcagtatt tcacatgcctgatttaaaac acttttgcta97621gttccgttat gtttccctgt caattgcaaa atcagctttatctggatgtt tgaacatttg97681gggcagaaaa gggtgtgcct gtggtgggtg atgtgctggtttccagtctc tgggtttcat97741ggcttggtat ctgatcctgc agggaggcgg acctcatcttccttctttcc ccgcccacag97801agacaactgc agagctacaa aggtaagaag ccaagaggcggtgggcctgg ggccatcctt97861agaagcaact tgggctcagg cagttgaggg gaaaggtgaccaagagacta ggaagagctg97921gggtatggga attcttcctg ctactgctgc actgaggaatgaattactgc ttaggttggc97981aaaggatttt aacttcctct agYgtgtcca gaccacatctggtccctgtg gaaggaagca98041tccccagaag actcagagga aggcaaaccc ttggggagaacataaagata ctgttagact98101ggcattacta gatggtgaaa actctggaaa agcccttacaactgaaaaaa gacagggagg98161gcaattatgg tacctacatc ttagggttgt tctgagaattaaatgagtta ctacacttaa98221ggagtttaga gcactgttgg catgcagtgg


following is a genomic nucleotide sequence of a PROL4 region (SEQ ID NO: 2).

>12:10841901-109759001tgaggagctt gaccagccct ttaaaccaac tcagcaagtc tgaatgatgt gcaaagggac61aattagatat gggtaagaag tccccaacct caacccataa aggactgtgt ctgaggttct121tacagcatca agggagatgg ataccatggc ttccatcaag gtgctgctag tcctgctctc181aaaggctttg gtgaccctga gctctgctca gagcatagat gatggcaaRa ggaggaaatg241gggacaatac aatggataac ggggttaaaa tgcatggaaa gtactagagt tagattgacc301ctttcagaaa ttaagcactt tattttcaga gagtaggtca ataaaagagg aggaaacctt361aatttctRtt tttcactgat tgcagatact tctctgaaaa tctcggccta agtcttaagt421caacgtcttc atgatgtaat tttgccgttc taatgtatat ggattttcag ttgttgattc481tgtttgtgtg aatcagggca tctaaattga acggaaaatc tatatttttc atttctataa541tctataatag aattctataa ttctataatt catctagata tcRcatttcc ttgacatcaa601actcttgaac atttaaaaat attgataatt ttgattaaat ttgtacttaa tcaaaatttt661gatgctaagc aggcactatt aaattctttc tattccattc cttaatcctt taaaatacag721gtcacccctc attcagagtc aatgattggg actagggttc tactttggga aactttggtt781tattgtatcc aaatctttat aatttttttt ccctaaagct ctcttaggca tttttaaatc841tcttgtgtct aaacctaagt gtctttctag aaattcacag ctggggtttt atcaaatcat901gttttaaatt tgtcttcttt ttcatttttt tttttctctt aaaatcctaa gtactgttgc961tgaagagttc tttcaagagt aaggtaaacc tttattcagg gatgtgttct tttctttgtt1021cttcagaagc taccatagtt ttcttttttg tttaataaac attctcaaaa ttctcaaaca1081ttctcaaaat tgagtttagg gagtcccaaa gggaaaaaga gaattacaaa atctgaaagt1141tttagtggtt ctcaataata acattgattg attgagacaa gcctcctctg tcacccagat1201tggagtgcag tggcatgaac acagctcact gcagcctcca cctcctgggc tcaagctatc1261ctcctacctc accctcctaa gtagctggga ctataggcac acaccatcac acccagctaa1321ttttaaaatt ttttatagag atggagtctc accatgttgc ccaggcttgt cttgaactcc1381tgggctgaag atatcctccc acctcgtcct cctgaagtac tgggactaca ggcatgagcc1441accatacttg gcccaataat gttaaatatg gaccatctcc ttcattttca cattagaatc1501tcttgtgtca gagttgtaat tagcatttga acatcagcag aatatagaca cagtacttat1561ttgtaaatgc ttttctctaa atctttctac aaccaatggc taatgattga ataacacaaa1621tctcccattt ttgcaagagc aataactccc ttgacatata actaatttga agcataaaga1681tacataaaat ttgcctacat tattgtagtc aatcagtgaa tgtatcattg cactttcttt1741tgccactctg aattaaaaca caaatgcttc attctttagt tttcaagtcc tgataactgc1801ttaaacacta atttgtcaca gagtaagtga aatttaaagc caccattagt cacacacagt1861ttacatgaaa aatttgaagt ccattctaat ggcctgggga gagactctgt gtaggaggaa1921ggatataata catgcccaga gtacatgaga gagctaatga attatgccac caaagaagtg1981gcagaattga gtaagtgagt caaccaacaa ttttgttgtt caaagaaaac ttttatgctt2041aatgattttt ttcccctgtt tctgacttgt caatgaccct tctactgagt ttatgatgtc2101atttcaaact tcattctttt tctcttcttt ctttgaagga ggctttcaag aggaagatga2161aaagacctaa ctaccatgtg agctattttg agttcaatta agttattaag aattgttcta2221aatggattca acgaacctct gggttactgt tctaataaaa catttctaca agtttttact2281gtaatacaaa taatcatgtt taaccatgaa aacttttttt ctctctttat ttacaaatat2341tttctttttt gtacacaaag ttcctggcta ctctaggctg gttagtacag ggttgatcac2401cctaaaatat ctttgccaca ataYgaatga tgtgcttttg atggtatgtc ccagatacat2461atttcctttt gtggcctgac atatggcatt gtctggagaa tattcaatat atgcttgaaa2521agagaatgtg ttgtctcttc cttttatgga atctttcata aatatcagat caggttgctt2581gatagtgttt gttaatgtat tctatattct tacagatgtt ctgttgttca acaaattact2641gaaatagaat cattgaaccc tttaaaaaaa gatgtcttat atacaatcca aacaatattt2701ctctgggatg tagagatgat ctacattgag gcaatatatc ctttgagagt tttgacattt2761tagcataacc atgtattagc ttttgattga atgtcttgtc acagcatctt gataatcatt2821gcctggtgca gtccgtggac atacgtcttt tgtggagaaa ttttcttcaa taaataatta2881atagttcaat ttaggcttct tattttatag acattttcta cataattttt ctcactttta2941cttatagatt gtccttcatt cattgatctg caattctcaa ataatctttg aacttactgt3001gacaatatat ttagccataa tatatacctt ttctgtgatt ataagattat tcatagaatt3061ccacagcatt tattaagaac tgtcacttta ttgagtcttt cccaaaagta gagctttgtt3121ggatgatcca agaggaacca tctaacgcgg actatgagaa ggaactagtt gcttttcata3181aagatgcaaa taacagcaag atgctgttac agttgttttg aattagtcac acaactttgc3241atctggaaac acggtttaga actatgaaaa tgccctctac tcttgatagt tgatattagg3301atattaattt ctatttgctc tgaaacatgt tttaaaaaac agcaactcta aagaaaggaa3361gagttacaga agagagaaac agggatacac agacagagtc agaaacagag acagagataa3421agagatccag ccagctgtac ataagattcc ctacattaca attacagata cactaattaa3481gttttaggag taattaatca cataaaacat taatgcaaga actgaagtta atttagaaac3541atcttatctt tgtttgtcct agaaaagcat agtttctctt cagatttgtt tatgttgttg3601gaattttctt ccttttagaa tagaYattac tttccaaatc acctttagag atgcatgtct3661taatttattg ttccccagta ttaggataaa tgaatgactt gaggggtaKa ttagagctat3721ggactcacca aaaatcacag ctaattccgW ctctggcata aagtagctgg aggtggcaat3781gagaaaggac aaatagtagg caataaagag gagaaggaag gaaatgacag ctttcagggc3841tctcacatgg gcttctgtgc tggggtctct gcaccctgtg gcactgagct gcattcgcct3901gatatgtctc cgcagggaga ggatcaagag gaaaaaggac attaggcaca cacaaaaggg3961gagcagcgtt gccaggttga gaaataactt ggtagaagca tgttgagttt tatttactct4021gcaactccaa gttaagtttg ttttcctctt tgccttcaca caaaacctga aatcagcgtt4081caaattctca gtggctggaa ggctaataaa cacagagaga accacgcacc ccagtagaat4141ccaggaaatc accctgtcaa ttctccactt catccagagg aaaagtgggt gaaagaaatt4201acctatcttg aagaaatagt aaatgctgag gcaggttgca aaccagatac ttaaatgatt4261ggttagtgtc cagaagaagt caatgattct catttcttta ccagtggcat agacatctgg4321atatagcacc aatataaaac aatctaatag tattacgcac aatagacaaa ttctggatat4381ggccagactt gtgaggatta aatcaatgga ggcaattttc ctcttcttga cccagtccat4441gcagtttacc aatccaatga atgcattccc taagatcccc actgaaaact ctccaactgc4501taagaacaat aaagtagtct gcactttatc tgccatgttt aaatatgcaa ttagtttcta4561gttgacctga tggagtttga catccacacc tgcttcttag attttgatgt agttttcttt4621acctctttgt tgtagtctgt tttgtgatgg agactggaat gataaatgaa gactggagct4681atcttcatta aatcctaatt agtcttgaca aacaatgtgt ttgScgatcc ttggcctggc4741cactgtatgc ccatttacct actcagcagg ttgtaatttt Ycacatacgg ttaatttagg4801ctgagctact gtttactaag atgcaaattg ggccaattcc ctttcatggt cctgcattgt4861ctttctgagg ctaaggtgta cgcattttgg attcattaat ttgtgatgta tgctagtaac4921ctcaataggg ttgctagatt tagcgactaa aaattcagga cactcagtta aacttgaatt4981acaggtaaaa aaatcaataa ttttttagtg tatgtccctg attacttaag atcagtgctt5041tcaggaagta ctgaagttca aattagattg agtgttccat tctggcaacc tgaacatcaa5101gaatttggta gcaagtataa aactggtaaa attggaaagt tcttgaagaa tttttatttt5161gctgaatgtt aatattgata attagtaaag aatccaaagt ttggttccat agtgagagtt5221atatattttc aggaacttta aaaagttaac actaaatgta ggttatttga ttccaaagaa5281actttaggtc attattttgg ctgttcagat gaacaattac atggcatagt gtctcttaat5341acaacacatt gtcttactga ctaaatgact tttaatggtt atttagcaat gttatatata5401ataaggtaga ggacctgtaa taaaaaaaga ctattgatta ccttaaattt ttcattttca5461cttaaaatgt tctcaaggaa actttgagag gtattagata tgtccattac cttgtttgtg5521gtgaagatat catgggtgtt tgaaatttta tacattaaat atatgcggtt ctttttatac5581caattatact ttcataaaga tttcaaaaat ttaaaaaatg ttctcaaggg tagttgtatg5641catgagagag gagatagtaa aattctgtat ttcattctct ccactgtcct ccatacaaat5701tgcatgagta tctagatcct caacccttct agcaggagac tgaagattaa actttccaca5761tctctagaga tgaattttta gtttgaaata gcttctctaa tttagagtta ctgagaagcg5821ctttactaca tggggttcca tagaatagtt cttgggtatt cacaccttcc tgggaatgca5881tgtcttctct tatccttcct taaaggacaa accatcattc cggagatgta gccttaactt5941ttggacaatc tgtatgatta tgtagccatg ttcacaggca actggaacat cacctatgat6001aggacgatct tggatatgat ccctgaccta gacttatcat ttcttttgtt ttttttttga6061gatggaattt cgttcttgtt gctcaggctg gagtgctatt ttggctcacc gcaacctcca6121tctcccaggt tcaagtgatt ctcctgcctg agcctgccaa Rtagctggga ttacaggcag6181gtgcaaccat gcctggctaa ttttgtattt ttagtagatt ccgggtttct ccatgttggt6241caggctggtc ttgaactccc gacctcaggc gatccgtgtg ccttggcctc ccaaagttct6301gggattacag gtgtgagcca ctgtgcctgg cctagactca tcatttttac cctacagttt6361atcctggtaa atgaagtgct catgggaact atgatgatgt attttctcaa ataattttta6421gacttgtttt tgtttagttt tggaaataaa tgtagatttt atgaatacca atgttgtata6481gcgtgaagtt atgtgaatat atagttaaaa aaaaagttct atgagagagc attttgtcaa6541aagcttacta ctttgaaccc cagtcactgt ggtcactaga gatgcttgaa acattagaga6601ggcaggaaac aaaatatgga agaaaaaaac ttaaccctaa tggggtaaaa ccttcccaaa6661agtactaatt caataaaacg tttatttcac ttaaacctta ggaaaaatat aaagttcatc6721ctagtataaa atctacctgt attttgtaga atacattaat atatttcatc aagagaacat6781gaattcttgt gtcttgtaaa acaaagagta acatatacag ctagcatatt agaaatatag6841ttcataaaat ttatatactt ggggctataa atattagtac tttacagagt gagttttaca6901taataataag acaaacaact gataattttc cggtaattag tattttagtt ataataaaag6961gaaattagta gattgaaata catcagaatt aaacagaaag taatgggagt aaaagcaata7021atgtacagcc atattagtac atacacaacc tgagatatgc cagaccaaac gtttcaataa7081tattatagtg aggatgKatt tcatgttcac agaaaaatta aaaattttag tgacttattt7141tccttttttt tttaataaaa atttatctgt attttttgta aacattcgtt tcttcttcca7201gggacagtat gtgcttattc catggtatac gctattttct tcccaattta tttcttttgt7261taagtcctga gtgaaaacct ttgcagggtc tggttagaga aaagaacctg attgagcagt7321ctgactaata tttgttatcc ccattctttt atccagattg tgaagagggc ttaggaacac7381cccttggtgg gtggcacttg aatgggttcg attcccacct aggtgctgca tgaaaagcaa7441gttgtttgag aggaaattta attccaagga aaatcaatag aaatcatcag aataaggtca7501accagaaaat attacctagg agaccatgga aatcatcatt cgggaaaacc aaagacagac7561cagagaacat ctgagttcct aatcaataag ccaaatgggg gtgactcagc agagccatga7621aaggagcaca attaaggagc ggcaataaaa atgtatgaca aagaaaaatg agaaaccagt7681tactgtagct caggtccact ttaccatgag ccaaagtaaa atctaaaaag actttaacta7741ggcaatacag gcctaacact tgcgttgagg agacaagaag agaagcatga gctctgaaat7801tcttcgagga aagggagtgt aaagatgagc atttctgagt tgtaaaggga tagaaaagat7861gtattcagta gtttgctact aggtcctaat aatatttaaa gatatgcatc caaaataaat7921gagataactg gggaaaaatg agaatagact attaagaaaa ctatattttt tgttagagaa7981gatttggttt taaattccat ttatacagct aagatttcat atcaYgcagg caatttttct8041acatgtcagc attctgacaa atgtctgcct cagtttatta tttaaaacaa ttaaaataag8101tgagtgaccc aaggggtaga gaattgctgc aatctctcca aactccacag ctaacttgta8161ttttgtcata agatagctaa aggtcatcaa aatagaagaa atatagtata ggaaaaaaaa8221gaagataaat gaagtcatag ttttaatggc tctcacatga acttctgtgc tggggtctct8281actgccggta gcatagagtt ttatttgctt ggtatgtctc cataaagatc ttactaaaag8341gaaaaatgat atcagtgaca caataaatgg gacaattgca aacaggttaa agagagtYaa8401gggttcaaag tatggtattt tactcacatg gaacatttca gtaatgtttc ttttatgttt8461ggcaattgca tgaaacctat aatcacaact cagtactatt gctgctataa ggctgaccaa8521caaggaaatg gcaaagcatc ccagcaggat ccagtgcacc accatatcaa ttttccactt8581cagccagaga aaaagtggat gagaggaact ggctatcttc agaaaataga agacattaag8641gcaggtggta atccacatat ttaagtagtt ggcaaatgtc cagaaggtaa aaatgactat8701ctgttgttta ttttttgtat aaacatctgg gttcagtact attacaatgc catttacaac8761cattacactg atcaaacaaa ttctggcgat aactaaattg gtaaggatgt agtcaactgt8821ggaaatcttt ttcttcttaa tccagtcaat ccagttgact agtgcaatgt atccattccc8881caatattcct agtatgaatt ctccagttat taggattata aagatgttat ctgcaggact8941gaacatgttt gtagagagaa caatctgatt tcaaatatca ctgtagatga gctaatttac9001aggtgacctg ttaaagcatg atagatcaat tcttcgaatc atgcaataat gttttcatct9061gctgttattt cgacgttgtt attcttccgg aagtgttcag ctctcctctg aaataggatt9121gtctctacac tcctgaagat gaaaccaact aatgagcagc ttgactagtt atttatagcc9181tggaaaaatt ataattatta tcctttagtg agtgatacct gaaatgtttg gctgaaattg9241ctcccatgca aattcaaaga gattttatat catgaatttg caacaggctt cttgctgtag9301ctctatattt ggatcttcaa attgagtttt gaatagggag tcataaaaaa agagataaat9361gtttaataaa aacccaactg tgtaaataaa acttcatttt catcatgtaa gttataaata9421agccacaaat cagttctccc agatgcaaag aaattttcac tttggaagta attagtacaa9481ttagattgta gatatttaac atttagtcag aggataataa ttcttgtctt catttaaacg9541gctaattagg gaaggatata atacaaatct aattagaaat gacttttttt taggcaggca9601catgataata tttactaaga atttgctttc ttttcaattg ttcctcagaa gtgaaatatg9661ccaggtaaag atttgttatc tttagttttt ttttaatgtg acaaataccc ttgaagacaa9721ttcatttcct gaatcactgt ctcttgtata ataagcattg taatctaaaa ttaagaaaat9781ttaaatttta cattattcta gttccaatca actcctttta taagatttgt aatctcacag9841tgcatattat agtcatattt ctagataggg caaacacata aaaaagtaac tacttgggag9901actgaggcag ggggatcatt tgaaccggga ggcagaggtt gcagtgagcc aagatcgtgc9961cactgcactc caacctgggc gatacagtga gactctgtct caaaataata ataataattt10021ttttttttta cataccagta tttccaagga ataggactaa ttctactatt aaattagatt10081tatttgtttt ggggtaaggg aaagtacaac ttagcccaaa atacatttga atgtaggtaa10141tacRaatcac aataccctag ggcttcttgt atttaaatag ttctacaatg tatacaacac10201atgcaggatt ttttctattt cttacatgtg tgtaatgtgt aacaggaaag cataaactta10261ataacttaaa gaaacctagt tatctataaa ctactgctgg aaacaaaata gaaaagaaaa10321tgatgcagag ggaaaaaaat atgtcagaga tttctgagtt agaaggctag agagaacatt10381ccaRggaatc tttgggaaat gacttctaaa attgccatca ccagctagag tactcatgaa10441cacgctgact actgggaccc tcaaccttct ttctcaaggt ggttctgcta tacataactg10501tgcctcctct ctctgtcaaa ctttcattct tgagattata ctccttttcc cacatcatat10561atcatcttag atagaatctc attaaagatt gtttttctcc cttcttgatc aagacaaacc10621cttccagaaa tggagaggaa agggcggtga agataaggac cggccttcat ttcaaagtag10681agagttgttt tgcatgattg attttatagc aagggttgat gagttctaaa atcttttccc10741caaagcctgt ttgcctgaca ttcttctact cattgagttc aaggcctttg ccagtatttg10801tcagaaaaga agtagaacct ctttgtattt agtcaatgac ataaaatgat gaaatgttag10861tgtgggattt agatgcattt tttttttctg caacgacaaa gaatatacgg tgcaatgata10921acattagatt atccattaaa caagacaaaa gtgtgaagga acacaaaaca aatcttcaga10981atcatgacag atattaatga cttccaatag catataagag aaaatgaatg caaacaagag11041aagggagaat gccttttgtt gatttctttc atccttgtag tcaggatact ctttaggggt11101ctctatggaa caaaaRgctt tcttcttcta aRgaaacact tcacaaatct taacatcttc11161agaaaagctt ccctcaactt gctatttccc ataattagaa tgaatgaatg gcttgatggg11221aaaatgacag ttactatgtc accaatcatc aacactaatt ttccctgagg aatcagagcg11281ctagaggtca taacaagaaa gactgggtag tacacgatga ggaggagcag aaagatgatc11341actgccttta tggccctcat gtgggcctct gtactggggt ctctgaaccc tgtagcatgc11401agtcgaatct gcttggtgtg tctaactagg gagaaaagta acaagaaaaa tgagatcagg11461caaaggataa agggaaccat cRcccccagg ttcagggtta actgtttgaa agtacctgga11521attttactca ctttgaattt ccaagtaatg ttttcttcat gactgacttt gaaaaggtga11581taccacatat catcattctt tggaacacta ataattaaag agataagaaa ggaccccaga11641agaatcgcaa gcatgacctt gttgatcttt agcttcagcc agaagaaaaa tgggtgcgat11701atattggcta tcttgagtaa atagaagata ctgaggcaag aagtaaacca gagacttgaa11761ttattggcaa atgtccagac aacattcaca atgcttacta gcacgctatt gccatatgta11821cctggaaaga gcagcataaa gaagccatct aatgatatta cacacagcag acagattctg11881gagatggcca agctgatcag gatgatgtca atcaaggaaa tatctcttct tttgagccag11941tcaatgcagt taactagtac aatgaatcca tttccccaaa tccctatggt caattcacca12001gcaattaaaa taatatatat tgcctctatt gcacttggca tgccagcaaa gacttgtgat12061ttttgaatat cactgatgat gaattgactt tcagctgacc agtgaagaac aatgtatctg12121tctgcctctt agaccatgat atagttgtct ttatctctcc tttttgttag ctgtgatgca12181gatgaagaag atagccagtc ctgctctggg ctagagctgc ctaaagactt caatgattgg12241ggccagtaat ttcctttggt gcagtgatga ctgaaagcct ctaggatgca aatgggaatg12301gatctgattt cttaaatttg cacactcttt cttattttaa gctctgtata ttttggattt12361atcaatctga gctgttgacc aggaacttca agaaggtatc aattacttgg aaaatatggc12421tagaatttaa tttgctggat gactatccat ccttgttagt atattgacat agttattgct12481attacagatt ctaggtttac tgtgttagct tgtgtggcca gtttgcttgc ttggttgact12541aaagctttaa acaaattatt attaacatta aatgaggctt aaatggcata actggtggaa12601tgtagaggaa agaatctaaa ggtgtaggaa gataggagta ttaaggtgaa tttatcatat12661gcgaacttca ccttctcccc attatatgac ttaagagggc caaaaggaca ctccattcac12721tagggcattg agaaatacat taattaggta attcccaata tcctcaaaaa gctctgcagt12781gtttgtcttc tcaactgaag atacaatgag ggaaataaac atgacattgt agtgttgtca12841gcaaatgaga cacggaaaat tctggtttag atgttagggt ttcttagagt gttcttgctt12901tgtacctgaa tgtagcttcc atacatagaa aaaatagtca aaatactggt cacttatctt12961tagaatggaa acagatcagc ctgaacagtg aggaggacaa agagcaagaa agtgatattt13021ttggaactaa aaagcgtgat agatatacaa gactcttcag tctgaactga gtgataagaa13081tacatgctct gaattttctt agctctattt tttggcagca ggtgtattat aaatattagt13141atgctaatta tacacacatt ggaaacacac tgtttcattg ggacatattg aaacatgtca13201ttgggcatag tagaacatat ttgaaataat agaaaaaggc acacagcaat acacagttcc13261cagaaatatt attttgaaac taatattaaa ttttaaggca atattaaata ttgcttatca13321aacaaacaca acaatacaaa gtatttaatg agataatgtg tcatatgttc agggttttag13381acaaaataaa gagataaaaa ttaatcttgc agatttttat gagaaagtaa atagctattg13441ttattctatt cagtgaaatt tggggtttct ttcatgcttc tctgtgaatt ttgtttctga13501agaaatatca gattatacaa ctcaaaaata cacactgtgc ttgtcatgac caaagccata13561aaacaggtaa tattctgaga aggacttcac tagagtaaag aaattgattt gcatgcaact13621gacagacaag gtcgcaccat gttcacatct cagggaatgc aatatttcat tattttaatt13681aaactttttg aaagataaaa ttttgtggag gggaataaag taggttcaag gttattattt13741ggaaatggaa ctactctggg atcaatttgt aatgtccaga aaagatgaag atgaaaatat13801atcatgtagg agggtgatta ataactgaca tattaaaaat tcctggtaaa tccagatata13861gaatccaagc ttgccttctg aatcatggtc tttcccacta cctcacttct tttccttagc13921cgtgtggaat actgatcaat ttaagaaagt tatgcctata ttcaaatgta aacgaaaata13981tgctatagga tatgaccaga gttacctaag ggcctatact tactaaaatg ccaccctctt14041ttatctttcc ttgctataaa taaaacccaa atgatctcaa tttatttgac accgttgaat14101atgttttttt tgtgtgtatt gtgtgtgtgt gtgagtttat gtgttatttg ccctttggat14161tttatcttag cattgagaag ttaaagaggg atcctagctg acagacttta acatctattt14221tcattgcaga aacactttaa tctagaatgt tagtttattg attatttctg tctctactag14281aaaacagatg aaatactggg aaacttatga catcatttcc tgtatgtctt tctatgagaa14341gtgagcaaac acaaacctac ttaggcagat atttcttaaa tttcattttc tttcctttgt14401ttaaatactt tttaccattc tttagaacct tacatctttt acaggcattt gtccttgagt14461tatgccactg attattactg atcaagagaa atgactatac tcttcagatt tataaatcaa14521gaacaggata ctgcgatact gtcYtatttt ctgacaactt atattttgaa tagttgctga14581ctttatctcc taccccattc taaactcttc actatatcca ttgggatccc tagtaaacca14641ttagcagaag ccatatattc tcatttgttt ctctaacagt tcactttatt ttcttcattt14701gaactcgagg ttctggaact tttttgttca atggactact ttgccagtct ggtgcatgct14761ataatttcag aataatgttt ttaagtgcat gaaataaaaa tatttgaaat gtataaggaa14821tccatatata tatgcctttt tcttgcagta tgaaatatat tgttaatata atataggaat14881ttatgtgctt tttaattgac ataacaaaaa tatctggcag ataaagacta gtggtgaaag14941taaatgacaa taggaggtac ctgtaacgac aaaaattttt ggcttcctga agtgaaaaaa15001ttacagatac tgctggtatg gtatgtgctt gttacttaca ttcaagacag aagaaatact15061agacttaagc taaggattaa taaaaataag tatataattt ggtgcccctc ccagttcatt15121catcactcat gtccatgaat cttttcattt taatactcta caattaaatc ctgtggcagc15181tgttttctct ctcacaccct catagaagtg ggtctaaagc tgggatgggt gtttttcttt15241ccctctcgta actttcagat tactctactc tctttccttt ttcctttttt tttttttttt15301ttttgagaca aagtttcact gtgttgctta ggctgttctt gaactcctgg cctctagtga15361tcctcctgcc ttggcctccc aaaatgttaa gattacaagt gtgagtcact gtgcctggcc15421agattattct ccgtctaatt cctcacaaga catacagcag ttcattatct cctgtcatca15481ctctatacaa aatattacct ttccttgtca caatcataag ccagtcttcc ttccttgatt15541tttgctttct acctgaaatt aagtagttaa atatactaaa tttcaccacc attctttttg15601ctaaagttcc cctatctttt tgttggatga aataatcttc tattttttaa aaaaattcat15661tcagtaatct tgtttgttgt atttttcWtt ttttaaaatt taattatgga catataatag15721ttgtacagat gtatgggggt acatgtgaac ctcatgaaaa cagagcaata taaagacccc15781tgttgagaag ggataacatg aatgagaaat atgcatgtct ctttaagaag aggaacagtc15841ttaattaatg gataactata tagagtcaat aattcaagca taaaacactt tattataata15901gcatattggg aatagtcttg tctatttgta taaaaatggt gaagaaatag aatatttggg15961atccatggag acaaataatt tatttgctaa ataacaaaat ttggacaagg cttgaaatat16021atataacagt taagagcttc agctctggtg ccagacagct ggagttgaag cttattctca16081gttttaatga ttgtgtgatt taaattgtgc tgaatctttt ctttctccaa tgtgtaaaac16141attgatcata gtgctatcta tctcatagaa atattatact taaataaagt cttgcattta16201aaatacttag aatagttctt accatatata ctcaaaaaat tttaggtact attattattg16261aattttttgg cattccattc aataaatcac gattctctta tatagttgtt ttgctataga16321gcctttatta atgtgtctta attacaattt cctatccata atatttggcc aaatttcaca16381ttttatgatt gccatagttt gaatgtttgt attttcttca aaattcatgt ggaaatgtaa16441tccctaatgc aacaatatta agaggtgggg ccttttagga gatgattatg atgggtttgc16501cattatgatg ggattaaaag gcctgaaggg aactaaatag gtcttttaac ctttcccctc16561ttctgccatg aaaagataca gcattcaagg ttccatgttg gaagcagtga cgaagccctc16621accagacacc aaacctgcca ctgccttagt cttggacttt ctagccttca gcactatgaa16681aaaataaatt tctgttattt ataaactacc tcatctcaga tactttttat agcagcaaaa16741tggactaaga caatgccagt cacatgaaat cataaaatat ggcaacataa tagttatggt16801ttaacaattt gttttgtttt ccattactca ctgaaaatgt aaacaaactt aaatggactt16861agttgttttt ttccttcata tgtagttctt ttctttattc aatattaatg cccagtgcat16921ctcataatat taatggacag gtgactattt tgtttctctc tgcaatggca taaataaaat16981gattttaaca gcatttcaac ttaaacacaa taaattattt atttatattt gacaacacat17041ctaaatgttc aggttaagta aaaatattct cagatatata ggtttcagac gtttactaaa17101catagaactt ttttcaacat tttggaggct acattaacaa aaactataat ggggtgagga17161gatacctata tgaatatgtg gagtaaagtt tataagaaat tttgtaaggc ttaggatgtc17221aaaaaatttt ttaaaaataa gaaaagaaca tttgtatact ataaaaatct taaaactcca17281gttgtaggta gaagatcaac acataaaact Stgttgtgtt tctacacacc agcaatctga17341acagtgaata taaaaggtaa attaagaaaa caattccaaa ataatgaaat aactaggaat17401aaatttcacc aaagaagcaa aatacttata tacaaaaatt gatgaaacat tgctgaaaga17461cattaaggaa gacacaagta agtagaaaga catcccatgt tcatggataa gatgacttga17521tactgttaag atatcaatac tacccaaagc aatctaaaga ttcattaaaa ttcctatcaa17581aaatttctac agacttcgtt tcagaaagag gaaaactaat gctcaaattc aggtgaaatt17641acaagggaat ccgaataccc aaaacaatct ttaaaaagga gaacaaagtt ggaaaactca17701catttaatat ttttatttta tatatatata tatacatata tatatataca tatatatata17761tatacacata tatatatata tatatatata tatatatttt tttttttttt tccctgtatg17821cctcattaag Kcttccctga gccctgggct ggcttcttcc atggaagata gcagaagaag17881caaggcttgt ccctgttcac agaagatgct agccagatca ggagctgaag atagcaaaag17941agggagaagt ccaacccaca gtcccaggcc ctggtgagta aggtctggtg cgaggagaag18001gctgatgata tggaagggtg ctccagtcct gcttcttctg cttggaaatg gagaatccgg18061agaacctggg ggatgcaaga tggacaggct gctccttgag aacatccagt ctcctagaaa18121aaatgggtgc tctcaaggtg actgaatgaa ctcaactatg ccttgttatt ttaaaaccca18181ctgtctgctt tctgaattga caatcaagaa tccatgtgtg tcttaaacaa caattgttca18241ttgtagtaga acccactggg agaagccttt tggctcagga actccatcta gccacagctg18301attgaattag gggtggatac ctaacccaag tggagccaat cttattctgt gcccactgca18361atgtaagatg taaaataggt atttttgtct ccttggatca gtgctgtatc tttagtgtct18421agaattctgc ctaccacaca gtaggggcta catgaatatt taatgaacaa atgaatgaat18481aaataagtct ctgtgaggaa tttggaattt tgaccttgga aacacagaga atggcagttg18541tggaaactga gtcacattgg ctgcataagc tagaaagaac acccactcct tcccatgtct18601gaggtcttcg ggtctatctc agtcatgact gagtcctgac tctttctaaa gatgattgga18661ctcctcttaa ctttaggaca gatggctcaa catcctaact ataaaactcc ttcctccttt18721cctgcttaca ttcatttctg ttgcaaccaa aaacctttaa tgacatgctg agaaattttg18781caccttgaca tattctgttc cccaccttag gagcttctct aggagtcata atcactcctg18841gctgtacctt gggctgcatc cagatctgcc ccaatgccac cacccccagc tctgtgggct18901ctggctctaa gactacaggg acccagaagc aggaaagagt ggcatcatgg aattccatgt18961cctttagggc aggtgggagg tactatgcct cttctccatc caagaccgct cactacatcc19021tgtcctcaga tatggctctt gggaccctca agtcagatac tcctaatttt tcatctgctt19081ttgctctaca gacagaaaga ggaggtgcca aagaaatcta cagattcatt caaatcctta19141ttaaaaattc tcacagactt tttttttcag aaacagaaaa attgatcctc aaatccataa19201gaaattacaa gaaaccttga atttccaaaa caatcttaaa aatggagaac aaagttggaa19261ggctcacact taatatttta aaaattcact acattacttc tcagcctttt ggctaagatc19321aagtataaaa cttactacaa agctatggta atcaagactg tgttttattg gcataaggat19381agacatatag atcaatgtaa tggaattgag agtcttgaag taagcccata tatctatgac19441taattgattt tgacaagtgc gtaaaaattc attagggcat aaagagtctt tttgacaaat19501gatgctagga caattagata tccacatgca agagaatgaa gttggacccc taactcacgt19561catatacaaa acttagctca atatggatca atgacctaaa tataacaact 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aaaatgagaa20461aatctgtgtg attctactca tatgaattgc ctagactagg ccaattcata aagccaaaga20521ggagatcaga ggtcaccagg aactgtggga aaggaaaaat agggagttac tgcctaatga20581gtccagagtt tctatctgtg gtaatgtaaa agttttggac acagaggtga tgcttgcaca20641acattgtgaa tgtagttagt gccacagaat tgtacactta aaatggttaa aatgacaaat20701ttgttatata aatgttatca caataaaatt aaaacaaaat aaatgtgtaa attaaaaaat20761taatattcca gaccataaaa acatgcagca tggaaatgac tgtcattaga taagaacagg20821ttaaactttt aattttatat gaaatgaaca taaagatacc aattttaaac ccagcacatg20881aaaatttgat atcaatagaa acaggaaagg aaaaagatct gcaataaagc attaaaatag20941agtaaaaaga agaaatgaga agatagaaaa caatgcaatc acaattgtat tgagtgtaaa21001aatgtttctc aatagtaatt ttgagattac attattaaat aaagtgtcaa aaatgaaata21061tttgttttct acaagagaca tttaaaaata aaatgcagaa gtgttgaaaa tgcagaggtg21121gaaaacacac aatttagaaa tgataaatgc ttgaagtgat ggatcctaaa tatcttgact21181tttattacac attatataca tgaaacaaaa tatcacatat accttacaaa gttgaacaaa21241tattatgtat caaaataaaa taaaataaaa tgtaacaaaa ttagggaatt 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caggcctcat24661cttttattta attatatttt tcatatgaca taaattattg catagaaaat tacataatac24721tacaagaaaa taaaaattat ctataatccc aatatctaca ggtaaagaac ctagacatcc24781agtttatgta taaatctaat caaaacagat tttttaagta acatgcttat tatctgtcat24841ctatctatgt tgagatctat tttacaacgt atgtagaaac atgttaacaa tggttagttg24901agtactgcaa atgtgcataa tcaatttctt ctttatatat ttttgtgttt gctaatttta24961gatgaaactg tattttatag tacaaaatgg agcttttgat gaaaggaaca ggtatcagta25021aaaataagct aatattggca aaaatagcag aagaaaacat aaatcaatat gagatcatgt25081aaattaccca cctattgccc caaacattac aaactagtta cttactaaac agcaaattaa25141gaaaaaatca taacacatat atggcatagt gttaatgtat aaactagtca caaaattggt25201aagaaaaact ataagacatg aaaaaataag gagaaaacaa atgaacaatt cccaaaaagt25261atatgctatt ggttaatccc gtagtaatgc ttaacttcac tagtaatcaa atatatgtga25321agtaaagata tttttgcaat caaagtagtg acattaaaaa taataacctg tttgattttg25381agactgcaac aggacggata ttttttcact attaacatat aggtttatta tatctacaga25441gcaatttatc aattctgcaa ggaatttatc aagtttctcc ccattggaat 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aaatttcaga30541tttttggatt agggatactc aacgtgtaat aaagaaatga cctattaaaa tttacataat30601ccaattaaag ccattctttg aaggaaattt gtagccttga atgcatcttt tagaaaggca30661gggtaaaaac agatgaattt tgttttcatc tcaagaagct agaaagctaa gagtgaaaga30721aaatagaagt caagaaatta tagtWacagc agaaatcacc gatagaaaag aattaggtac30781agtaatatac taatgttggt caaaagaaaa tacaaattac tacagtcctt agagatatca30841gaaatatggc ctgggtgtgg tagctaatgc ctgtcatttc agcactttgg gaggcccagg30901tgtgagaatc acttgagtcc aggagtttga gaccagcctg ggaaacatag caagacctta30961tctctactaa aaaaaataaa taaataaaaa taatttagca gggcatggtg gtgtgcacct31021gtagtcccag ctacttggga ggccgagcag gaggattgcc tgagcccagg agtttgaact31081tgcagtgagc tataattggg ccactgcact ccagcctggg tgacagagtg agacctcatc31141tctctctctc tctttctctg tctctctctc tctctctcta tacatacata tatatacata31201tatatatata catatacata tatatatata tataatacta tataatatag ttacatatcc31261ttgtatataa tcttttatta taagacaata ctgtgaacaa ctttatacaa aatttcatca31321agaatactta taagactatt acaggctaat atagcctgaa catagatgca aaaattccaa31381acaaaataga gtccagcgat atataaaaga ataattcatt ataacaaaYg gagttttaaa31441agccaattgt gagattaaaa tgaaataatt gaagatacag tcaattaaca caaaagaaag31501ccagaaaaag gacagaggga caaaaataag tgagataaat gaaaaacatt gagcaaaatg31561caagacttac agccaaccat actgataatt acattaaaca tgatttgact aaacactctg31621atgaaaagat agagatcatc agaatgaata aatgaaagca caattaaatg ttatgcctag31681aagataaaac attaaacata aaggcacaga tagattgaat gtaaaggaaa gaaaaagcta31741tactatggaa tttgtaacca tagaaagcag gactggttSt attctcaaag tggctatatt31801atcaagacaa gtagtagaaa aatagaggga agttgtataa tgataaaata ttcaatttat31861caaaaatact taacaatcct gaaggtgtat cagactaata attgtgactc aaaataaata31921aagcaaaatt aacagaacta aagcaagtga taggcatagc aaagatttaa aaaccccttt31981gctgtgatct gcatgtgtct cctccaaagt ctatatgttg aaacttaatt gccagtgtgc32041cagtattaag agatggttcc tttaggaggt aatgagggca gacctctcat gaatgagatt32101aatgaccatt ttgatgtgca ttctaggtat gttaactcta catgccttag attgtgcaat32161agtaactggg ctcttatgaa agggttttaa caaMttccac aagttctaga ctaatttctg32221cagttacatc agcagcaaaa atattcacaa aaacaatggt gccactgcat ttcagcctgg32281gcgacagagt gagactccat ctcaaaacaa acaaacaaca aacaaaaaac ataaagtaac32341tggctaaatc catattatta cagagacaag attgttacct agaggaaata agtggttttc32401attctatttt gcttacttct gttaaatttc taacatccac Yttctgtaga tctRaatgRg32461tggattacaa cttattcaca cctctttttt atatataggt gattattttc tctttaaaat32521attttaaaaa ctattttaga ggtcagtcct ggcccaggaa gaatttattt attttatttt32581atttatttat ttatttattt atttatttat ttatttattt atttatttat ttttgagaca32641gagtctctct ctgtcgccca ggctggaatg cagtggcgcg atctcggctc actgcaagct32701acacctcctg agttcacgcc attctcctgc ctcagcctcc ccagtagctg gaactatggg32761cacccgccac cacgcctggc taattttttg tatttttagt agagacgggg tttcaccgtg32821ctagccagga tggtctcgat cttctgacct cgttatccgc ccacctcggc ctcccaaagt32881gctgggatta caggcctgag cccgcacccg gccaggccca ggaagaattt aaatggtact32941tactcagtga cacaggacat atacaaaaaa agagtacgat gaagcaagaa agattacacc33001aagacttctt gttgacttct ctctgaggcc tacctgtgta gctaagagtg cccgtccttt33061caggccacat ttcaggtgcc agagaatccc caagaaagtt ttcttcattt ggccgtatcc33121aaaaatcaca acatatgagt gacccaaaga atactgactt catatcataa accagatatc33181acaaccagtt tgttctgtag caaaaaatac ccctgtaaat gtcaagaaaa gggcaaattt33241ttatagagca acaagacaaa aaaggaaaac cgttttcttg gctctgaaat gggcccgtat33301actggggttc tgcaatccct gaaattgaac ctaatgtgtt tcatgtgtct tcacgaagaa33361aggagtaaca acaaaaagaa aatcgaagaa atagagaaag aagagagaga tccaataaag33421aagattatta tattattaac atttttatta ttacttacat tgagtaatcc agtcatatgt33481ctttcatatt tttttggaca cgataccaga agacatcaaa agtgtacgtc aaaggaaagt33541tggtaaacag aaaaggcaga taccagtgga agtatgaaag ctaccttgtt aattctccat33601tttagccaaa agtaaaagag ataggagaaa ttgacgatct ttaggaaata aaagacagca33661agacaagtag caaatcaagt gcacaagtgg ttggccagtc tccggacaat ggtaaggata33721tggtttcttt ccctagcatc agggattttc taatagaaga atattgattc tggctaaggc33781caaactagta agaatgaagc caaccatgca taacttctga tttctcatcc aggcaatgca33841atctgtgagt ccaatgaatt aatttcctac attcctttta taaatcccct acctattaca33901gtcatgaaaa cctccaatat attcaacatg gctacaaagc gaaaattctg atctgcagtt33961tgttgtgtga ctaattttca gatgacttac tggataataa catagatctt atgtttgatt34021gtgcagtgtt tttattttat catggctttt ctttttagct ataaagttta gcaaactgca34081gtaagacagt gaaatcactc tctgtaacat tcattgaaaa tttctaacta cctctgctaa34141gaatttccag tcttggtcca gctgtcagct acaaactgta aatttcttta tagaaagatg34201atcacactct ggggactgtt gtggggtggg gggaggggga gggatagcat cgggagatat34261acctaatgct agatgacgag ttagtgggtg cagtgcacca gcatggcaca tgtatacata34321tgtaactaac ctgcacaatg tgcacatgta ccctaaaact taaagtataa tttaaaaaat34381taaataaaaa taaaaaaata aaaacaaaat taaaaaaaaa gaaagatgat tgacaaacca34441aattatcatt tgctaacatg taaataaaga cacagactaa ttttcattgt tttgaataaa34501attagttctc ctcttccaat gaagtgtttc atttgattta caaatctgaa gtttgaaaca34561gaaacctttc accacattaa aattattcaa catgtaggga aaaccagcaa tccttatgct34621aattaattat aatgcagtca cagtgtagat tgctacatta caaagtaaaa tacagagctt34681gaaattttca agaaacttgg tgggcaatat atgaatctaa tatgagtatc ataattatca34741ggaaaacttc ccccaccgct ccccaccccc cactataaag atgcaggcct ttcaaataat34801ctgtcagtag cattttaaac acatttttaa aaatgatgtc tttcagtgaa acataagcac34861cccaaactaa acatggaaaa agtgaacttc ttttgtttcc tcaaaaacaa gattctagca34921ctttgggagg ctgaggcagg cggattgctt gggcccagga gtttgagacc agcttgggca34981acgtagcaaa accccgactc taccaaaaat acaaaaatta gctaggttag gtgtgttggc35041acacgcctct gatcccagat acacaggagg tggaggtggg aggatcacct gagcccaggg35101aggttgaggc tgtagtgagc cacgaaaaaa aaaatgtttt ttttgagata Waagagtctt35161caaatatttc cacagaactt tgttaaggtt acattgtctt gaggggaaaa tgcttaaaaa35221gtcatgaata tacttaggat gatctgttat gtgtatatcc atatacacag atataggtac35281atatatggct acatatacat aaacatatac atgtatacaa atacacacag acacatctat35341ttatacacac attgtactgt gWtttgtcct ctacttctct gtattttagc ttgtctggtt35401tttgttactt ggattgcttc tttttttgca ttattttatt atttttaata aacgcaataa35461ttgtacatat ttatgtgata cagtgtgata tgtgaataca tttatacaat gtgtaatgat35521caaatcaagg caattagcat atccgtttct caaatattta acatttcttc gtgttgggca35581cattcaaaat ttgtttttct agctcttgta aaatatacaa taaattgttS taattgtagt35641caccctactg tgctatagaa cactagaact tgttccttct acctggctat acttttgtat35701tcattaacca acctttggct atctccctct cccttctccc ctatcacatc tctaggaacc35761attattctgc ttcctacttc tacggaatca actttattag cttccacata tgtgtgaaca35821tgtcatgttt gtctttctgt atctggctta tttcacttaa cagatgttct ccagtctcat35881ggatgcttcc ataaatgacc aaatttcctt cttttaatgg ctaaatagta ttccattcat35941tatgtgtata tatcatgttt tctaatccat tcaaatgtta atggacactt aggttgattt36001catgtctcgg ctattatgaa tggtgttgca aaacacatgg gagtgcagat atcacttcga36061catattgatt tcctttcctt tggatacata cccagtggtg ggattgctga atcatatggt36121agttatattt ttagttttta agaacttcca ttctgttctc cataatgact aaactaattt36181atatttgtac caacagtgtg taaaacttcc tcctccacat cctcacaagc atttgtgttt36241ttttgtcttt ttgaaaatag ccattataac tagaataaaa taatatctca ttgaggtttt36301tatttgcatt tctctgatga ttagttatat tgagcacctt tttatatacc tattggccat36361ttgtatgtct tcttttgaga gatatatata cagttaattt gcccatgttt taatctaatt36421atttgtgttt ttgactgagt tccttctata gtctggatat gaattccttg ataaatgaat36481agttttcaaa tattttctct tattctagag gttgtatcgt cagtctgtcg attgtatatt36541tgtgtatgct tttatcaaat caacataatg taaactaaat gagataaagc taaaatggtc36601atcgcttgct taacataaaa tgcattattc atctaatttt attgttacta ttatataata36661ctataatttt aattttgcca ttgattatat agttgcaatt ctgatggaaa cagtgaaatc36721actttctttt aacttatttc aggcagataa tttcatcaat gaggctcaat gatctatcac36781caaacataat aaaagaagtt ggattaaatg aaagggatgt gtgctgagtt atttgttgtc36841ttcatttttg agagaattac caatcaattc aggtgtgttt atgaggattt agatttcctt36901atattcatgt aacaccgaag gttcctcagS acacagagag aagcctgttt cagtttgctg36961ttccataaaa tcagaaaaaa atgaatgact gaatagatag aaaaatgcta actcaagagc37021aaaaatctgt gccacaatgc tatctagatt aaaataattt cgctttataa tcgtattgct37081caaatagtat ataataaaga ggagcaggaa tgaaattata gatattaggg gatgtcaaac37141ttatccttgc attcttattg tacaaaattt cctcagttta catttaagcc cacatgtaaa37201attacagcag aatattctgg aaattgccca acaggtgaga ataaaatcta tcagggagag37261tttccagcgc ctgatccaat caatgcagtg aaccagcacc ataactctac ttctctgaat37321ccccattatg aaatctatag cagaaatcat tgtaagcata ttcttcaaca tgtttgccat37381gcttgattat gggatctctg ctttctgtac accactgatt tataaataag atgttataaa37441tttgtgtatc caaagcttta gtgttcaata tgtttcttta tcctgtgctR ttgattgaca37501ctggaaaaga atggaatgcc tccagtgtgc tcccagacaa agtcctagtt gtctttgaaa37561aacgaaaact acctttattt ttctcagaat ttcagctagt gattttcaag gcagatatta37621tattacctgc tgttgtgaca ctgtttataa tttccttgta aagctatcaa ctaggatttg37681aattctgatt tgttaaaata caaaatagag attttaaaat attttttgca tctttttttc37741cttaagattt aaatgttttt tattcattca ccttagttat aagctagaaa cattaaaata37801tggtgtcttc atggatctcc tgagaagcaa ggcagtcatt gggataaatg cctatatgag37861aaagcaagga gagagcgaaa ggtgaacaga gctattgtac taggatataa ctttgacccc37921tgtgaaggag agagagaggg aaagaaggaa ggtcttaggc agcagtgcag tcctgagaac37981atttcaagat gtccagtagg gagttatcaa gcccaaggtg caaattagag gagtcctgag38041tctcccagga gcaggcctga ccattgaatc tgcccccttc tctgtctttg gctgaaagcg38101gctcatggaa gtgaatgggg tgatagattt catagcatag gtgccatgct tgttagctgt38161tggggaaata cgattaaaaa caaagtctcc tcccaaccca gaaagtctct ccacaaatgt38221aatagagaaa gaaaatagtt ttcttattaa ataaatatta aaccagaatc tgatatacat38281tacaggcaac ctactaagag actgcaaaga cagaaagaga tctcacccgt ttttatatag38341ccaatatatg catatgaccc aatatataca ttttctcaag ttaagtgata actaatcccc38401aagagagagg acttggcagc attatttatt aYgcatagtt tatcttaaat ttacctggaa38461attggggtgg ccatctgtgt tagttaacag actttaaaca aaggacaaat aaacacagat38521ctttatgtag gagatagtct tgccatttgg agcctggtgg ccattgaagt taggctcctg38581ctcccagcag aaactgagag ataagggtgc ttatttgtaa aagagatgat taagcttctt38641tatttttagt gtgtatttgc ccttctgcag ctaattgtgc tccctcaRga cagagatttc38701agaggcacat tcctatcaca tgccacaaat gtctaaaatg acagtttatc ttcttactca38761cctcgccaat acatattatg tataaagtac ccaaggttta agtaaataca caaaatctgc38821tttctgatac tatatcagga tcgcttagag tctgtggcag ttttgaaaca tggctgcaaa38881ctctttgatc ctcttccttt tgaggcctag ggtctgcaga ccttcctctt aaaactgagt38941gggcttgtaa ctgctttaaa caatgacgtg tggtggaaac gacatcatat actttctaag39001gctatcaaga aaaactgtat ggcttttccg ttactcactg gaaagtttcc tcttacaatc39061ctgaaccact tcataagaag tctgacaaag ttgagaccag catgctgtga ggaagctcaa39121gccacacgag gaggccacat gtaggcaata tagtcaacca tttcaaatga gcccgtactt39181ctgatcatcc aagtccagtg atagacatga gagtaaaggt ctgcttggtt attgcagccc39241ctgccacttg agtcatagtc cgctgtctac atattctaag gtgaaggtct agacattttg39301aagaagagac aagccttctc atagtgccct gtctgaatta ctgacccaca gaatctggaa39361gcataataaa gtactgttgt tttacaccca ctagggccta ttggggtggg ggttggggga39421ggaggaacat caggaagaat agctagtaga tgttgggctt aatacctagg tgatgggctg39481atctgtgcat cagaccacca tggcacatgt ttaccaatgt aacYgcacat tctgcacatg39541tacttcagaa cttaaaagtt gaagaaaaaa tacacaaaat aaaataaaat aaaatattgt39601tgttttgtat ctctgagttt tggactcagg gtgttttaaa gatcaatgca taactaaaat39661agaattattt agcacataca taaggaaagt cttttactag cttagttttt attttcttag39721catcattatt tatagtagcc aaaagataga aaaaaaccca aatgttcatc aatgaataaa39781taaatagaca aaaggtggtt tagtcatgta atcaaatatt atttaactat taaagggaat39841aaagtactga tacgtacaac atgtatgagt cttgaaatta tgctaagtaa aagaaaccaa39901tcacaaaaga tcccatatta tataatgcca ttcagtcgaa agtccagaat aggaaaatat39961acagatgcag gaagaagatt aatagatgct taggctgggg tggggagaaa ggtgggatga40021tgggggaata gggaggtgat atctaatgga tatggggttt ctttttgaag tgataaaatg40081ttctacaatt gacagtggtg atggttgcac atgtctgtgg aatatattaa aaatcattta40141attgaacact aaatgagtga attgtatatt atgtgaacta tatctcaatt aaagcattta40201aggcaaaaac aagttacata tgacattttt ccttatagaa tatgtaacat ctgtgtatat40261ttttcataat tttattatac cttgtagtaa cactattagc tcagtcatct ttaattctgg40321tgaggtataa ataaaatacc aaaagcttta catcatttca cttttgttga ctattactta40381ttgagaaact ttttactctt tggatgagac atgataggat aggctatgct gtagcatcta40441caatgtaagt ttcatgaaag gttcatttct cggttcacat tacatgacta attgaattta40501aaaatgcaga gtgaggtgag gatagttttc atgtagtctc tcaggaatac aagctagtgg40561agtatctaac actaaacatg tgtctttcaa gtccctcact taggaagaaa agagacacga40621agagccttct tttacatatg aatattcaac tgttccaaaa tgattagttg aaaagataat40681cctaatcttt ttttttcagt ctttaagtgc tcttttcttt tattctcagc cccctttatt40741gttattatta ttttcatttc attattatta tactttaagt tctagggtac atgtgcacaa40801cgtgcaggtt tgttacatat gtatacatgt gccatgttgg tgtgctgcac ccattaactc40861gtcagatttt atgtttcttt atcctggctt gataaaaccc attgtctcag gacttttctt40921ctaaatagaa aagtagtctg aaggctcgtc ctgattcatt ttaagactgt agtatttctc40981ttctgccagt taatatgttt tcactttttc tattttcttt ttatatccaa tacatttcag41041tatgaaattt tgtgatggtc cactagtctg atgtgcacaa tttagccagg aataaatatt41101agtggattca aaataggcac tcaaactatc tgtccagatt ttttaagtgt tgttggtttt41161tttctttctt tttttttttt tttcaaattt caactgatga atgaaagtag ctgcctagag41221aataatgagg tgggtgccaa acctgggttc attgaaggcg ttatagcacc tgtgccatgc41281tataacttag ataagtgacc ttatctaagc ccatggcttc aaatgccact gaaactggtg41341aatttatctt ttaggaatgg aagggctata gagatatttg atgaaagaaa actaagagga41401tttgtcacca gaacatctac cttttaaaag ggggctaaag aaaattctct agccaagaaa41461aataaaaaag aaagtttcaa acaaaaagat taaagaaaac acaatggaaa ggaagaatga41521ataaattcat cttccttttc ttcttcagtt tggtaaatgt atttgacagt tgaagttacM41581attatgacat tatcagctgt gattgtaaac ttgatttcag taacatttga agccatgggc41641ttagacaagg tcacttagga atagtgtaga tatcaggaca agtaagacct ctgagacagc41701catgtgggaa ctcgacatag caagcaagcg atggggagcc ccacccagtg actgtcttca41761ctctagcagc tctcagtgaa ggcttctgta ttaggccatt cttgtgttgc cataaagaaa41821tagaggggcc ctgcatggtg gctcacacct gtaatcccag cactttgaga ggcagaggcg41881ggcggatcac gaagtcagga gattgagacc atcctggcca acacggtgaa accctgtctc41941tactaaaaat acaaaaaatt agccgggcgt ggtggcgggt gcctgtagtc ccacctactc42001agcaggcaga ggcaggagaa tcacttgaag ccgggaggtg gaggttgcag tgagccaaga42061tcgcgccact gcactccagc ctgatgacag agcgagactc catctcaaaa aaaataaaaa42121aataaaaaat aaaggtaatt aataaaagag atttaattag ctcatagttc tgcagggtgt42181acaggcatgg cactagtatc tgattagctt ctgatgaggc ctctggaagc ttacaatcat42241ggcaagaggc aaagggggag gaggcgtgtc acatggtgag agtgggagca agtagaggag42301gcgccacaca cattcaaaca accagatctt gcatgaactc agagcaagaa ctcactaatc42361accgagagaa tggtgttaaa ccaggagtgt ccaatctttt ggcttcccta ggccacgccg42421gaagaaaaag aattgtcttg ggccatacaa aaaaatatac taacgatggg tgatgagcta42481aaacaaattg ccaaaaaact caatgtttta agaaagttta tgaatttgta Ytgggtcata42541ttcaaagcca ttctgggctg catgcagaat gctggccatg tgttggacaa gcttctgcta42601caccattcat gaggaatctg ccccatgatc caatcacctc ctaccaggtg ctatcacaac42661atcgRgaatc acatttcaac atgaggtttt caggggacaa acatccaaac catatcagct42721tccctgtgcc aagcatggat ggagctgaga gctttatatg ggttacttac aaaatataca42781tgttttatac aataatatta atagtacaaa ataattactt tgtaccaaaa attaattgta42841caaaatatta aaatatttaa cataacattt gtacaatgta tataaaaata taaatatccc42901ataaaatttg ataatagcat atgctatttt atttctataa tatagacact cttcaatact42961cagcaacttt gttcacatta gaccactttt atttgtaatt attgatatgt tgggtcacaa43021acctgccatt ttactttRtg atttctgctt atccgttttt ttttcttttt ttgtaattgt43081tgttttgtac gccttgcttt catgtgtgtt actttaattt tcttttttta gaattccatt43141gaggtttatc tgtggtattt ttgagtatat ctctgtgtgc agacatctta gtggatgctg43201taggttttac agcacatgta ataacttatc atggtttaat agggtcaaaa ttttagtact43261ttgaaagatg tacggaaacc ttattccttg attccctata tgtctcttta ccctcctctg43321ttccttatat agttgtctta aatatttacc tatatacact taaaatcgca tctgataatg43381tcataatttt aacttcagct gtcaaataaa tttaccaaac tgaagaggaa aaggaagatg43441aagttattca ttttttccct ttccattgtg ttttctttaa ttttggtgtt ttaaagtttc43501ttttttaatc ttttttcttt ttttttttcc tggatagaga attttcttga gccccttttt43561aaaaggtaga ccttctggtg acaaatcctc tcagctttct ttcatcaaat gtctttatag43621cccttccatt cctaaaagac aaatatacca gatataaaaa ccagaattga aagttatttt43681atttcatcac atagacagtg ttgtgccact tttctatggc tttcatctat ttctgatgtt43741tcctgcttcc atttgtattg ttttctctcc tatagatgag ctatttcctc tagctgcttt43801caaaatttgt tctttctttt aattttcaga tattttacca tggtatacct tagtttggat43861tctttgtgtt tgtcttggtt agttttatgc actgaaagtt tgtgtcccct caaaattcat43921atgtagacat cctaaattca atgtgatgtt atttggaggt taggcctttg ggaggtaatt43981agggttagat taagtcatga gggtggggcc ctcatgttga gatcagaggc cttataaaaa44041aaaaaaagag agagagagag ggagaaggag acaagagata tctttttctt ttctccaaca44101tgtgaggata caatgagatg atgtccatct atagccaaaa aatgtcttca gcagaactca44161tctgtgctgg cattctgatc acRgtcttcc agcctccagt attgtgagca acacattttt44221gtttttataa accacccatt ctatggtatt ctgatacagt agcctaaaat ggctaagaga44281ttttgggttt gcttgaattt aggaatctgt gggtttttgc ctattgccaa attaaggaag44341ttttcagtct ttgagacctt tctcaaagtt gcccatttct tctctccttc tgggactctg44401ataacacaaa aattaggcct tcagttataa tactacaggt ccctgaggct gtgtttatag44461ttttttcctg cttaccttca tgaatttttt atgtggttat tgtaagtttc agttctaaaa44521tgtccattca gttctttcat atattttaat tttttggctg agataatttt taaatttgtt44581tcatatatgt ttgtaagcaa tatactggaa gcatttttat gatgactgct ttaaaatatt44641ttctgaataa ttccaacatc tttgtcattt ttgttctgga atcttctaat taccttttac44701attcaagttg agatttttcc tggttctttg tataccaaat gatttctaaa tgaaccagga44761cattttaggc attatgagac tctagaactt atttaccttt tctgtcttag ctagcttcct44821cagacactac tccagcaagg caagggagtg agggagggac actgcattac tgccaggtga44881tgatagaaat aaaggtttcc tctcaatctc tgttgacacc taggcaggcg gaggttcctc44941attactgctg gctggagggt ggattctggg tcaccactgg gcctccactg atagcctgtc45001tcggaggaag aagtgacttg ttactgtttc ccacatggcc tccacaagca ccacctggta45061tggaaaggag ggtgcttctt cattgctgct tttagagtag atccagctcc ccatttgctc45121tccagtcata tcaaggtgtg gaaggagagt gaggggctta ttaccacaag ttggggatga45181aagttccaac ttctgctatt ctgagatact attctggagg agggttggga caccttgtca45241cagcctggct ggtatgaaga tctaaagatc taagctcttc acttgaggta atagtgtttt45301ctgtggtact tgactacagt agagtggtta ttgtcgaaat gttttctgcc ttggtagact45361atttccttga cctttgccta aaataatagg cttttgttgg gaaattctca tatgtgcctg45421ttagtatttc tatgttgatg gcattttcag ctaaaagtct gcaaattata aagcagaaaa45481gaaaacttag aggattcatc actatacaat ttattaagtc cctaccacat ctgccttggt45541ctctccaggt ctgagttttc atatatttta tatataatgt tcagggttta tagtttttct45601tagtagaagg aatagggcaa aatacattta ctccattttt ctggaagcag aaattggttt45661actttctgta agaaagcagt tggtgaattt ctgtctaaat tctctgcctt ttcaagagga45721actgggcttt acttctcaga taacaactga gcaacgatag acctacaggt ggcattactc45781tctgtatagg tagagaatag gctgaatatt aaatgttaag gagcagaatc attggaattt45841aaatgaggaa ggagacttag tttttattca cgttaaccag ccacctgatg acatgcaaca45901gtgcgtttgt tcatcaacat accttttaga tggcctttct gcttcttttt tgaatggctt45961taatgctaaa gaaagcaagt gtttatcaaa taatctattt tttagataat tcattattag46021aagttaattc attattagaa agataattta ttattagaag gtaattcatt attagaaaga46081acaaaacgag tcttttttaa taaaagaata aataaattta aatgtattga acttttattg46141ttgtatgtca tgtagggtaa ttttgtatac atgttgcatt ttacaagact taaatcgtgt46201aattttatat acatcttgta gggtaatttt atatacattt tataaggtaa ttttatatat46261attatgcatt Waattcttgt aagtagccct ctgccttagc cagttcgagc tgctattaac46321aaaatatctt atcttgggta atttataaat aatataaatg gatttgtcat agctctggag46381gctggaaagt tgaagattga gatggtacca gatttggggt tgagtgagag cccattccaa46441acagacaatt tctcctggct tctctctcat gaggcagaag tatgaaagaa acatgaacat46501tgagtcccta catgtcaaaa gagatggaac agctcagcag cctttgggag cttctttttg46561tagggaaatt gatcccattc atgaaagcag agtccacacg acttagtcac ttcccccaaa46621gactccatct cttaatacta ttgcataggg aattaagttt caacataaat ttattttgta46681gagacataaa cattcaaact atagcattct gtccctggtc atcccccgaa atatatggtc46741ttctcacata ctaagtacat ttatttcatc tcccaaatcc caaagtctta actcattcca46801gcatccactt taaaatctaa atccaaagtc ttatctaaat atcatcaaaa tcagatatgg46861tgtggccaat tttctaatat tgaaccatct ttaacatcct catcctcttt caacgtggtt46921tattattctt ttagcatact gttcgtttgt ttatgtacta ttgaatagtt tccctaacag46981agtatccttg ctgtcctata tattttgttt aatgaaactc agaatgaatt cagaaacttg47041ttgtttcctg tacttaaaaa atctaaaaaa gaattatgtg ctttttaatg ataaagatta47101gatattaaaa ttttctgtat tcagcgacat tggaggtgat aatgagaggt agctggagac47161agttacatat caaattcttt tgcttcttag ggttattttc tattcaactt tgcctcagca47221acttgagtta aatttggtag tctatattat ctgacaataa tactgatatt gctggaattt47281ttacaatcag aacagagttt tactcaaatt tcttgccctt taaagtacat tatgctgcac47341cctttatgaa atccactcaa gtttttaaaa agaatggtga acgacttagg gaggaagaga47401gctgagcaat gaaaaaagag gagaaaagag catagtgagt tttatagaga agagatctag47461aactacattt atgcccctag aaaccaggat taatagtttt ggaaatttta agaattcccc47521agcacttgca actccctctc atttgttata tattccttgt tttcctagag ttacaagaat47581atcaatgaaa gatgtaaaaa taattttaag aatttgcatt tgtgctatgc aatctaggac47641agaaggggaa caatggaact ctttctcctt ggcagctggc tttattaaga taaaggagga47701gggaagcctg ctggaagcat caatgagcaa gagtcccaga tattcttaga ttgtattaat47761ggccctcaaa ttctagactc agaaacaccc acaaagagaa gcaacaatca gaaattgcat47821gctattaata ttttattggt atactgaaga aagagttatg accacattat ttcaatgtca47881tggctttctg aaggaagtta tcttcttatt tattttctga aacaaaaaaa aaaaccaagg47941aaatttatac acaacataca acatggcaaa acttatctaa ttccttgatg atattactga48001agtaaattat tgctttcaag attaagaaaa cagatttttt tatggtgttt atgttttggt48061tactgttcaa aacattcaag gttatattta tgaaaatgac tgcaacttga acctgtagta48121gtgaaaaact aatacaagcc tacatatcaa ttaacagtgg ttgactgagg aaatcatggt48181acagtcacac aagagaatag tatacaattg taacaacaaa agaaaaatgt acaaataaat48241caccaagaag atctataggt ctccgtgaaa tgataaagtt gtctaagaca tgtattattt48301gaaataagca aatacagatc tgcatataaa ataatatgtc atttgtggga aaaataatga48361cgtatgctta tatacatata aatatttcca ggaggatgtt caaaaaatta agggtggtga48421cttttggtga agggtgtggg taagtaggat aaggcgtcac tttaagattt agcttcatac48481cattctgttc agttagattt ttttttcctt gagcatgtac taatttcaaa ataagtattt48541taaaaattaa ataagatata agagcatcaa gttcaagtat catttagcag ggacactgga48601cctgagaggc tagtgtgagg caggactgag caaagagtcc tctggcggaa acctgagaga48661aacctgagat ggagagtcct tgggtttgag aaggcagact caaagacagg aggcagagca48721ccaaagggag agcacacccc acttcctcat taccaactca ttttaatgag acaagtcatc48781ttaagaaaaa agttggggag gtcagtattt caaaagataa gaattctttg aaccacttgt48841taaaaataca aggacttgca accttatcca agaatatctg aatacaaatc tttagaaatg48901gggtccagga ttatgtaatt tcaacatatt tccaattgat ttgtgaacac gataaagttt48961gggaatggta gcagtttggg catttaatgg agaatgaact ggaatcatac ctgccactga49021attctagatt accagagtgg ttgctcctgg ggatgtcttg ctggtctgtc cctcYggaag49081aatgatgatg cttcctgcag gctgacagaa ggaaatcggg gtagagagag ttgacggtgt49141cctcgtYggg gtggtcgttg ctgattttga aaaggaggtS ggggaggatg gcggtgatgg49201cctcctggtt ttggtggtct ctgctgagga ccatcatctt ggttaccact atcaccaggg49261ggtctaggta ggagtccttc aggaggaggt ctctggggtc cctgatctgg tctctgactt49321gagtcctcta catctgtgtg agtaattaat ggacaagaat gcatgagctc agtgaagaaa49381aactctcctc tctttatact tctctcacct taccacacag ccctgttctc cccaaacctg49441ctgcttgact gtcaacttct tttgtgccca ctgttttttt tttcttttta tgcagctctc49501aacttaatcc atgtaagagt gatatggaaa gtctcattta tttgctcctg tgacaagtat49561gtttccttaa atgaaaagag gggttcttgc atatcttaga gttgccagag gatgtctcca49621aggacagaaa aaaaaaaaaa agcaaaagca ttatagcttt cagttatgtt actggttatt49681ttttattttt attttttggt tgctgtaatg acttacaaac tgtgactcca tctctgggca49741cctaagccct atgtggaaac tagagctgat ttcccaggct cctggaacca agtagagaaa49801tactaagaga cagaagagaa agacaatgtg aaagcctgca catgatcact aaacagctgt49861ggcaactatt tatcatctgt agtgacacag ctgagtgggt caacacagag aaaagacatt49921catgcagtga tttttttgtt ttgttttgtg ttactccctg aagccacata accgtgcggg49981ggaacactgg gggaagaaag aagcagttaa ggatggagga gtcagaatga gaacacttct50041catttgttca tcatctctca gcagtcattc cagcctggga aaaaagcctg cccactccta50101ttgtcctcaa agccaggcat ctctgtattc aagttggtgg cctggctcat ggtccccaga50161atcaaagatg ggtaagaatt gcctatatat ttaggggcac taatattaat caatgcctga50221cccctcttac cacctcctcc caaaaaaatg atgagaagaa gacactgaag gaaactaaaa50281agaaattcta gtggaaaaag Raagaaaaga attggattga ggatcattgg gatttacctg50341gtatggtgaa agtaaagtct tcatagttca catctaggaa aagaagcaca ggatgaagtg50401aacattacct cataaatctt tcagggctca tagtggtcta tagggaaagg ggtcttctgg50461ccacaccctg tgcatcccct aagttacctc atcaaccatg ttctgtgaag ctgctggaag50521gggaggaaga tgttagggga ggcaggattg ttactatcgc tgagcatcaa ccacgaattc50581aatagaagag tccctttttg tcatccttag gatccctcaa accctaatgc taatttaggc50641acacttctct gggtattttc atgtcatatt ttagatcttt accttcttcc ttctttaaat50701attttgatca tattcacaag cttgcccaag aggagcaacc aggagtaaat atttggatat50761aatcttacac atRctgcctg caacatattg aaattttaaa tgtgattgga agaaaaatgg50821gaatttgggg acctgatatt tctataccac tatgtagaaa gacacaaatg tattatccag50881tcctctatgt ctgacagtac tctgatgttt gtttatctct ttcattgatt ctgcatcccc50941tgtacagcaa ggacaccatc atcgctgtcc actgagatta ctgtagcatc ttcatagctg51001gacttccctg gatcagtctt gcattctcca ctgcatcctt cacagcacag ccaggtcttt51061ctaaaaatac aaatcttact ttgtcattcc tctaattgaa attctctatt gggttccaag51121tgtatatcaa ataaagtata aggccttggc atggaatgag ggcacaacag atgtcatcct51181tggaatgaga gctccaaagc cctacccttc ttctcaacct ccttcctccc ctcctgctct51241tcYgctgcag tggtgtaggg tgaacccctg aggccctaga agagtcatgg cccctcatcc51301cactccccat ctcctttttt aaaaaaataa tttttttacc attatctgtg ctctgagctg51361agctcagagc cagaaggacc actgagagca ggaccagcag catcttgaag gaggctctgg51421agttgctccc aactctgcgt tgagagaaac atggcagctc cctttataaa catgagcaga51481acaatggcac ctttgagctc catactgggt ggacctcacc acctgaaagR ttaggttttg51541ctttcctctc ataaagttga atgcgtctct tattactttt tgggatttta gcccagcagg51601atgtggtggt aggatgtggt taggtacaaa ctgtgacttg agcatagttt ctgaagaaac51661agtatccaag caatcagcac aaatactaca attgaagttt ggtcatcatt tgattttcaa51721ttgggttaga cagttagtct ttccccttca ttggttgtct gtgtgcacac gtgcttacgt51781ttgtatatgt ttgtcagcag tgatcttata gccagaagtg aaaatgatta atatctctag51841ctattagtgt agcataaatt ccatttttat agcatatata cctatatgga tgatatgtag51901cttaatttca taataatata gagatcattt ctgtttaatg ttgagttgtg tgaggacaac51961acacacttgg gcacacgtgg atgacagaag ttttaccctc aggctactct ggcccaaaga52021gattaagatt ctcctaatct agcattaacc agagatactt tattgttgta gaacacaggt52081attaaaacat tctatcttta ttaataYcct ggaggttagt aaggcaaaat tggccacaga52141aagcaccatt agatttctgc atcagaacag tgtgaataca cagttccttg aacaagccat52201gctattttat gtccctaaga cttcttccat gatctttctc ttttctagaa tgttctatat52261gattcagttt aggtcttact tcttgtacca aatattttaa tcacactggt tattgagtgg52321acacaataat acaatctaat tagatagtat gatagcctgt tgaaagcctc aagtattaca52381ttgattttct attttttaat tagtttccat tctatttgct tctcagattg cctttaccaa52441agattatttt ctctgcaata ttcttatact cattcttctt cactcttgtg ctgaacctta52501cttgttgata tgttatattg tgaatcaatc ctccctatgt ctatgtttta tatcttactg52561ctttcttcat gcgttctggg agaaatcttt atttgatttt ctaaacaagg ttctgtactt52621ctctttgctt gctttcttct tttttgtttt taaaatttgg caccaaggtt ttgtgtttct52681gaaaagtttg gtagggtcct gagttggtag cttaatcttc acctgctgat ttttctgtcc52741tatctagtag ttttctgctt atattttcat ggaaccccta gatcaatcag tatcaccagc52801tgccactttt cattacaggc Rttgtatagg tctcgtatta ttgttacatt tttgtacagg52861gctggtgata atttgaggat agcttggttg gaagtatgac agggtcgggg gaatgtgact52921ggaaatctta aagacaggcc tcttgaccat tgtggataag tggatcctgt gctgtgcaga52981tgaaggtctg gtctggcaat tctgaagggt tggaggtaat attacaggaa gattttctaa53041tcaatggtgt ttgttatgga taactttact ttggcaaagt gaccaaaaaa taaatatttt53101ctctggcata attatggaca tattttgaag gtgaaatata ttatgagtta gcaattcttc53161tctatgtggg aagcagaaga gttctagctg tgctttaggg ttttatgggt gagagagagt53221agttgtttgg gcctacagac ccagctgtgt tactaggatt gctgcctctg atttcaccag53281acactgttta acatgggaag tggagataag tagttctgcc taggtggctt atggtagacc53341Rtcaggtagg aaaggaaggt cagcgagaag gagcaSaggg gcgtgccatg cagacatgat53401tcactgtgtg ggtggctgag gaaactgcag tcctggtgga aggcaggctt ctccttggct53461ggtgagtgca ggaagacaac aggtgatgcc tgcaaatatc actcagctca gacccttacc53521ctgacattct ccagtgtaag caatgagaga aagagattaa tgtatcagga aataataaac53581atcagctatg atctcaccac acacaaccac aacagaggtg acggaggagc tgaaacagac53641actgtcagtg agtgagggtg gggtcaaatc gagaagcagg actgcagcag gagcttaggc53701acttgtaggt gagtggacac tctcagcaat ccacttgcct tttacaacag atgaaaactt53761aacatacccc taatataatt cttgatttct acttcctaaa acctgctctc cttcatacta53821atttgttatg gctaccctaa aaaaatgccc cacaagtggc ttaaacaaca gaaatttact53881ttctcatagt tctggagctt gaagtacaag attaaggtgt caacaggttt ggtgtcttct53941gaggccctgt ctccttcact tctagatggc cggttcttgc tgtatcttca catggggttt54001tatctgtaga cgtgcatccc tggtacccct ctgtggtctg tgctaaYgtt cttttcttat54061gaggacaggt gtcagatggg attagcacca accctatcag cttcatttta acctaatcac54121ctctttaaag gccatgctgc aaatagagtc acattcagtg gtatcggggg taagggattc54181aacatgagag tttggaggga acacaattta gctgataaca cctcacaatc ttttctcagt54241tcatgacatt tgtttcactc aaccattcaa aaacataagt gtcactcttg attgtttagt54301ctcctccgtg tactgccctt agcaaatcca attggttcta ccttcaaaag atatcccata54361tatgatcagt ttcataatct ctatcagaag gYcctgagtc aagccatgat tctccctcct54421ggaggacttt caacagtctc cagctgatct tggtgacatt cctgcccctc accacatccc54481aWgcagttct ccttacaaca gccagagtga tcttttaaaa atagaattta gaacatcagc54541aagatggctg actagagttc cctggcactc atttccccac aaaaagaaat caagaaaaca54601aacaatttta tgtcagccag tgtgatttaa aaagtatgct ggagaccacc aggggaacag54661aaacacctct gtgaagtaca gaaactcaat atagcatcct gcctctgaca tactctctct54721tcagtcaagg ttggctcagg gtcatcagta actccattct acaggaaaaa gtaagctgta54781gttccccagt ggtccacatt gccataaaaa atgtcaacaa tctttgcccc actgttctca54841ctggcacaaa aaccagtctg gagagcagtt gggatttcca aactgcattg ccttacatag54901taagagacca ccttgagcac cctctgcccc tgcaatgtaa ggtgctatgg ctcagtgcca54961tctccaaact gaacctacat agagagtgtg tcttgctttg agcatcagta gcacctggct55021ctctatcact tgaggcccca ccatcattcc aacacattca tacaggtatc tgcagcacca55081tgaccctagc ttcccagagc ctagccagat aaactaatca agaccccggc atccgaaccc55141atgtggtgca ccaccaatcc agggaagaag tgaacagcag ggaagccacc catctgccta55201ctagccacga cacccacatg cacccacacc tcacaaccag ctagtctgct gagcctgtgc55261atgctggtgc ccagcctgaa aactggtcct gtggtgggcc cacccccagg actacagcct55321gcttgggcca caacaactct gagtttgtgc atggtctaat aattggtcct gcagtgaccc55381tgcctcctca gatgggactc tgcagagatg gatggccctg ctacacctgt gagcactgac55441agcaacccgc ccacccagca ggaagacMgc agtgcatgta agtgcacaca ccttgagaaa55501aggctcttcc cactgctgct ggtggcacag ttgctgctgt caccaccggg ggctgcagca55561gtgaaatgcc agttggaccc agcaaagtgg caggatcctc agcattctag catatgcagt55621gttctgcacc tcaggcactg gaaaggctgt gaaccagaca tagggagcca aagcacatgc55681tttccagaac cagagagctg cctccctgtg gctgctgaca cagacagcaa tgtcaccccc55741gcaacacagc agcagagatg ctgcacactt gcatgcaacc tggggacagg ccctctccat55801ctgctgctga gtctgctgat gcagctgggg gccagagcat gtgccactgg cagtgacctg55861acttccacca gcagcagagc cactgtgaac ttgcacgtac cctgaggact ggcttatgct55921gctgccagaa gccaaagtgt gctccacatt gccagagagc tgcctgctag tggctgctgc55981cactgacaat aaccacaccc tgccctagca gcacagctgc agcaaatttg catgtgcctc56041gaggacaggc tttcttcagg tattgctcct gctattggga gatccaagga ttaccccatc56101caacttacca cagccaacat ccatgtacat aactaggggg actgaggaca ggcctgccaa56161gcctggttcc atcatcccag tgcccaggca cactacccag gggtgtggca atcatcctgc56221tttgtccacc accactggca tttgcacatt cctttaggag gactgagaat gggcccaacc56281agcctgacag tagcactgta gccagaaaca atatgcatgc aacatctgaa ggtctggaga56341ctggccccca gcccatcaca accacctcta acaccagagc ttgcaacttg agaatctgag56401ggttgtccaa ccaagctaca gaaattgccc atggcaagca cattcccaga ggcctaaagg56461cccacccacc ctttcagcct accattgcaa ctgctagtac ccaggtaagc tacttaaagc56521ccccagaatt gttctgctta aagctgctaa aactggtaca aacatatgtt gcctaggtgc56581caaatatagg cactctcagc ccactgttac ccctactggg gcccaagaac tggcccacct56641aaaatctctg tccccaggaa aacctcacta cagcctccaa tcacaactac agcctaagcc56701actgaggaag tcacagacac cacttatgct gttaatagct gaaggaataa tataagacca56761ccttactgta cacacacaga atcaaagcca aagtgtccta ctgaatcaac accacagata56821catcttcaga aagaaaagtt aatgttttgg atctatgtca ctgcccaaat ctcatgttga56881attataatct ccaatgttgg gggaggggct tcattggagg taattggatc atgggggtgg56941atccttcatg aatggtttag caccatcccc tgcgtactat tcttatgacR atgagtgagt57001tctcatgaga tttgcttgtt taaaagtgtg tgtcacctcc cccccaccca gtccttctcc57061tgctatgtaa gatgcctgct cctgctttgc catttgccat gagcaaaagc tccctgaggc57121ctccccagaa gcagatgtca ctatgcttcc tgtacaacct atgaaactgt gagccaatta57181aacctctttt cttcataaat tacccactct caggtacttc tttatagcaa tgtgagaatg57241aactgataca gaaaattggt accgaagagt agggcattgc tataaagata ctaaaaatgt57301ggaagcgatt ttggagatgg gtaatgagca gaggttagaa gagtttggag gactcagaag57361acaggaagat aagggaaaat ttggaacttc ctaaaaactt gtaaattgtg accaaaatgc57421taatactgat atggaaaatg aagtctgggc tgaggagatc tcagataaaa ataaggaact57481tattgggaac aactggagca gtcacttttg ttatgcttta gcacagagcc tgggtgcatt57541gttcccctcc tttagggact tgtggaactt tgaacttgtg agtgatgatt tagggtatct57601ggtggaagaa atttctaagc agcaaagtgt tcaaaatatg acctggctgc ttctaacaac57661ctaagctcat atgcctaagc aaagaaatga gctaaaactc aaatttgtat tWaaaaggga57721agcagagtgt aaaagtttgg aaaacttgca gcctggccat gtggtagaaa aaaaattccc57781attttctaga gaagaattta ccctagctgc agaaatttgc atgagtaaag aataaccaaa57841tgttaacagc caagacaatg ggagaaagac attgaaggca tttcagagac tttcgtagcc57901acacccacat cacaggcctg gagtcctagg agggcagaat ggtttcctgg tccaggcgca57961gggccccact gacctgcaca gcctccaaac actgtttcct gcatcccagc tgctccagct58021ccagctgtgg ctcaaagggg tccagctgca acttgggctg ctgcttcaga ggatgccagc58081cataagcttt ggcagcttcc atgtggtgtt aagtctgtga gtgtgcagag tgcaagagtt58141gaggtttggg agcctctctt ttgatttcag aggatctaca gaaaagccta aatgtccagg58201cagaagcctg ctgcagaggc agtgccctca cagagaacct ctactagggc agtgcaaagg56261gaaaatgtgg agttggaacc cctacacaga gtccccactg gggcactgcc tagtggagct58321gtgagaagag agctgtcatc atgcagaccc cagaatgaca gatcctctgg cagcttgcac58381catgcacctg gaaaagctgc aggcactcaa tgtcagccct tgagagaagc tgtgggaaat58441gaaccctgca aagctacagg ggtggaactg aaaaggcctt gggaacccac cccttccatc58501agtatgcctg gttgtgaaac atagaaagtc aaatgaggtt attttgcagc tttaagattt58561aatgacttcc ctgctggttt cagatttgca tggggtctgt agcccctttc tttttacagc58621tttctctttt ttggaacagg agtgtttacc caatgcttgt actccccttg tatcttggaa58681gtaactgttt tttgaattta caggctcata ggtgaaagag actagccttg tctgagatca58741gcctttggac tttcgacttt tgagctaatg ctgaaatgat ttaagacttt gggggactct58801tgggaaggca tgattgtatt ttgaaatgtg agaaggacat gagatttggg agtagtgatg58861ggctgaatga catggtttgg atctgtgtcc ccacccaaat ctcatgttga attgtaatcc58921ccagtgttgg ggaagactgg catgttggga ggtgactgga tcatgagggc agattcttca58981taactggttt agtactattc tctcactgct gttctcatga tggtgagtaa gttctcatga59041gatcttgttg tttaaaagtg tgttgcatct cgcccccact tggtcctgat 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accttgctga84301tggcctccct gttggggtgg tccttgtggc cttcctcgag gaggacgggg atggcctccc84361tgttggggtg gtccttgtgg ccttccttga ggaggagggg gatggcctcc ctgYtggggt84421ggtccttgtg gctttccctg aggaggtggt ggaccttgtt gctgctggcc tccttgttgg84481ggtggtcctt gtggctttcc ctgaggaggt ggtggacctt gttgctgctg gcctccttgt84541tggggtggtc cctgctgagg gccatcatcc tggttcccat caccagcaga gggttgagat84601tgctgtcctc ccaaaggtgg tccctgacgc tcctcatcta ggaactgctc agagtctcct84661ccatctgtgt gagttgaaac aagaagagct gagctcatgc tggaaaaccc tcctgtcttc84721atacctctct gtcttcacca cacggccggc ccctctctgc ctgacctgcc tctcaactcc84781caacctcccc ccttcccaag gcttcctaat tagaactcct cttaatccac ataagggtga84841tgaaaaattg aatttcttta ctcatggtcc ccagaatcaa ggttgggaga aaactgtttg84901tatctttggg gcattggtat tagccaattc ctgacaagaa aatggtgata agaagacact84961ggagaactca tcaatttttc agggaaaaat ggagacagag tttactgaga atttattggg85021atttacctga tattacgagg ggaacatctt cctggctgac atctagaaaa gaagtacagg85081atgatgggaa aagttacttc ctgaatcatt caaggctcat agtgttctac gaggataaag85141gacctctgat cacaccctgt gcatcccctt tgtgatctca tcagccactc tctgatgcta85201ctggaagtgg aagaagatgt aagggaaagc agtattgtta ctacactgag cgtcaaccag85261gaactcaaca tagaagggcc cctgtttgtc ctcttttgat tccccaagcc ttgatgagga85321atgaagatac aataggtctt ctgatcctcg gcatgaaaat tctgcagtcc catctgtttt85381ctcatcctcc tctcttccct ccactttcct cctctatagc atttgcctgt aaacccttag85441cgcttattta gttaaactgc tctgagtatt tcaatgacat atttggggat tcttctgccc85501tctttcatct gtaaatatgt tgtttatgtt tgcaagcctt ctcaacagga gccaccagac85561atagccactt ggatataatc ttacgcatgc cattcccagc acattgaaat actacattca85621ggagacagaa aaatgacaat gtttcactct ggttattctc taactctatg tagacagaga85681caagtgttta cccaattctc tgcctcggca gtagctctga catgtgttta tctccttcat85741taatgctcat ccactgtaca gcaaggccac catcatccct gtctactggg atcagtacag85801gatcttcaca gctgtacttc cctgaatctg tcttgcattc tccacatcct tcacagcagt85861cccatgtctc tatataatgc aaatctcact ctctcacacc cctagtacga attctttatt85921ggattctatt tgtgcaacaa ataaactatg aggccttgat gaggaatgga ggtacaatag85981atcttctgat cctcagcatg agaactctgc agtcccatct gttttctcat cctcctctct86041tccctccact ttcctcctct atagcatttg cctgtaaacc ccaatcagag tcacaatatc86101ttcccccaat tcatcttacc ttcatttaaa tcctgagctg agctgaaggc cagcagggcc86161actgacagca gaatcagaag catcttgcag gaggctctgg tgtcactccc aactttgtgc86221tgggagaaac gtgtcagctc cctttataaa gacaagcagg acaatggtgc atttgagctc86281cctaccaggt gggcctcctc gcctcagaga ctggcttctg ctttgcttac ttcaggtcaa86341gtgtatccct catttctttt gggactctag ctcagcagga agggttgggt aggatattgt86401ttgtgtctaa ttcctaaaag gcacaactat gacttggaca aatgttttga cggaactgtg86461tccaagcagt cggcacagtg tcaggattga actttagaca tcttttggtt ttcaatctgt86521ttggaaagac tgctattctg cttttcactg tgcttttcat ttStgtgtat gtgagtttgt86581gtgggtgtgt cggggggtgg acactgatcc tacagctaac agtgaagatg gtcaatatct86641ctgactgttt tgatagcctc tttccatctc tcatgatgtg tgtgcgtgga tattttcaca86701tttagctaaa tttttcatgt aacagagatg gtcttgctta tctgtgagat gtgtgaggac86761agcacactcc caggcacaca tatatgaRag aaaggKgctg gcagcctgct caggctacaa86821gaattgtcca aacttctgtg aatctcacta cactcaggca agccttggtg ctatacaaca86881caggcaagct aaaatatttg tattttaaaa atatctttag ggtttattaa agcaaaactg86941aactcagaaa ccaccaagga atttctagac ctgaacaaac tgaatatatg gttccctaag87001tgagccacac gatgtcatat agctaagacc tccactttct ccagaatatt ccatagaatt87061catcctctac tttatttctt ctaataaata ttgtaattgt catcactgat aattaaatgg87121ccacaattat acattcatct aagataattt gtaatacctg tccaagcctc aattgccttg87181attggtcttc tgcttttact cagtaattat gtcacctgtt tcatcagagt gttctttctc87241accaaggatt tttatctgta atattccaat actcattctt tctcattctt tttctcgcac87301ttatttgttg aaattttgta ttctgagtct accttgccat gtttactttt cgtcctatat87361cttttttttt ctccctacaa aggtgtcctt tatttatcct tctaagtaaa ggtgtgtggt87421actcctcact acctttactt tcatttttgt ctgtataatt tgacaataaa aaattaagtt87481tccaaaaagc cctgtcaggg tcctggtttg gtagctctct cctcagctgc tgattgctcc87541aaaaattaag tttccaaaaa gccctgtcag agtcctggtt ttgtcgctct ctcctcagct87601gctgattgct ctgtgatacc tagaaattcc ctgYtcatca attcataaaa tatactactc87661agaatcacca gctgcacttt ccatttcaga ccttgagtag gtcttgtgta atttttcact87721ttttgtgcat ggttagtctt tatttgagga tagcttggtt ggaggcatgg ctgagaagcc87781aggtgacaga aaatcataaa gacaaggccc tagacaggtg tgcatgagtg gatcctgtgc87841tgggcatatg agggtctggt atggctcttc tgaaaagttg cagataataa tacaagaagg87901cttcctagta gattagattt tgctacagac gacattgttc ttgtaaggga cccaggcaga87961ttggtatttt ccctggaata aatatagacc tatttcaggg gggaatgcat tcttaattgg88021caattcttct ctggccctgt gggaagtaga tcagctctag ctgggccgta tgagttgtat88081ctcaggcaca gagtagttgc ttgagcccag cagctcccaa tgcgttatgg agattattgt88141ctctggtttc accaggtact gtttcccata ggacctggag atgagcagtc ctgcctcggt88201gacttcaggt caaccatcat gtcaaaaagg aaggtcagag aaaaggaaca aagaggagtg88261ccaggcagat attgcctgat gatgtggggg actgaggaag ctgcaggcct ggtgcaagac88321aggtttctcc ttggcagcag agtacaggaa aagaacagga aatcctccta aaggtcactc88381agctcaggcc tgctccctaa cctgctccaa tgtcagcaat cagcgagaga ctagtgtatc88441aggaaagcat aaatatcagc tatgctctca ctagacacat caaaaacaga ggtaatggaa88501gagctgaaag ggacactgtc tgtgagtgaR ggtgggtgaa agggagacgc aggactgctg88561caggagcttg ggtacctaga ggtgggtggc agccctcagc accacacttg ccttctacta88621tagatgttca tattctgagg ccctgaaggg ccagtcttca acatatgaaa ttttaggatt88681catctctcat aacacatccc aacattttct cggtcactga caggtgttta cctagtggtt88741caaaaatcct cgctccctcc aggaacttat gcattagccg atctaattgc ctccactttc88801aaaatacgtc ccaaatatga ccacttgcct gatctttact agaaggtgat tgttcagcca88861tgatgctctc tcctggagga ctttaccagc ctccagctgg tcttggtaat gttcttcccc88921cagctcatcc catatcagtt ccctcacaac aatcagagtg atcatttaaa agtagaaatt88981aggttatatc acatttgtgc ttcaaatctc ctgttttttc ttctgcactt gtgataagat89041ccaaatttca tgcctcagct ctttcacacc cacatgcctc actctttttt gaaaaccagg89101aagctctctg aatggaacag aaagtagaat cttcttcgac ttcaccatgc tctagtttgc89161ctggaacact aaagatggtt tgccaggaaa gatgaacatt gRcagaggga ataaacttct89221ctgagagtca gtgagtttca ttgggtcgct gtggtctggc agtgttatga attggcagaa89281ttattctatt aattgcacca actaagcatt ctgataatac agttagcaaa taaacacaat89341agtctctgag acttcaactt gctttgactt gtctaaaaag tttggtgaca ctattatggc89401caattaacta ttaaaaatat cttctatatt tttaaatttg atgttagtgg tccataaata89461tatatatttc acaattaatt tagcatattt cttttttttt tttttgagat ggtgtcttgc89521tctgtcaccc aggttggggt gcagtggcat gatctcagct cactgcaact tccacctccc89581gggttcaagc aattctcctg cctcagcctc ccaagtagct gggattacag gYccctcgcc89641accatgactg actaattttt tcccatctct actaaaaata caaaaaaaaa attataYcta89701aagaaattaa gtcacatggc taRggtcact gtagtaaatg aggaaaaatt aagttgattt89761tctcttctct ttgtaattcc agtttaaccg gatgttgtcg atgttgtttt caatttagaa89821aatatagcaa attgttcatt agccatgagt atcactctgc tatccaccac tttctaagaa89881ggcgcttatt ttagaacaag gctaacacta aattacagga aattaagtaa ttgtggcaaa89941ctagagaagc atagtatgta taataggtct tactcagtta gatccacctg tcaaggctga90001gtccctttct ggagtctcta gagaagcacc cattttttgt ccacattcct tggccttctt90061ccatcttcaa tgccagcaat agccacttga gcctcccatc acatagcatc acgtcgccct90121tgcactgact cttctgcctc cctcttctgc agttaatgac cttatggtta cattgagtcc90181acctagataa tccaggataa cctttctaaa ttcaggtcaa ttgattcgca aatgtaattt90241ccctttgtca tgtaagttaa tatattcact tgtctgagaa ttaggaagtg tgtgactttg90301ggagactgtt aatcttcata gaacacacag gatggacacc ttacccatct agacctggtt90361tggctcagtg agagttggag agactcaccc aggcttcttc cagatatttg catgagaata90421tgaatgagtt tatgtataat tagttgttat acaaatattt gtgacttaaa gtatatatct90481atgcaaaagc gtaaatcaca aactgagatg gcaaaaattt actttcaata accattgaca90541cttaatgcat tttttgatat tttagagctg tcatattttt tgttttttat ttatactact90601tttgattgtt ttctttttcc tgatctccta tggggccact gaaagtgttt tataattcta90661ttttagttga tccgtataat ttttgagtgt atctctctga acagtgtttt tagtgattct90721tctatgtttt actttacatg tacatagctt ataatctagt ggtgtacact ttttaccagt90781tttagtgaag tatggaaacc ttacatccct ttataatttt taggtcaaaa tgaatttatt90841atttttcagt tttgtaggtc agaaatctga actgaggttc actgagttaa atccatgtgt90901caaggctgag tttcctccta gaggctctag agaagaatgt catttttcca catttcctgt90961ctctcttcca tcttcaatgc tagcaatggc tggttaaaac atatgaagaa aactcaagtg91021aaaaaggaag atatattgtg tttgcccact ttcccccttt ctSttatttt tacttcattc91081ttgatgttcc acaaatttct cttctattct ttcctttatg tttagagaac ttcatttggc91141tattatttaa agataggttt gttggaaaga aattctccta ggtttctagc ttttcttttt91201ttcttagaat gcctggattt cctttacatt aatgaaggat atttttattg aacataaaca91261tctggtagac catttctact tttgagcact ttaaatattt gtgctccttt ctactgttat91321ttctggtttc tggtSataat aaccactatt atttatattg cattttccct ataactatga91381tgtcatttcc ttctttctgc tttcaatatt ttgtctttaa ttttcagaaa ttggacaatg91441aattttcctg gaatggattt cattggttgt attctggttg ggatttgctc agcttcttga91501atcYgtaggt ttatgctctt tgctgtgttt ggaaaatttt tgatcattat ttctctgagt91561cctttttcaa catcaacctc ttctgctttt ctgaaactca gaatgcatga atagtacaYc91621atttgttata gcctttcata ttcatgatat gatgtataat tttttcaatt attttaccct91681gtattgttta gagtatataa tttctattga tccaacctca agaacactgt ctttcctcca91741tcattttctt tatgctattt atcatgccca ataaaggttt tttaagacat tatatttttc91801atttctaaaa tatctgtttt cttaatttat aatttataat tcctattttt ctgctgacaa91861gtttttcctt tccattcatt ttgagtgtct accttgacct catgaaggat gggtacaaca91921gctcctgtaa agtctttggt cattttaata tctaagtaat ttcaaggttg taatttcttg91981attgtttcat tccttgagaa atggtcgatt ttttgtgagt tgttttgagt acattgagta92041attttctgtt ttatcttgca cagagggatt ttctcttttt gcaatacaca aaaagcccaa92101taagggtagg ttcggacatt ggagggtgaa ggcactcatg gtaaattatg ctccaccaac92161tggctcaaat ggccagggag tttgtcccac taacattttt ggtggttttc cctgggtcaa92221tctctctggc acttatgaga taatatttta agtatttaat atcacaccat acatacagat92281ataaagacaa taaaaagcag tgcatcgaat gggtccaaag ggccctatcc acaaagtctt92341cctaactttg gtgtgtgtgt gtgtgtgttt gtgtgtgtgt gtgtgcactg tttgttcaat92401cctcatcagt tgaactcagg cacttctttt tcctttttct ttctaaacct gcttgttaga92461ggctgtcaca gtagccagaa ggccctgcta tcttctattt gagtatttat agaatgcagg92521aaaaaagagg gtaaactata aagaacgact gtaggcctcc ccggtgcagt ggctcatgcc92581tgtaatatca gtacttggag aggcagaggt gggaggactg cttaaggcca ggagttctag92641accagcctgg gtgacatagt gagactcctc tgtctttaca aaacactaaa aaattatcca92701ggcatgatgg tgtgtgcctg ttgtcctagt catttgggtg gctgaggtgg gaggaaaaga92761agggaaggaa agaggagggg atgggagggg aggggagggt tggctttttt tttttcctct92821tggcttcttg cccttctttc tagtgcacct cccagtaggg tctcttttgt atttcctcac92881atgctattgt cctccatccc tcagcacccc ttcccccaac ccccagaacc aagtagaatg92941gtgatttgtg cacatatatc caacagggct atactaattt gagtccctac tctccttgaa93001gctttgcaat atgttgggat ggttctgtag ggtctttggt gtcccttggg tcaggaagat93061ctcaggccca gcccgaatcc ctaaagcaat tgacatcaga atagaggtaa agaagttatc93121agggaaatat agagaaagtg tcttcaggcc agtatgcaag acacatttac tttcaaataa93181gcattattgc cactactcgg tggttaactg aataagcatc tgaatgtaac aactttggga93241gatccttaat cttttcacct ttccaccaaa ggcctgtaac aactttggga gatctttaat93301ctgtctacct aatgttatct ggagaagaca gctaaatcta aaagtgtcat ttggaagtct93361gtttcagttc taccagtggt actcaatttt caaccacttc ccaatcctcc tcattaatga93421gcaacataat agaagaatat ttatttacca attacaaaca ttttagtcaa catgttagct93481accagttccc atggactttc agcaaatcct attaatcagc ttgtaggatc cttcactttc93541tcctcagaag gccaggtctt tgggctgtgt tccatcctcg ttgccaaaat tattataagc93601taacaactta gcttgtcact tgttgtactt gcagaaggca aaagatggtt tattattcac93661tgaagtacta gcagtagtca gaggaatatc atcgtactat ttcttcaagc ttcaRtcccc93721tcacagggat aagatgagaa actgatgtta catgtgcaag tagtggtgtc tatcaaaaga93781gaaatctcaa aattaggaaa ctccagtctt aaaaactttg atcactgtga gtaacctgtc93841catcttgcct tctgaagaag aagctttaca ctggaatgta agcaaatatc tctggagaga93901agaagaagaa gagaagagtc tttatcttta aacaaatctg ccttYtgacc aagagggata93961ccctatttct aaatcccaag gctctttgcc atgacctggt cttgggcaaa gtgaacgaga94021ctcctagggc acaaaacgta aaaaggcatt caataggttg cagggcccta aaaccaagtg94081gctcctcaaa ctttgcaccc tgcatgcctt gctcacctga tcctagttga ggcccttctg94141tttgctcatc aaacatactg tttgctcaca agataagagc tagaccatgc agaagtgcaa94201tacattcatg gagaattttt ttcccaacat ccatYcccaa gatcaaggtt acacagttgc94261caaagattgt agagtattct gaatatatca tctattttct tcctggacag aactaaatcc94321atcagaagta acttttttaa aaaatgtttc tttcttttgc atacaatttg tttttatttt94381agattaagag atgagtccag aggtaagggg gacaggagaa ctgtgacatc agggatgaca94441ctaccctttg agagcactgg agcagttaga aaggattgaa agtgaataat cttatttcat94501aaggggtatg tcattttatg attcaaatta agtctgtgat tatcacttag caaaattgct94561aaaatcatta tcagaatatc ccatatcatg ataggaggaa gaaaaagaag taaaatctaa94621aattgttatg gaggtaaata gaagactgcc ataaacaagc tatctacaga attatggggc94681ttaggaattc acagtaccct ataaacaaga acacagcttt gagaatttct atactctaat94741ttttaaaaat gaagtatatt ttgtgaattt ttcacccaca aattatttta actggaagcc94801atcacagctc attaatcagc aattggtgaa ggactaaagc agcccaaatc attcctgtct94861caaagtaagg cctgcttgta agcaagtgtg aactggggat gtatgtgcag aaatcagagc94921ctaagtatgg taagctggac atttcagaga taaggaaggc agctggtgtg tgtgaaatct94981tatatcaata actgatttta ttttttcagt cctaattgct attatggaat ttgtgctttt95041cattattaca tcttcacaaa gcatgatttt taactttaga acaatttaca ttttatgctg95101gataattctg ttgtgaggga ctgtcatgtg cattgtgaga tattgagcag catccttgtc95161ctcgtacagt tatcaggtaa aatacagagt gtgtcagttc aatttgaatt tcaaataagc95221aacaaataat tgtcattgtc tgtgtatcca attatcaatg ctgcaggtct gtaattggtc95281ctccatagca cacttacatt atgatgtaaa ctcatattat ggttatcaca agtaatactt95341atttataaat ttattcttgt tgttttttct tttgtctgaa atgtaaattt aactaggcct95401cctatatttt tatttgctta atctgttaac attacaatag atgccagcag catccgtcca95461attttaactg aaatgtctcc aggcattatt aaatgtcccc taggggggca aaattgccct95521gtgtggagaa ccactgtcct aaagggattt catcctttgc acatggaaat ctcgtggtct95581attctctgga tattttaatt ttattcacac atttaaaatt tcgttttagg cctgcaatgt95641ccaggttatt tttctagggt ttactttttg ttctatcgat taccatataa ttaacttttt95701aaaatacttt ctgcaatgtt gaaaatttgt cttttgtctt tactgctgaa aattatatta95761tttgcttgca atatgttctt ttttttctta gagagaacgt aattgttctt caaaatctgc95821ttccaattat ttcattttaa atatttatta Ytgttacctt aaacttgcga ttgtgttctt95881ttatttaacc tgctattttt acatgctttc tcattacatt tttaagagga gacgttctta95941ttaaattcaa ttctgtaaac tgattggtta tccctgattt gtttttcttt tcaaaacttt96001atttattttt ctttctttac acagtgactt tcatcaaatg agatcctgta tttgttacta96061tcgtcttggt cttctatatt tttatttact aaacctggta actctacact agatgccagc96121agcagtcctc caattttgct tacttaaaat cttactgatt ttttaatacg tgtccttgcc96181ttccttacac agttaaccaa ttgagtaaaa ttttattgtt agtccaaaga ttcagattct96241acagtacaag tctgttgtag atggtcaaga ttgtaacatt tttgatggtc aaagttgctt96301agtgttttta actgaaaatg actgaaaata ttaacagaat agggcttata tttggaaata96361actcttagtg atgtacattt caattgactt tgtttcatat cctcaaagtt ttcactaagc96421tgtagactct actaactatt ttcatttgag ttttcctttc tagttttaaa ttatcaattg96481atcatcattt ttaggatagg aactaaatcc ctatgtgttt gtacatataa atctgatttt96541atatacactc tatacacata catagatatt ataattcttg atgtatttct attctattct96601aatgcttatg caacatatta ataaaattta aagatagagt aatctattat attgatcaca96661gtgcctaatg aaaaatgcat tttcaatata ttagaatttt actattaaat acataatctc96721catatatggt gcaaacaagg tagcaatctg ttctgcttaa tttaaatcag caagtatttt96781caataatgct caatatatca tagaacataa tgagaaaata agaggtaggt gaaagaaaca96841aatgtgtagc cctcctgttc ttcttccttt ttttctttct gagaatatca tcactcatat96901caggcatgtt tataaaaatg agagattatg tcctttttgg catacttcat cttcttcagg96961acacagagag aagcttgctt cagtttgctg tcccgtaaaa ttagaagaaa tgaatggcca97021gatggatgga aaaataccag cacactacta aaagtccttg ccgcaacgaa gtctagaaga97081ggacaggcca atgttagtat gatactgatg aaataatgca caataaagag gagtagaaat97141gaaattatag cttttatagg ttttacatgg gcttctgtgc tgggatccct ggaataaata97201ccatgtagct tcatctgcct ggtgtggctc cataaggaga ggattaagag aagaatggaa97261gccagtgttt ccacaaaagg aaggatgaac atcatctgaa ggagaaacag agaagtgaaa97321tcatgcatgg tatccatata attaaatgtc aagttgcctt ttattgttac ccgttcttag97381attaaactat taattattat ttccttcaga atggaagttg tgcagaaaga gatcgttgcc97441tctagtacaa taaagagaag caccttgtga attttccatt tcatccagag gaaaatggga97501ttggagaagt tggctacctt gaggaaatag aagacactga ggcaagtggt acaggacagg97561cagaaatagc tggatcctgt ccagagaatg tcaaaactta ctgcaagatt cttagaatca97621ggcattttct catagcctat attgaaagag gtagctaaaa ttgttatcta caggaaacat97681atcctggaga tggccaagca gttgagaata aaatcaatca gggagacctt tcagttcctg97741attcagtcaa tgatattaac caatacaatg aatcaatttc ccacagtccc cattatgaat97801tacactacaa gaattcttat aaacagtgtc tcccaaatgc ttgacatgcc tctacatagt97861gaatctctgc cttcaataca ccattggctg attgatccta gctgcactgt tatagattta97921tatatccaaa ggagtgactt ctttctgttt tattgatggc cattggtgta gtctggagag97981atccaaggtg tgttctaaaa ttagatttca actaaattgt aaaatataca agtttttttc98041ccttgagggt atcagctagt gattttcaag gcaaatatta tattccctgc tactattgac98101tctggttgta ttttacatgg aaagttctgc attcaaattt gaaccctcat ttgttaacat98161gcaaaattga agtagattct cctttatagt tttacaatgc catcttttgc ttaaaggtta98221ttcatttgta tgatgtatcc ctttgattca tctaccaccc tgggctagaa attctaagcc98281cccatataga aaaatgcagt atatatttag agtttatgat cagcatattt cttcattatc98341aacctcacta atgcagatta tttataaaat atgcaaagtt taagaaaatg gagaaaactg98401ctctctgata taataccaaa tcttttagag agtatggaag tttttggcca ggcacggtgg98461ctcacgcctg taatcccagc actttggaag gccaaggcag gtggatcacc tgaggtcagg98521agttcgagac cagcctggcc aacatggtga aaccctgtct ctactaaaaa tacaaaaatt98581agctgggctt ggtggcatgc tcctgtaatc ccagttactc gggaggctga ggcaggagaa98641tcgcttgaac ccaggaggca gatgttgcag tgagccgaga tcacactact gcactccagc98701ctgggtgaca gagtgagatc cgtctcaaaa aaaaaaaaaa aagagagaga gagtatgcaa98761gttttaaaac atacgataca tactttggca cttcttctat tgatatctta ggagtctgtg98821tactctgtcc ttaaatctag aatggtttgt gactaattca actaataaaa atgctataat98881aattctaaag ctaaatcatg aaaagccatg cagttttttc ttaatcactg caatatttac98941tcttggagtc ctaagccaca tgtaagtagt ccaactactc tgaggtcaca atgtccaaac99001ccacatgcag aggccatgtg caggccctct ggctcattat cccacgtgag cccagctttt99061acgtcctttt accccaggta ctaaacctat gagccaagaa agcgatattt gacctgtctg99121atacggtaga tactagccac atgtcacacg tggcttttta aattcacatt aataaaaatt99181aaataagatt aaaagtacag agcctcagta ttactaacca tatttcaaat gctcactagc99241cacgtgtgac tattttatag ccaacataca taggggatat ttctatcatt gcctatcatt99301gacatttcta tgtatttctc agctccgcct tagataagtt cagcccctgg tcacttgaat99361tgcccccagt tgttcataac tttctggcta aaggcttaga cattctggaa caaaaagaag99421ccatccctgc tatgtcttga acaaaaccct aacctacaga atctttaagt gaattagtct99481attcttgcat tgctataaag aaacacctga aactgggttt ctgtaagagg tttaattggc99541tcatggcttc acaggctgta caggaagcat ggcggcatct gtttctgggg aggcctcagg99601aaatgtataa agatggcgga aggcaatggg gaaatcagat acatcttcac atggttggag99661caggaggaag agaaagatgg gggaggtgcc ttacactttc aaacaaccaa atcttgtgat99721aactcactca ctcactattg ccacaccacc accaaggggg aaactgcccc ccataatcca99781atcacctccc accaggcccc acctccaaca ttaggggtta caattcaata tgagatttgg99841gcgaggacag aaattcaaac catatcaaca agcacaataa aatggctgtt attttacacc99901atgaagtttc tgggtgattt tattatgcag caatagagca tcagaataga attatttagc99961atatgaatgg tatcaatatt ttgtcatttc taatttccat gtctgttttt ctcttctatc100021ccaaataaag gtatccatag catctttatt ttcctcagtg taaggggaac ttgtataaat100081tttctataat tttttcatac gttgagctga acttaatctt aattctgatg aggtcaaacc100141aggaaaggcc aattagtcat gttctttgtg taatgcaact gctgcatttc cctcccaaag100201tagctagtcc aaaatttagt gacattcaaa accaatggag atataatata ggcctaagag100261gagtcaaaga aatgaatgag ttggacagcc caccaaaaga tacaccctag gtaaattcac100321aaagaaaact ccatgactaa aagaaaggct aattgtgata ggcaaacatg aaatgcaaac100381aaaactgaaa ctgaaataaa caaagggaaa ttcaggaaaa tattatatgc tgaaaaaggg100441ttattttatt tgtcttattg aatatcttct ttgttccagc cctctaggag gtgggatgaa100501gcattaaata caactatttt taaatgccct taataagttg acattctgaa aagatgaact100561ctaaacatat aactaataaa atatatatca tacagatata aaatatagtt tataagaagt100621tgcaaatata agtagagagg gtcaatagaa agcatgtcag aagaggggtt gaaattttaa100681ataaggtgct tagggaagga ctcattgaga aggtgatgtc tgaacaaaga cctaaagtag100741gtaaagaaat tatccatgtt ttgtctgggt aaagtacatt ccagacacac ggaacagcat100801tatcagtgtg ctaacattgg atgtacctag tgtgtctgag gaagaacaag gaaagcagtg100861tgactgttgc ggagatgaga gagtgagacc actaagagtg aagtctcaga aagaagaggc100921atgtgcccag aaggcagcac atacagtcaa aagagattat tttagaacgt taatatttaa100981cgcctgccct gctgtgtttt gtacttgcgt ggtgcctact gctcctctct tgtggctgat101041ttctcccttt tggaatgaga atgtctatcc aatgcctgta caacaactgt atcttggaag101101gaaataaatt gttttttatt tcacaggctc atagctggaa ggaacttgac ttccagtctc101161aaatgagact ttggacttca gacatttgaa ttgatgcagc aacgtgttaa gaattggggg101221actattgttg ggatggaaag attacatttt tttttatgtg agaaggacac gagttttcag101281gggaccaagt cagaatgcta tggtttgtac acggtttgtt tgtccccatc agaactcata101341ttgggatttg atccccaaag tagtggtgtt gggaggttga gcttagtgag aagtgtttga101401gtcatagggt tggttccctc atgaatgcct tggtaccatt ttcaatgtag tgagtgagtt101461ctcactctca caagactgaa tttgttctag gggaatgagt tgtttttcat gagagtgaat101521tgttataaag ccaggatgcc cctttggttt attctctctt cacatgtgcc cgcttctgct101581ttgaccttct ccaccatggt ttgacccagc acaaaagctc tcagcagaaa ctaagcagat101641gctaatgcca tgcttcttgt acagcctgcg gaaccatgaa ctaaataaac ctcttttatt101701tataaattac tcagcttcag gtattccttt ataccaacac aaacagacca agaaattgag101761gaataatatt tataaaatta tttcagtgaa ttaaattaga taaaatggac aaattccctg101821aaagaaatta ctgaatcagg cacacaaaga aatagaaaat cttagtgtct atttttaaaa101881attgaattct taatttaaaa ctttcacaca aagcaaggga tgacctgaat gtttattttc101941atcacatatt taagaagaaa aaaataccaa cctacataaa tttttcaaca aagtctcata102001aaggttaact ctgtgagctt tatttcaaga aggaaagtgg gaatctacca gaatcataag102061gacacacaga tcccagggag gggaacatgg gcaaacagcc cccatgatgg cacccagtta102121aaaaagtgaa tgaagctcca gtaggtgaga gaggcagaga gcctccctct gtgactcacc102181tttccactgg ggatctgagc aacccagtgc tcagagggaa gagtaccttg tttctccaaa102241gccctggaga taacttggag aaaggcttag agacattgta agggaaagac actgggaaaa102301ggttcaggcc ttttctcaga cccaggactg agagcaggat accattttta attcagatgc102361cacaaagtca atcattcttt ggtaactaag cagcgtagct gtgcaggcat tttagtcttg102421ggccagatat tggagcacct gctttagagc agggtgggga cctccatggc cagaattgtg102481gggaaaaaaa accttagcag caaacactga aactgtgcta tcccccatca caggcctggg102541gcaggagggg agctgctaca gccagtttat cctatgtgat gagacttgca accaggcagc102601ttagctactt ggaactagtc tgtgtgtgtc attgctgggt accccaccct gttcccctgt102661gattgtggtg cagcagactc tcctccactc tacctctagg cagaaatctg ggcatttgga102721tcactcattc acctggttca gcagcttcat ctgctccacc cttcttgtgc agagatccta102781gaatagggag gccctctctg cttcatgcct aggcagatcc caggattttg gagcacctgc102841tagcaaggtt cagcaccctg aaccacctaa ccttccttga cgtaggtcat ggtgcaatgg102901ggccctctct gctccacagc caggcagaac tctagatatc tgaagcaccc attcacctgg102961ctcagcagcc tatcctcccc tacccttcct gtgcagagat tttgatgcag ggaggtcctc103021tctgctgcat accctagcat tcaaagcacc tgctcacaca gactggcaac ctgtgctgcc103081tcacccttcc cgttcacaga tccatgtact gggctgatcc tctctgtttt atgcccaggc103141aaatatccaa gcattaagag cacctgcctg cctagttaag aagcctgagt caccccattt103201accctgtgca gaaatcttgg ttggtggggg tgggttctgc tccacaagca ggcagatttc103261caggtattca gagcccccac tctcctggat taagagttta ggccaatctc tccaatatcc103321ctgtgcaaag aacttggagc cgagggggtt acctagctcc acccctagac agaactctgg103381tcacttggta gccactcagt agattctccc tcagtgttgg tgcttgtgtc tgccattgga103441agacctatag gtggacctgc cttgtctggc cccacccacc ttgctcccca caacccccaa103501ggctgagcag ggagttcaca ccactgtgta ctccatgagt cagaccatta tctgcagcaa103561cagagagttt cttccagtaa acaaggatca aatatataac catcacattg tccaaaactg103621gctcttacct ataagtgcca tctactggct tgtaggttga accgcacagt ctaatataaa103681acctgcaacc tgtaagtgca taaggctata gaagctgggc aaaagaccta cccagaattc103741tctaaagtca tacctcctaa ggagggaggg ggaatggaaa gggaaagaaa aaagaacaat103801aatattatag ggaaataaag aaaaaaatcc taccttatgg aaataattac aaaaattaga103861agtgccagta ttgccagagg aggaggaaag agaacaagaa ttctaccacc ataaaaaaag103921tgaatgtaat gaaatcaaca ccatcaaagg agcacagtac ctctccagca atggtcccta103981accaaaacaa aagctcagat atgacagata aaaaattcaa agtatagatt gcaaggaagc104041tcaatgagat gcaagacaag gctgaaaatg aatacagaga gatttctaaa gcaatccagg104101aaatgaagga agacataaac atcttacaaa gaaatcaatc agagcttctg gaattgagaa104161acttacttaa ggaattataa agtacaattg aattcatata aagtacaatc tctcatagac104221tggaccaagc agaagagttt cagaccttga aaactggtct tttgaactaa cccagaaaaa104281aaaattaaaa ataatttaaa aatatgaata cagtcttaga gcaatatggg attatgtgaa104341gcaaccaaac tcataaactg ctggcattcc tgagaaagaa ggagaaatag ttaataacct104401ggaaaacata tttgaggaaa taatttaaga aaatttccct aatcttgcta gagaggtaga104461catacagata caagaaatca agaggacacc tgactgatgc tataggaaat gaacatcacc104521aaagcatata gtcgccagac tatccaaggt ctacactaaa gaaaaaaatc ttaaaggcag104581ctagagaaaa agatcagatc acatacaaag ggaaccccat aaggccaagt atatagctca104641gcagaaacct tacaagccag gagagattgg aggcctactt tcagcattct taaaggaaag104701aaaattttcc aaccaataat tgtatattcc atcaaactaa cctttataac tgaaggagaa104761ataaaatctt ttatagacaa gcaaagggta aaggaattta ttaccactgg accagtctta104821caagagatcc ttaagggagt tctaaacatg aaaatctgct accaaaatag cacacctaag104881cacatagccc aagaccctat aaagaaacca cacaatagaa actacaaagc acccagctaa104941caacttcaaa atagaatcaa aacctcacat agcaatatta gccttgaatg taaatggtct105001aaataccctc acttaaaagt cacagagtga caaattcaat aaaaaacaaa agtcatcggt105061ctgctgtctt caagagaccc atctcacatg taatgttact gttaggctca aagtaaaggg105121ttgtagaagg atctgtaaca caaatagaaa agaaaaaaag aaagaatcac tattcctata105181taagataaaa cagattttaa accaacaaca gtaaaaaaat gacacagaaa ggcactacat105241aataataaag tgttcaattc aacaagaaga cttaactgcc ccaaatatac atgcactcag105301cattggagca ccaagattca tgaaacaagt acctccaaac ctataaaaag atttagatac105361ccactcaata atattggggg acttcaacac cccactgaga agattggaca gatcattgag105421gcagaaaact aacaaggaaa ttctggactc ttgaaaaaac gctcaaataa ttaggcattg105481aaggaacata cctcaaaata ataagagcca tctatgacaa aactacagct aacattacac105541tgaacatgca aaaactgaaa gcattcccct tgagaactgg aacaagaaaa gggtccccac105601tcccatcact cctattcaac atagtattga aagtcctagc caggacaatc aggcaagaaa105661aaaaaaggca tccaaataga aaaataaaag ccatagtcaa actatatctc tttgctgatg105721tgaatccata catacaaaac cctaaagact ctgccaaaag gctcctggca cagataaagg105781acttctgtaa agtttcagga tacaaatcaa ttcacaaaaa tcagtagcat ttctatacaa105841taaaaatctt caagctgaga gccaaatcaa gaatgcaatc ccatttacaa tagcctcaaa105901aaaaaaaaaa aaaaaaaaaa caactaggac tacagctaac caaggaggtg aaagagaact105961gtgaaacact gctgaaagaa atcatagatg acacaaacaa atggaaaagt attccatgct106021catggatagg aagaatgaat attgttaaaa tggttgtacg gcccaaagca atttacagat106081tcaactctat tcctatcaag ctaccaatgt cattttgcac agaactagaa aaaaaaaact106141attttaaaat tcatataaaa ccaaaaaaag agcccaaata gcaaaagcaa ccctaagcaa106201aaagaaaaaa gccagaggaa tcacattacc tgacttcaaa ctatactata aagctacagt106261aaccaaaaca gcatggtaat attataaaaa cagacacata gaccaatgga acagaataga106321gaacccagaa ataaagacac acaactacag ccatctgatg tttgacaaaa ctgacaaaaa106381taaacaatgg ggaaaggact ctgtattcag taaatggtgc tgggatatct ggctagccat106441aagcaaaata attaaactga acctttacct ttcaccatat acaaaaatta actcaggatg106501ggtcaaaaat ttaaatgtaa gactttatac tacaataatc ctggaagaaa acttaggaaa106561cacaattcta aacattggcc ttgggaaaga atttatgact aagtccccaa aagcaattgc106621aacaaaaaac aaaaattgac aagtgggacc taattaaact aaagaatttc tgcacacatt106681gtataaacta tcaacagagt aaacagacaa cctatagaat gtaagatttg caaactatgc106741atgcaacaag ggtctaatat cccaaatcta taaggaatgg aaacaattga acaagcagaa106801aacaaataac ccctttaaaa acgagcaaaa gacatgaaca ggcacttttc aaaagaagac106861atacgagcag ccaacaaata ttttaaaagg ctcaacatca ctaatcatta gagacacgca106921aatcaaaacc acaaagagat accatctcac accagtcaga atagctacta tcaaaaagtt106981aaaaaaaaaa aaacagatgc tagtgaagct gtggagcaat gggaacgctt gtaccctgtt107041ggtgggcatg caaattacgt cagccactgt agaaagcagt ttggagattt ctcaaagaac107101ttaaaataaa ctaccattca acctagtcat cccattactc agtatggtgt atgcacgcca107161cacttttttg gtctaatcca tttttttttt tttgagacag agtttcactc tgttgtcctc107221tcactctgtt cacaagaaaa taaatcattc taccagaaag acacatgtac tctcacaatt107281tcattggaac actattcaca atagcaaagg catgggaatc aacctacgtg cccatcaaca107341atggattaca ggccaggcac agtggctcat gcctgtaatc ccagcacttt gggaggtcaa107401ggtgggcaga tacctgtggt cagcagttca agaccagcct ggccaacatg gtgaaactct107461gtctctacta aaaatacaaa aattagccgg gcgtcctggc acctgcctgt aatcccagct107521acttgggagg ctgaggcaga agaatcgctt gaacctggga ggtggaggca gcagtgagct107581gagatcatgt cactgcactt cagcctgaga aacagagtaa gattctgtct caaagaaaaa107641aaaatggatt agaccaaaaa agtgtggtat atatagacca tagaatacta tgtagccatt107701aaaaaaaaat gaaatcatgt cctttgcagc agcacggatg cagctaaagg ccattgtcct107761gagtgaatta atgcagaaac agaaaaccaa atactgcatg tttcacttat aaataggaac107821tatacaattt taactaacac tactaagtga tagaattgag aattgtacct ctgactccag107881actcagtcct taactattat agtgtttttt gtggggacca tatgagtgca gaggtgaaaa107941tactgacaga tattgaaaga tgctattggg taaataaact acaagagagt tcagagaaat108001taatgataaa aatgatcata ctactcctct cacttaccta acttttaagc aaacccattt108061gggaggtcct ttctaaaaag aaaataaaag agagaaaatg agaatgctca agtagatagt108121actattgaaa caggttacta aaaatgcatg tggtatcacc aaagaacctg ttctgacagc108181agagaaaatg aaattaggct ttctgtcctt atactcaagg ataactgtgc cttattgcaa108241atatttattc caactgttcc ataaaatatc tttgagtttt gaaagcaaaa aaagttaaaa108301ataattttct tacaggaaaa tagttgatta ttgaacttca ttaaaagttt ttaatgtcct108361ctctttgaaa gacactgtaa agaaaatgaa atgacaagcc tctggctggc agaaaatatt108421tataaaacat atgtctgata aagaacttat attcagaatg atatggtctg gctgtgtccc108481cacccaaatc tcatcttgaa ttgtagctcc cataattccc atgtgttatg ggagggactc108541agtgggagat aattgaatga tgggggtggt ttcccccata ctgttctcat ggtagtgaat108601aagtctcatg aaacttgatg tttttataag gggtttcccc tttcgcttgg ctgtcattct108661ctcttcactg ccaccatgta agacgtgact tttgtctctg ccattattgt gaggcctttc108721cagccatgtg gaactgtcag tcaattaaac ctctttttct ttataagtta cccagtcttg108781agtatgtctt tatcagcagc atgaaaatgg actaatacag agactatata aagaacattt108841acaactcagt aataaaaaca gaaagcaatg aatcaagcta agtagttggc aaaaggttta108901aacaaacatt tcataaaaag aggttgtatg aatgacccaa agcatatgaa aaaatcatca108961gcctcactag ccattaggaa aatgtgaatt aaaactatga tgagatgcca ttacattctg109021actagaatgg ccaaaataga aaacaaaaca gagtacctac caactgttgg ccagaatgtg109081aaataactga aacactcgta tattgctggc aatagtatga aatggtgcaa ccactctata109141gaactctggc agttttttct taagttaaac atacacttat catatgattt gacattttta109201ctcataggta tttactcaag agtgaggaaa ttgtatatcc agaagaagag aaatacatga109261atgttgatat cagttttatt tataatggcc aataattgaa aaccatttga atgttcatta109321acaggaaaga gaaatttttt aatgtggtat atccaacact actcaggaac actgctcagg109381aacaaactac tgattaatac aacaaaacag aagaacttca aaaacattat gctgagttaa109441agaagcctca catataacaa tacacactct ataactgtat gtgtgtgtgt gtgtgtgtat109501atatggcatc tatatatcta tatctataga tatatagatg cataaaattc tagaaatcaa109561aaactctctt attgttacca aaagcagata agtagttgct tgggaaaaag ggctggaggg109621gagagggtaa actgcaaagg gcactgacat tgtggtcaca caagtgtata cattgtcaaa109681actctaactg aaatgtggac taacatgttg cattttatta tatgtaaatt atacctcaat109741aatatttact ttaaaaggca taatgtaaaa tatgtatgta cacatacata caatataatt109801actaaaaaac cgttatcttt ttatgtggca gttactcata ttaaactttt taaccctctc109861aattctctca acacatcagt atagtaatag tggcaagtcc aaacttccct aattctattc109921caaataactg ttctaattat ctgtagctca ccatttaaat aggagtactt gagataataa109981aataattacc taaatcaccc atctcaatga atgatttaga attgaagagc cattgccaaa110041caaaagattg tagatttaca attaacatct aagtatgctg tagtatatgt ttttaattta110101caatagaatc tgccaataat ttcctcaaat aagtttcaaa ttcctaataa tgtagaaata110161catgtcataa atacataata ttcttaggta agatgctatt atagagaaga atttaaaaca110221tttacagtga ccttcacaat aaaagaaacc aggggaagca taaaatatct tttaaactcc110281ttgtagactc ctgtttctgt ctgcaatatt caataatctg tggtctgaat ggcttatgaa110341attgtgagtt tctcatcgtt tagcccatac cttagctgcc accaaaagaa aggcctgtct110401taacttagcg tttcctagaa tcagaagaaa ggagtggctt gaaggagaga agactccaat110461cgtctcacaa agcatgtaga tcactgtgtt ctgatacagc tcagaaatcc atgatatgag110521aacacataga aagaaactag catagaataa aaggaatgag atcacaattt tcaaggcatt110581tgtatggacc ttggtcctgg ggtctctgtg tcctttgtaa ttgagttgca ttttctggag110641atgtttctgc agggagaaaa ttaacaggag aaaagagatg aaggccacag taaatggtgt110701tagactgaac atagtcatag tgaatttgac cgacactgaa aatgtttcaa agtcactcat110761actgaaattc caagttgtgt ttctttcata tcggtccagc cagtctttta tatgcatgtt110821tatttgtatc agatttaaaa ataagaagac caaggttcct agcagtatca tcagaatcac110881tttgtttact ctccacttca aatagagaaa agcagggcta gagaaactcg ctattttgag110941caaataaaag atgctgaaga ttgtagcaag ccagagattg aagtgattag aaactatcca111001gctaaaaatc ataattctta atcctgttcc agacacaaat atggctagat aatgcagagc111061taaaaaccaa cttactaata tttcccagat cagcccaatt ctggagattg ccaagataat111121gaggagttta tcgactgagg acagctctct tttactgacc cagtcaatgc agttgatcag111181tactataaat ccattgctca aattcccaat tatgaattct gcaattatta caagagtgaa111241gatactcggc agggcacttt ccatgtcaga acagagaaag ttcaatgtct aatgtcactg111301ctggttattc actgatctaa aatgctattc acatccttga gtgtccagtg gagttcttct111361tccttctcct ttttctgctc cttctttcat tgttggctca acgtcaaagc agaaatctct111421aaagtttgct gatcgatctt cacataactg ttctggtgat atctttattt ttcttcaatt111481tctctgctga gccctagcta agatatttat gtcttcacca tgggcagaaa tatttcatag111541atgattatgc agcaaagtta aactcacatt tgcaaccatg caaataaaga tatattctct111601ttcattgttt tgtacttttt tgccttgtct gagcatagaa aattagattc aaccagcttg111661agttctgagg tacaaatatt ataaaaatct gattcataga atatgtagct aaatgaagct111721tttatggcta atagcatagc caatgaagct ttataaaata tgcaaagact tacctatgct111781atttcaaaag agtgctcaat ttcttgtgga gctaaagctg gatctggtca atactgtgac111841taaagagaaa ctcgtttaca aagcatccat ctttctcatt ccctgcctca tcactactta111901gcagtgctca ccaccatccc tccataggca ccaaatgcct tcacatttta tccgcttttc111961ccctcatatt tcttttttaa acttaaaagt gataaaaaaa caaattttac aaaatcagca112021acagctacca aagaaagcag tactatatta catcataact tgcaaaactg aaaaccaagc112081aaagaaatag atacactagt tccccttatc catgaggcct atgtcccaag acccccagtg112141gatgcctaaa acagcagata gtaccaaact ctatatacaa tatatttttt tcctgtattc112201acctacctat gataaagttt aatttgtaaa tcaagcacag taaaagatta caaaaataac112261taataataaa atagaacaat taaaacaata tactataata aaagttgcca ggggttgtgg112321ctcatccctg taatcctagc aatttgggag attgaggcgg gaggaccgct cgagcccaaa112381agtttgagac cggcctgggc aacataggga gaccctgtat ctaaaataaa taaaaattaa112441aaaaataaaa agtaaaaaaa tgtgttaaaa tatatagtgt ggtgtctctc actctctcaa112501gataccttac tgtactgtac acacctattt ttggactgtg gttgaccttg ggtcactgaa112561actgcagata agcggggact aatgtgttca ttgtgaagag tcaaggttcc tcaccccgcc112621ccactctttc aaaaactacc gaaaaaaagt ggattaccaa aattctgaaa acgtggagac112681tcaagaaaga ttgtctaatt caaaattaat ataaataaaa cactttatct tgattataag112741ataataagta gccatttagc tagatgaata caaagctatt tttatttaat aaagatataa112801tttgtgaatt atgaatgttt gtattttatt actcatgcaa tctttattgg gtgatctaca112861gagtactaaa aaatttacaa aataattgca tcatctttaa tgatttgcaa gtttcaatta112921taacttaaaa taggtagata ttttctattt tgttgttata atggtatatt tgtcaagata112981gaatagaaaa tgtctccttt aacagtttgt taggtttgta tatttatgac ctttaaatat113041gtagctatgt ggcatgtggt cttccatttg cattcttgac ccagggctga agagatcttt113101tatacttttt cattttaggg tgttcttcct acctatctag agaaaagggt ttggggatgc113161cggtcacaac ttgataatac cccaaatctg tacaaatagg cctgaggaat ggtactgtac113221ttgctggtat atgaaaaaat accacagttt ttagaacttg tgatataaca catgacaaag113281acatagagaa tggataacag gcttgcggtt ctgagctgca ttttcctggt gtgtttccat113341aagagaaaac atttaaaaat ataaatttaa tcaaagagat gtagtctctc acttctataa113401gagaaagaga atagatgcta gggagcatca cagaaaaact ttttcagcag tctgaactga113461aaaggaaaat gaggcaaagg gcaggaagag gaaacaatga aaggtttgag tatgtaaagt113521attttttaag tcactgatgg atgcagtttg ccaacgttgt gttaggatat ttgcagctat113581gtttttaagg aatattgaca tttaattttc atttctcata ttgtgcctat gagaatttgg113641tattaagatt tagctaacct catatcattt gtttagaaat atttcttttc tctttttcat113701ttttgctgcc tattattgtt acatataaca aatatagaac atttaatgaa gtttaaatgc113761tatagtataa agtgcacact aatttaaaag cctcccatgg caagaaagag aactttgtaa113821accccataac accttatttg ctcctttcta atcacaaccc ctatcttcat tccagaagta113881acaactatct gcaattcaaa tcacgttatt gtttaacttt gtatatttta atttgaatat113941gtatccctaa gcactagctt ggttttgcct ggttttggat tgcacatgaa tggaataata114001ctgtacacaa tatttttgaa tttaactatt tttgatcaat attatgtttc taaaattaat114061catgttgcat atagagatag atcatttatt caattgctgt atagtattaa tggaatgaca114121attcaaaatt tatctagtct agtggaaaca caaagttggt ttattttgag tttggagact114181atgatgatga tgatgctacg aacattcttt aacatgtaac ttattattga gtacatgagc114241atacatttct atgatcttga tctggaacca ttccgttgcc tatttcttct ggtcttgttt114301tggcagttac gactttctag atatttgtca gtttcaatta tttatgtttt catgtaattt114361tgattataat atcatcttat taaattttta ataccaacag aatatatcct ttaaattctt114421catattattt gcttttcttt tcatgattta tcttaccaga agtttgccta ttttgttagt114481ctattcaagt ctgtcttggt cgatcttttc agatgtatta tttttcatta atttcatctc114541ttatattgtt atttaattat ttttacttcc gttgagtatg tttgctgtta tattcctggc114601atacgttttc ctcttagaat ttttcagcat ttctcacaag gttttactat attttattat114661acttaatttt aaatattttc taaatttatt gtgatttttc ttccaccata gactattttt114721aaaatatatg ttcgagtttc catttacata aaattttctc tgctaaaatt tatgttatgc114781atatatggtc aattttgata aatgttttgt gtttgctgaa aataatgtgt atcctgtagc114841tttggggtgc agtgtttcat acatccacta gatctatttg taatcatgtt atttaaatcc114901tatttacctt ttctgagttt tgtcttttta ttctattatt tcttgagatt taatgttaaa114961ctatcctgct atgagtatag gtttatctat gtcttttaga agtcctgtca acttttactt115021tacatatttt gatgccatgc tgatgagtgc atagagcgtt agaattgtag tatcttcatg115081gcaaatataa cctctactca catgaggtga cattatctat tctaatgtct ttttccttaa115141aatctattta gcctcacgcc tgaaatccca gcactttggg aggccgaggc gggtggatca115201tgaggtcagg agatcgagac cagcatggct aacacatggt gaaaccaagt ctctactaaa115261actacaaaaa attagccggg catggtggca ggcacctgta gtcccagcta ctcgggaggc115321agaggcaaga gaatggcagg aacctgggag gtggagcttg cagtgagcca agatcacacc115381actgcactcc agtgtgggtg acaaagcgag actccgtctc aaaaaaaaaa aatctattta115441gtatatatta aaatgattac attagcttat ttttgttagt gttttatggt gtgatttttc115501taaattttac ttttaacttc tctttgttat taggatttag atatatatct tgtacatagc115561atagaggtcg taaaatggga cctagagcta tatgctaaca ttttattcct tgtaggataa115621gaaatgtagt cttgtaggag tcccctctcc cccttgaagt tgtatattat gtaaattttt115681ggtcaataaa atattgtgga aatgacatgt tgcttcagag tgagagcatt tactcaccac115741tataagactg caaatttctc atcttcttgc cttgacactc aaacaagggt caataaacca115801tctatcagcc tggattcttt tgtgaccact atgagcacag gacatgtaac agaaatcaaa115861aacaaaaaca aacaacaaaa acttctccta cgtggagtcc ctgagctttg gggatcttgt115921tagtacagca tagactaagc tatcttggca agtatgagac tggcctcttg aactggtatg115981ttactaaaac aaaacaccta acttatgtga cactggctta atacttgatt cattggcagt116041gagtggcaag aaaaaacatt actgtttact gtaaaacaag atagggagtg gcaaaacatt116101cgatagcagt cacctgtggt tatgtgggag gtaaatcaca tatttgaaag ttttgtaact116161ctagaaaaaa aatataattg aatatattaa tggttcattt gacaattaaa aaaattgact116221ttagaaaata attgcctact gtctagctaa atagcaaaca gagggagatg ctctaaaaga116281aaatgatatt tatttgggag taatattgca atgagaatac atgtgccata gtaaattatg116341tgtgtattca gggacattag aaaagacaag gatttctaaa agaggaagat tacataattg116401ttttgagata attaaccttg gatccaagga tcaggaacaa gggtgacacc tgtctaaggt116461tagacaagga ggttctgagc agatgtcctt gcagaagtat ctttttgtgt agggttgcag116521tggcctttgt gcaatgttgt tgttttgtag agtcttttct ggtagctctt gttataagtc116581gtatttacat taagaactct cccctcatgg ccttctccag ctccatttgt cagagtttta116641acacaagtga cttcattttg attctgacaa ttttatacta ctttgcaagc aggaaaaaaa116701tatatcagaa agaagagtct agaaacttga gattttgcag agctggaaga ggcaactgct116761tctcaacact gaatagtatt tgagtttcta agcctggtta aaactcagcc atggctgggc116821acggtggctc acgcctgtaa tcccagcact ttgggaggct aaggcaggtg catcacaagg116881tcaggagatc gagaccaccc tggctaacac ggtgaaaccc catctctact attaatacaa116941acaattagcc tggcatggtg gcgggcacct gtagtcccag ctacttggga ggctgaggca117001ggagaatggt gtgaacccag gaggcagagc ttgcagtgag ccaagatcat gccactgcac117061tccagcctgg gccacagagt gagactccgt ctcaaaaaaa caaaaaacaa acaaacaaaa117121aaactcagcc ttaagactag gattatctca agggtatggt tgttacatcc atgttaaaaa117181ttctgactag attatattta cagaaaaagg ttcaactgac agttactgct ctttcagttt117241gacaaggtaa tatcaaggca gagtgattaa atatctggtt tcctgaatga agccttacaa117301tgctcaaagt atctgatatt aaatccagag agaaaagcag aggggtgaaa aagcaacaaa117361acacagcaaa tataagaagc agcagactag acaaaaactg tgacttgttt gcttgtatgt117421gaagctgaca ggaattaagt agactaaaaa attgagtttc ttaaaaaatt gtgcttctga117481aagaaatgcc aacccaaact aggtcacacg tgtcaaagta tattaaaatg gaggccaggt117541ctgaagaatc cctaggcaga caaagccagt taggtctcat atgaccttaa aactgattga117601tttacaaaag taagcaaaaa ttaacttgag ctatttttta taaatgccta tagtaaagaa117661aaacagaact taaactcaac caatcaaaga cagccaacag gatagccaaa catttgattg117721gttagctata aagttacctt atttcatctg tcctgtcttt gcttttcttc tttgtctgtc117781ctataaaagc atccccatcg cgttccctcg gtagagctcc ggaaccacct cagtttggag117841ctttccaatt tatgaaccat catttgcaaa taaactttta aaaaacttta gtgtgcctta117901gttgacctta ttaacacatg ttgagctaaa accctgtatt agtctgttct catgttgcta117961ataaagacat acacaagact aagtaattta taaaggaaag aggtttaatg aactcacagt118021tctacatggc tgaggaggcc tcacaatcat ggtggaagac aaagaaagag gaaagggaca118081tcttacgtgg cagcagacaa gagagagttt gcaaggcaac tcccctttat aaaaccatca118141gatctcatga gaattactta ttcattatca taagaacaac atgggaaaga cccgcccacg118201attcagttgc ctcccactga gttcctcccc atgacacatg ggaattactc gggagccaca118261attcaagatg agatttggat ggggacacag aaaaaccata tcaaaccctg ttccagagat118321gcagtttaac atattatgag acaaatggga gctcacagac aatatgagaa tctcttgaag118381attacacttt ttttcctagt tctaaaatta catctttttt aatgagactt atattcttcc118441cccaactcag aacatttcct tgtctttaag ggagacctgc cacagataga gaaccataga118501aaataacagt aacaaccaca taaactgtca tgttagctat gaaaagagtt ggtggaagga118561atgggctctc accaagacag tgaaaaatag aggtaggtgg taaacaaata tgcaaaagga118621ccattcagaa acccaagcaa actatcattc tccccatttt actggtgcta taaatacctg118681aaaaaaagtg ccacagaaat ggattagtgt tatcatcaac aaatatattt gagccgggca118741cagtggctca cacctctaat cccagcattt tgggaggcca aaatgggaag atatcttgag118801cccaggagtt tgagaccagc ctgaacaaca taaaaagacc acctctctat aaaataagat118861aaaataaaat aaaataaaat aaaataaaaa aaatagctgg gcatggtggt gcacatctgt118921agtcccagct acttagaagg ctgagatgga aggattgctt gagcccggaa ggcccaggct118981gcagtgagcc atgcttatgc cactgccagt cagcctgggt gacagtgaga ctcatatata119041tgtatacatt taaatatatg tatacatggg tgagactcat atatacagat atgtatatat119101ttgtacgtat gagataagct ggtgagaatg aggtcattga agcagatatc ctgttccttg119161ccaattaagt cagtgatgaa ttccatagtt aataccacca tgaaaatgtc ctcctctata119221cctggcttct cttcagagag aaaaattcct aattttataa ttttttttat tttcaactaa119281gggattaata caataattaa gggattaaat atttaatatt tattgtttca gtacttctct119341cttgctatgt ccattaattc cattgctcat tgttaatttg ttgttaatta cattaaaatc119401agttcttctg taggatcatg tcatattgat ctttatgaaa tcagagcaat catttttcaa119461atgattcagc tggcaatttt catactaaca aatattttag ttttttataa gagccacagg119521tgataacttt ccatattcaa aagaataccc agtgaagtct agtgttctca gatgcagtta119581cggacagttt tcctttcact gttttcactt gttgcttcac cctaaacttc aatttatgta119641cacattacag tccccaatta ggagactaac aggatgttga agaatggcat tggcaggaca119701tttctgaatt cagtagcagg aatgaactca aaaccagcag tactgagtca gttcttgttc119761tcttctgact gaattcgtgt tcatggaaat gtttctgcaa gactgagtgg tcacagtgtc119821agaaggctcc tcaggttttg cctcttcaca catgtccatt tcccctttga ccttctgcca119881tgtcaagata cagctggaaa gccctcacca gaagctgagc agatatcagt gcctgctttt119941ggaacttccc agcctgcaga aacattaggt ctttatagat tgtccagctt caatattatg120001cagccttaaa aaggaacaag atcatgtcct ttgcagggac atggatgaag ctggaagcca120061ttatcctcag caaactaatg caggaacaga aaaccaaaca ccacgtgttc tcgcttataa120121ttgggaggtg aacaatgaga tcacatggac acagggaggg gaacaacact tagcgggcat120181gttggggcag gacgggggtg ggagagcatt agagaaaaga gttgatgcat gctgggctta120241atatctaggt gataggttga taggtgcagc aaaccaccat ggcacacatt aacctatgta120301acaaacctgc atatcctgca catgtacccc agaacttaat aaataaataa ataatacatt120361tttaaaagat ccacatgatc aaaaatgcaa aaaaaaataa attatccaac ttcaggtatt120421cttttatagc aacataaaat ggactaagac aaaactctgt ggtgaaatct ccaattattt120481gtaagatgaa gtcgtagaaa tgggtgaagt ccaaaaagca ggttataatc tatataaaca120541tttaagactt ttattaatat tgacaaagtc ccctacaaaa tgcatgcacc aatgtaagct120601ctcactagca ttaaacgaga ctgctcgtaa ctttgcacac attataattc tatgtaacaa120661tttacaaaag caaaatgtgg ccaatttgaa atgcaaaata gagcacttgt tattcatttt120721accatagtac tatactaaac ttacgttttt gtttaaatgt gaggctgaat tttttatata120781tgataatctg gtttttaaaa ttatttttat cttttttata aaacagtaaa agtattaaat120841ttttttctac tgtttatatt gcaaatagac tttaaagttt ttaatctatt atttaccttt120901ctatatttat tttcttgagg cattcagaaa ttcttccagt catgctatta aatgcattca120961ttttaaatgt actctgcctt taatatcatg tttaaacatg tcttcccaac tttcaagatt121021acaaaacaat tcttggtatt ttctctgttt gattgtttac tttttcaatt ctatatttaa121081tcctcttatt tactttggaa gaagaagtat gttacacatt tgtcttattt caaattgcaa121141tattgttgtt acaatactaa ttattgcagg gttaattttt cttcacatat ttaagatgga121201aaaatctatc tcacacaata tatttgtaaa caaaaaaaga tatttataaa ctctataatt121261tttttgttgc actggagttt cctcattctt tcatgatgtt attctatgcc actctttaaa121321gagaagtgtt ggaggacatg aaaggtgaga ggatagacat gtaactattt gttggacacc121381taacttagga tggacagatt atattatttt tatcagcaaa tgtgaactca tcagtctttt121441ccttaatgac atgtgcttcc tcaaattaaa ggcagtagag tcttattttg attttcttgt121501aaaagtttta aagaattgtt ttcaaatcta aagtgatagt acatctaatg tagtttttct121561gtttgttgtg agttagaaat acaattttgt cccaatatta aatgacagag gtctcaatat121621cattagttga acagtctacg tttttttttt gttgatttct aatgccaaat ctatcacgta121681cggaggttcc tatgtgataa gaataaacaa tctggtctca ccagacctgt ctttagtttg121741atctgctgac ctattactta ttatatacat tttatttctg tgtcacaacc ttcattgttt121801tgattttttt aataattttt ttgagacacg gtcttgctct gtctcaaaaa atattaaaaa121861aattttttta atcttttttt tttttttcct gacagagtct tgctctgtag cccaggctgg121921agtggctcaa ttaaggctca cttcagcctt gacctcctgg gctcaaacaa tcctcctgtt121981tgattctctg tgtagctaag actacagttg ccactatacc cagctacttt tttgatgctt122041ttagagacaa ggtctcactg tgttgctcaa gtgggtcttg aatgccttaa ctcaagtgat122101cttcccatct cagcctccca acatgctggg attacaagta tgagccacta aataaataat122161ttaaataagt cttgctatct actggatacc cctaccttaa ttttcttttt caagaattgt122221ctgaattatt tttgaatact taattcatgt gtaatttagg actgttttgt caatttgaaa122281ataaatttct ttaagattct ggttagaatt atattgaata tgtgaattaa tttgagcata122341atcaatgtct ttgaaaatta atttttgcat atctatatag ttcaaatcct tcactaaagt122401attatagtta tgtaatttca caatatataa catcatgaaa cacttttctg agacttagtc122461ataatcaaaa tatagttctt atttgtaata agaaagggaa tttttttaat tccacatttt122521aatggaccag tgctggtgaa taggtgtaat tttagcccat atatattgat attgtactca122581gcaagcttat caaatttgtg ttatttcaaa agttttcctg ttgattttta aattatctag122641gtggaattac tactattagt atataatttc tttaaatttc catccaaatt tctatgtaac122701aatatttttg tcaaagtgta ttagttaaat gacctaacga aattgtcaat aaacaagtat122761ctttgtctta atcttgatta aatgaaaagc tctatgttac actaataact atgcttctgt122821atttgtttag tagacataca agttattaaa tgttgcttct atttaaactt ggtttgggta122881tttatcttga ttaggagtta aattagatta aacatttttg caacatctgt tgagataatt122941ttatgtaaat taaaattatt tactttctag ttttaaatta tcttcaaatt cttagaatga123001atcttttcat ttgtaatata ttttaagtat atattatgag actaatttac ttttacactt123061ttttttagca gttttgtgcc tgtatctaat tgcctacctt ctcattattt gctgtcctct123121actgttttta ctcactttga gaataatttt ttaacttctt aaaataaatg agaataaaac123181atttaggttc actgaagtag tttggagaag gtaaaaatta tgacattttt aaacttagta123241aaagtttttt ataaatccat ctgaatttga tatcttgtgt atattttgat agtccattca123301aaatctttga aattgttgat ttattaaagt tttttactac taatataaat ttttgttaac123361ctatgctttt taaaaacttg gcaatttcaa ctgagttttt aaattttgga ataaaattat123421ttagaacttt gattatataa agctctgcta tttagtattt tctacatttc atcaattttt123481ctgcttctcg tatttcttga tcagtaccat cagacttttg aatttcctaa tctttaaaag123541attttggttg tactaccatt gtctattata ttttgatttt ctatttattt attcattcat123601ttatttattt actactttga ttttggttga catccaaaag cataattact gcccttcaga123661caaattctaa cttttccttt tgctgagtct atgacttggg aaatttactt aaccttgcta123721tcccttggat ttttgtttgt ttagtttttg agacaaggtc tcacgctgtc acccggggct123781ggagtgcagt ggtgcgatct tggctcactg tagttttgac ctcgcaggct caagtgatcc123841ttccacctca gcctccctag tagctgggac tacaaaggtg caccaccata cccggctaat123901ttttgtattg tttgtagagg gcagtggggt ctcaccatat tgcccaggct tgtctcgaac123961tcctgaactc aagcatccac ctgtcttgac ctcccaatgt tcggggatta caggcaggtg124021ccacagcacc ctgtcatgcc tctgattctt taaaaaccaa agggaatgag actgttttta124081ggaataaata taaaataaat agcacaccta aaccacctag aacagtacca tgtactaagt124141aagcgcaagg tacatattag ctccttctta acttattcac ccttctttaa atttttctgt124201tgttcatttt tcttaactga aggtgaatat gtgcctcatt catctggaaa acttttttat124261aaaacatgta ctaatggata tggattctta gctttagccg gttttttcat tttgattgtg124321aaaagctttt tcgttgctga gttctaaaca tttatctttt atgtagaaat gttcatcttt124381ttctcagtta tagagaatag ttcaattttc aaactttttt gattgattta acattttact124441actttacatt ctacgtaata cttattccat ggaatctgtt ctttgttata gtgtacatgg124501tttaggtgtg taaatgtttc atgtgtattt gaatgtttgt gtccagattt ctgtcaagta124561cagatttcta cataaaagta ttgaattaat ttttgctaat tgcattctta aaatattcca124621tatcattctt tcttctgctt gatatggcag tttattaagt gtgtcttaca ttcttattat124681ttgtggattc ttcagtttct gtttgtgagg cttctgcttt atctatttac gtaatgcatt124741gttaggtatg tccaaattca tgattattgc atcttttcca tgaatttttt ctttttcttt124801tttttgagac ggagtctcgc tctgtcgccc aggccggact gcggactgca gtggcgcaat124861ctcggctcac tgcaagctcc gcttcccggg ttcacgccat tctcctgcct cagcctcccg124921agtagctggg actacaggcg cccgccaccg cgcccggcta attttttgta tttttagtag124981aaacggggtt tcaccttgtt agccaggatg gtctcgatct cctgacctca tgatccaccc125041gcctcggcct cccaaagtgc tgggattaca ggcgtgagcc accgcgcccg gccctttttt125101ttttttttga gacagagttt tgctcttgtt gcccaggctg gagttcaatg gtgtgatctt125161ggctcagtgc cacctctgcc tcccaggttc aagtaattct ccttcctcag tctcctgagt125221agctgggatt acaggcacac gccaccatgc acagctaatt tttttgtatt tttagtagag125281atgggggttt caccacattg gccaggctgg tcttgaactc ctgacctcag gtgatctgcc125341cgccttggcc tcccaaagtg ctggaattac aggcgtgagc caacatgccc agccttcgat125401gaattgtttt attcttacta ctctgtaatc acctgtcttt aactgttact gttgtttact125461ttaaatgtta tgtgattatt agttataatt cagttaaata tgacaaatat aaacaagcaa125521ttgaatatat gcatgtggaa gagcatctat ctttcacata actaaaaaat acataggaaa125581gtttttgtgg cacaaattgt ccaagggaat agtgtgattc tatcaccaac aaatgatagg125641ataatagaca ttaggcataa gtagcagtta ctgtgctcat tagttagtgg tagattctac125701ccatttattt tctgtcactg tggttttctg ctttaggtat gcctcttgaa agcagaacat125761agtcgtgttt tgttttctta tttattctct gtcttttgat agatcaagca aatttattta125821aattcatgaa catttctgat aacattgaac ttgcttttac tgtcttatta aaattttgct125881agttatcact ctcttttcac tctttttttg ctttgagatt aaagtgataa gttcttttta125941ttcatttctc catctgtttt tttttttttt tttttttttg agacggagtc tcgctctgtc126001gcccaggctg gagtgcgatc tcagctcacg gcaagctccg cctcctgggt tcacgccatt126061ctcctgcctc agcctcccga gtagctggga ctacaggcgc ctgccaccac gcccagctaa126121ttttttgtat ttttaataga gacggggttt caccgtgtta gccaggatgg tctccatctc126181ctgacctcat gatccacccg cctcggcctc ccaaagtgct gggattacag gcgtgagaca126241cggagcccag cctcatttct ccatctattc taagtttcta tttttatata acaaatcatt126301ccccaaattg caggcttaaa acagcagttt attacttttt tcctcacgat tctgtgaatt126361gcctggactt agtggatagt ctctcattgt ggtatttcat gtagttgcca tcagataagg126421gatgggacca cagtcatctg aaggctcaaa tgggatgaac atctacaatg atccaactca126481atggctgaca tagggaggat tccctctttt tctactgatt ggaatagttt cagaaggaat126541ggtaccagct cctccttgta actctggtag aattcggctg tgattccgtc tggtcctgga126601ctttttttgg ttggtaggct attaattatt gcctcaattt cagagcctgt tagtggtata126661ctcagggatt caaattcttc ctggtttagt cttgggaggg tgtatgtgtc gaggaatgta126721tccatttctt ctagattttc tagtttattt gcatagaggt gtttatagtt ttctctgatg126781gtagtttgta tttctgtgga atcagtggtg atatcccctt tatcattttt tggggggtct126841atttgatttt tctctctttt cttctttatt agtcttgcta ctggtctatc aattttgttg126901atcttttcaa aaaaaccaac tcctggattc atggatttct tgaagggtgt tttgtgtctc126961tatctccttc aattctgctc tgatcttagt tgtttcttgc tgtctgctag cttttgaatg127021tgttggagag cagtttctca taaaagcttg tggattcaac tgtaaaagtg gcaatccact127081ctgactcccc tctccactgc agagagcttt cttctttcac ttattaaact tttgctccaa127141cctcaccctt ttgtgtccac actccttaat tttcttggtc atgagaccat gagctcagat127201aacaccttag taataatatc aatgacccgg acctgttttg gtaacaccag ctctggggcc127261aggacacagg ggcactctca ggcagaagac tgaaatctgt gcaagtggta tacaaattta127321tcccttcata cacaaatctc aggccagtct ctctcttgga cttctaaaat tttacattca127381ttgtgatgag aatcaacatt tttggttcat ttcaaaggac aggctcaagt tttgccaatg127441ctaatatggc tcagcagaaa aatgcatgtg gcttgtatta agaaagcaca taaaggatct127501acattgactg ggttttcata atcacaaaaa acgaataaat ttgtatgagt atctttatat127561gaaggcaagg aggaaaacag gtgaatggaa gcctacgtaa atgtgcttat gatttaaaac127621aaacttattt cctcaggaaa aatatatttt tcacctcacc tgttaaagtc ttaggaaagc127681ttaaccttga taatctccta ataacagaac ttatgtttct tttctgaacc tcattccttc127741tcatattgta ataatgaaat gaataaatga atagcaagtg agtagtggtg cacactaaac127801tctgagtact gactgccttc tattccactt aataccttta taagaacatt gttatgtacc127861taagtcatgt catctataaa actaaggtaa tgataacaat catatgtccc taatataatg127921gttttgatga ttaagtggaa catagtaaat gtttaaaaat gttttctatt ataaccaatt127981tggctaggat aggtggaaag aatagaaata tgataattaa ttgtgaaatg tataatatat128041attaataggt catcaacatc aaattaaaaa atatagatga ttaccatgat agtgaaacca128101aagtttttag acaagtcaaa gcaaagttga agtctcagag accattgtgt ttatttgcta128161actgtattat cagactgctt agttgataca gtgaatacaa taattcttcc aatgtacata128221aactgccaga caagcaactc aatgcaattc actcactctc ggagaagttt atcccctctg128281ccaatgttca tctttcctgg caaaccatcc ttcagtattc caggcaaact agagcaaggt128341gaagttgaag aagatcctac tttatattcc attcagagag cttccgggtc ttcaaaaaag128401atttagtcat gtgggtgtga aagagctgag tcatgaaatt tggaccttat tgtaagtcca128461gaaggaaaaa caaggggttt gaagcacaag ggtgatatga tctaatttct acttttaaat128521gatcactctg attgtcgtga gggaactgat atgggatgta ctgggggaag aatgttacca128581ggaccaggtc gaggctgtta aagacctcca ggagagagca ttgtgggccg aacaacaagc128641ttctagtaaa gatcatgcaa gtggacacat ttgagatgta ttttgaaggt ggaagaaatt128701agataagcta atgggtagtg cctggaggga gtgaggattt ttgaaccact aggtaaacac128761ctgtgagtaa cagagaaaaa gttgggatgt gttatgaaag atgaatccta aaatttcata128821tgttgaagac tgatgcttca ggacctcaga atgtgaacat ccatagtaga agggaattgt128881gttgttgacg gctgccaccc actctaggtg cccaagctcc tgcagcagtc ctacttctcc128941ctttcaccca cactcactcc cagacagtgt ccctttcagc tcttccatca ccccttcttt129001tgatttggct ggtgagagca tagctggtat ttatactttc ttgatatgct agtctctttt129061gctgattgtt gacattggag aaggtcatgg aagggacctg agctgagcga cctttaggag129121catttcctgt tcttttcctg tactctgctg ccaaggagaa atctgtcttt caccaggctt129181gcagctttct ccgttaccca catcatcagg caatatctgt ctggcacccc tctttgttcc129241ctttctctgg ccttcctttt tgacatgatg gttgacctga aatcaccaag gcaggactgc129301tcatctccag gtctaatgga aaacagtatc tggtgaaacc aaagaaaata atcccagtaa129361cccactggga gctgcttggc ttaagcacct accctgtgcc taagatacaa cccatcaagc129421ccagctaaaa ctgatccagt ttccacaggg ccagagaaga attgccaatt aagaatgcat129481tcccacttca aatatgtcta tatttatttc agggaaaata tcagtctgcc tgggtccctt129541atgagaacat tgttgtctgt agaaaaatct aatctattag gaagccttct tgttttgtta129601tctgcaactc ttcagaaggg ccagaccaga ccctcgtatg cacagtacag gatccaccca129661tgcacatctg tctagggcct tgtctttatg attttctgtc acatggcctc tcagccatgc129721ctccaaccaa gctatcctca aataaacact agccgtgcac aaaaagtgaa aaattacaca129781aggcctacac aaggtctgaa atggaaagtg cagctggtga taccgagtag tatattttat129841gaattgagga acagggaatt tctaggtatc acagagcaat cagcagctga gaagaggagt129901accaatccag gaccctggaa ggatttttca gaaacttaat agtttattgt ccaattgtag129961agacaaaaat gaaaataaag atagtgagga gtaccataca ccattgctta gaagattaaa130021taaatgtcat ctcccacaag tcatgtgggg agaaaaaaac tatataggaa gaaaattaca130081aacgacaagg tagtctcagc atataaaata tcaacaaatg aatgtaagaa agagaatgag130141aaagaattag tattagaata tcatagaaaa aatcatcttt gtgaaagaaa actctgatga130201aactggtgac ataaatactg agtaaaaaac agaagaccaa tcaaggcatt tgaggcttga130261acaggcatta caaatcatca agttgaatat ataagtatgg ccacttagtt attagtggtg130321aagactacgg tatttgttag aagaaataaa gtagatgatg aattctatag aatattctgg130381agaaagtgga ggtcttagct acatgacatc gtgtggctca ctttgggaac catgtttcag130441tttgtttagg tctagaaatt ccttggtggt ttctgtgttc agttttgctt taataatccc130501taaagatatt ttttaaaata caaatttttt agctttcctg tattgtacag caccaacgct130561tgcctgagtg tagtgagatt cacagagttt ggaaatttcc tgtagcatga ggaggctgcg130621gggcagcctt ctgtcatcta tgtgtaccca gcagtgtgct gtcctcacac aactcacgga130681taagcagaaa gcatctctat tacatgaaaa atttagctaa atatacaaat atccatgcac130741acacatcatg agagatggaa ataggctatc aaaagagtca gacatattga ccgtcttcac130801tgttagctgt aggattgctg cccaaccccc tgacacaccc acacaaactc acatacacaS130861aaatgaaaag cacagtggaa agcagaatag cagtctttcc aaacagattg aaaaacaaat130921gatgtctaaa gttcaatcct gacactgtgc tgattgcttg gacacagttc cgtcaaaaca130981tttgtccaag tcatagttgt accttttaga aattagccac aaacaacatc ctccccaacc131041cttcctgcta ggctagagtc ccagaagaaa tgagggatac acttgacctg aagtaagcaa131101agcagaaccc agtctctgag gcgaggaggc ccacctggta gggagctcaa atgcgccatt131161gtcctgcttg tctttataaa gggagctgac acgtttctcc cagcataaag ttgggagtga131221caccagagcc ttctgcaaga tgcttctgat tctgctgtca gtggccctgc tggccttcag131281ctcagctcag gacttagatg aaggtaagcc gaattggggg aagatattgt gactctgatt131341ggggtttacg ggcgaatgct atagaggggg aaagtggagg gaagagagga ggatgagaaa131401acagatagga ctgaagagtt ctcatgccaa ggatcagaag acctgttgtg ccttcattcc131461tcatcaagac ctcataattt attgattgca caaatagaac ccaataaaga atttgtaccg131521ggggagtgag agagtgagat ttgcatttat agagacatgg gactgctggg aaggatatgg131581agaatgcaag acagattcag ggaagtgcag ctgtgaagat cctatactga tcccagtaga131641cagggatgat ggtggccttg ctggacagtg gatgagtatc catgaaggag ataaacacat131701gtcagagcta ttgctgaggc agagaattgg gtaaacactt gcctctgtct acatagagtt131761agagaatcac cagagtgaaa tattgtcatt tttttctctc ctgcatgtag tattttaatg131821tgctgggacg ggcatttgta agattgtatc taagtggcta tgtctggtgg ctcctgttga131881gaaagcttgc aaacataaac aacatattta cagatgaaag agggcagaag gatccccaaa131941tatttcattg aaatactcaa gagcccttta actaaataag cactaaggct taaggaatca132001tgagaggaca aacaggggcc cttctatgtt gagttcctgg ttgacgctca gtgtagtaac132061aatcctgctt tcccttacat cttcttccac ttccggtagc atcagagagt ggctgatgag132121atctcaaagg ggatgcacag ggtgtgatca gaggtccttt atcctcgtag aacactatga132181gctctgaatg attcatgcag taacttttcc catcatcctg tacttctttt ctagatgtca132241gccaagaaga cgttcccttg gtaatatcag gtaaatccca ataaattctc agtaaactct132301gtctccattt ttccctgaaa aattgatcag ttctccagtg tcttcttatc atccttgtca132361ggaattggct aatatcagtg ccccagagat ataaacagtt ttctcccaac cttgattctg132421gggaccatga gtaaagaaat ttgatttttc accaccctaa tgtggattaa gaggagttct132481aattaggaag ccttgggaag gggggaggtt gggagttgag aggcaggtca gggagagagg132541ggccggccgt gtggtgaaga cagagagata tgaagacagg agggttttcc agcatgagct132601cagctcttct tgtttcaact cacacagatg gaggagactc tgagcagttc atagatgagg132661agcgtcaggg accacctttg ggaggacagc aatctcaacc ctctgctggt gatgggaacc132721agaatgatgg ccctcagcag ggaccacccc aacaaggagg ccagcagcaa caaggtccac132781cacctcctca gggaaagcca caaggaccac cccaRcaggg aggccatccc cctcctcctc132841aaggaaggcc acaaggacca ccccaacagg gaggccatcc ccgtcctcct cgaggaaggc132901cacaaggacc accccaacag ggaggccatc agcaaggtcc tcccccacct cctcctggaa132961agccccaggg accacctccc caagggggcc gcccacaagg acctccacag gggcagtctc133021ctcagtaatc taggattcaa tgataggtat gattccagtt tattatccat caaaggctcc133081aactgctaca gttctccaac ttcattgtgc cagtgaatct attgaaaagc tgttaatatt133141tccgtgtcct ggaacacatt tctcatgagt tttgttcaaa tattctggga taaggtagca133201agatcttgtt tttaaacaat ctcttgaagg caattccaat tttgagaatc actatcttca133261aattacctct cttaaatagg gttgggaatg aggacataga atcatgttct ccctttggca133321ctctgtttcc tttcctcaaa ctcaaagact cccatttatt taaagtttta cctgaacact133381ccttgttcag gacaggctca gtcctgcctc acactagcat ttcaagtcca gtattcctgc133441taaatggtcc ttggactttt agctgttaaa tggtatctca ttttttaaaa cacatttcac133501atttaaagtc atacatgctt aagctaacaa aaactaatct cactgaatag acatgtacca133561agctaaatag caattcattt ctcctcccct ctacccttac caaaactccc actttttact133621gtttggaaac tcctctttga aatatttatt gctacataac tatatataat tttcccacca133681ctaataccac actttatatt cagttctgtg tcttacttat tggaaaaatt tatttcttag133741ctttcacatg agtttattta gatctcttca gtgtttaYtg gttagttttt ttttttacaa133801ttatatatga tgctattgtt tggtttttcc ataatttact taaccaatcc ttgtcactga133861acattaaggc tgctttcaca ctgtccctat tacaggatat gttgcagtcc ccatctttct133921gaaaataacc cttaacgtat ccaacagcca caaagcatga acaacctaac aataatcgtt133981tttcgtcctc atctaagcaa


Following is a genomic nucleotide sequence of a GRID2 region (SEQ ID NO: 3).

>4:94744101-948417501tcaactcctg ggctcaagca atcctcccac ctaagactct aaaataactg ggactaccac61ccagtcaaat gccaccacat ttgactaatt tttataaatg ttttgtagag atagggtttt121gatatgttgc ccaaactagt cttgaatttg gggcctcgag tgatcctccc acctcaacct181cccaaagcca tgggattcca ggtgtRagcc actgtaccta accctcttct ggaaaatctt241aaRgccttag attgcattcc tgtctttata ggtcatattt ctcattattc tcttcttttt301gaccttttct ttgcaacttg agagttttaa aagttcactt attgtgtaac ttattcatta361gtcctgatat atcatttgca ttctttacta ctcccaactg ttatttttat tctgcagtag421aagtttgtct ttattctttt ttgttttctt ttctcatatt atctcatctt ttatatcatt481accttccttt cagcctattc tctttgttgg ttctctactg atgtttcacc tagattttca541ttgtttaaag gcattcatca gattatattg caacattttt attgaatgca gccagaattt601atgtgaggta tgtactacct ctgagacttg agggtgatat tctgatttgt ttagggtgca661atgagttttt gtgtttgttt atgtttctat aaaccatcca ggcccaatct ttatttttgt721caatagttaa agaaagtgaa gcatcttttg cctcctctac aatccattta gttaagttca781gtttttcttt ctcagaccta gagttaaaga tcaaatagat atgttcagca tttaatcaaa841tttaccatgc atagtaggta ttccatgtat aggtttttga cagagattta ctaaagttat901ttggtctaat tatgacagag catttattcc agacactgtc ttgtttatac tacttatcac961tcagtgacta aatcttccaa aacaaaaatt attgtcatct caccctctct acttccataa1021ccttacggtg gtttctgctt tgagtagtag tctctggata tttgtgaaag agtgtaactg1081agaaggcagc aggtagtgaa taagagaaca aagtctctgg atactaataa agatagttct1141catatagttc aggatagctt gctgcttact tggccataaa gctcttacag cctaaagtta1201ggcataatca aaggaaatat tgttgcggga agtcagggac cccaaatgga gggactggct1261gaagccatgg cagaagaaca tggattgtga agatttcatg gacatttatt agttccccaa1321attaatactt ttataatttc ttatgcctgt ctttactgca atctctaaac ataaattgta1381aagatttcat ggacactaac cacttcccca atcaataccc ttgtgatttc ctatgcctgt1441ctttacttta atctcttaat cctgtcagct gaggaggatg tatattgcct caggaccctg1501taataattgc attaactgca caaactgtac agcatgtgtg tttgagcaat atgaaatgtg1561ggcaccttaa aaaaagaaca ggataacagc aattgttcag ggaataagag agataacctt1621aaactctgac tgcctgtgag ccgggtggaa cagagccata tttctcttct ttgaaaagca1681aatgggagaa ataatgctga attctttttc tcagcatgga acatccctga gaaagagaat1741gcgcacctgg ggataggtct ctaaactggc acccctgggc atggtcatct cttatggtcg1801agactgcaga ggtgagatag actccagtct cctatagcac tcccaggctt attaggaaga1861ggaaattccc gcctaataaa ttttggtcac actggttgat ctctcaaaac cctgtctcct1921gataagatgt tgtcaatgac aatggtgcct gaaacttcat tagcaatttt aatttcacct1981gggtcctgtg gtcttgtgat cttgccctgc ctccgcttgc cttgtgatag tctattacct2041tgtaaagtac ttgatgtctc tgacccacac ctattcacac actccctccc cttttgaaaa2101tccctaataa aaacttactg gtttttgtgg cttgtggggc atcatagaac ctaccgacat2161gtgatgtcta ccccggacgc ccggctttaa aatttctctc ttttgtactc tgtcccttta2221tttctcaagc tggccgacgc ttaaggaaaa tagaaaagaa cctacatgaa tatcggggca2281attccccgat aaaatatatt atatagggag actcaaagca tatttctacc ttccctgtac2341taatttgaaa aagaatatat atggttgata aatatatata tatatttaga ataagtatta2401agccccaatg ttatgcatac tcaaaggaat tatacaacat aaagagaatc aaagtatatt2461tctactYtcc ttggactaat tcgtcctgtt ctggttgtaa gtatgggata tgaaatacat2521agatgaaatg tatgcttttg aatctatccc caatctcaat ttagttgttt caaattattt2581gagaatttct catttatctt tctctaactt gaattatgga gcctgtggct ttattttttt2641ttttttaagt tttttttttt ttggtcagtt gttgaaattt ttaaacagat atttggagga2701ggtgtatcag agccagctag ttttaagtct cagactggtc actcttaaaa taatcccacc2761cagtcatgcc atcatcaaat ttagttgcct ctctccttgg cttaaattta atacattttt2821tccccaatct attggactct ttagaaatgt tttaaacaaa aatgactaat ttatttttta2881aatgtaatta attttgttga ttgaataaga atgtttaaaa atgaaacatt attgtgaaaa2941ttaccacatc cttggtttaa aatagcctga gaaaggaaag cacagccata agaaataaat3001atacgaatag gttaatacag aggaaattgt gccagacaaa gctggttgct tttttgatag3061ctttacagcc ttagtaaatg aacagagtgg agtagacata atgcatcttg acttctagca3121aagtactgga gacaatgtcg tgtgaaattt tgattgcaaa attaatttga gttggcttga3181aaaacactgt taaaggaaat ataagctggt tgaaaagaca tacagagaag agtgttgatt3241aatgtcagtg aactaatgag ttgagtgata tctccagtta aatgtcacga ttgtgagtgt3301tggattgaat tatttttgtt atctgttgaa aaaataaata acatagggtt gattaaatta3361gagcagaaaa tttatcagga gacaccagtg attacagaaa atctatataa agacatgaat3421tcatttcaga gaaaaaccag tgaaacaata taattttact taaagagtcc atttttttaa3481tcacaaaatg gaattctatg aagtatcaat gcttaaagac cttcaaacta cagaatttct3541caaaactaaY tggaaaacaa aattaactat ctcagtaagg ctagaacatc attttaatcc3601agttagtagc tacattttat cccaaccaat aaagtgacag ttaattctta cctagaggat3661gtggttaaat gtataattat tatttaccag aaataaaaaa agtatctaga aaatcagtaa3721cctctagaaa ctcttgggca caggagaggg agaaaactat ggaaggggaa gtaattatgt3781tcttaactat gttacattct taagttacat tcttaactat ggggatatag taagactcta3841aataactaaa gttttttttt attatacttt aagttttagg gtacatgtgc acaacatgca3901ggtttgttac atatgtatac atgtgctatg ttggtgtact gcacccatta actcatcatt3961tacattagat atatgtccta atgctatctc tccccactcc cacctctccc cacaacaggc4021cccggtgtgt gatgttcccc ttcctgtgtc catgttattt ttgaaatatc cagattaaat4081gtagttaagt aaaacaataa actttttcaa tgtaggtttt ttaatgctaa tgaaaagcta4141gtcagcatgg ggtaaattag attaaattag attaggtaaa ttggaataag aatcaaatga4201tcacaatcat aaaatgggat tagtcttact ataagtcaca cctgcaaaag gaagaagata4261acctggaaaa atttaaagag tcttccactt tacgaagtcg tagtgagttg gcaagtttta4321ataatttaaa agaaaacgtt gatttcatct aaaaagagag agagaaagtt ttagttattg4381attcaacatg tatttattga ataacttaaa tgtgcactat ttttggtttt gtgagcagtc4441ccaaacgatt aaaacagagt gacttgttcc ctgactatct taaattatcg caaactgatt4501ggcttaaaac aacggaaatt tattctctca cagttttgga ggccaaaagt tcacaagcaa4561ggtatcagca gggctgcact ccccctaaag gctttggggg agaatgattt tgagcgtttc4621agcttctgtt agctgtcagc attctttgat ttgtggcaac atcactccaa tctctgcctc4681catggccatg ttgcctcctc ttctgtctga caaatctccc tctaccatag tcttaaacaa4741acagttgtca ttgggtttag tgcatattca tgtaatctag aacactctcc cctctcaata4801cttaacataa ttatatctgc aaagatcctt tttccaaata aagcaacgtt tgtttccaaa4861ttttaggatt taatatctct gggtgaccat gatttaacct actacaaaag cattttctaa4921caagcagctt aaaataggtt tcttttttct ttgagacagg gtcttgctct gttgtcaagg4981ctggagtgca gtgSacagtc atggctcact gcagcatcac actcccagtt tcaagcgatc5041tttccacctc agcctcccaa gtagtttaga ggacaggtgc atgccaccac acacagctaa5101tatttcattt ttttgtagag acagggtctc tctgtgttga ccaggctggt ctaaaactcc5161tgagatMtag caatcctcct gccttggcct ccYaaactgc tgggattaca ggtataagcc5221actgtgccag gctcaaaatt aggtttctat tgctgcatta atatatacac agRgccatct5281ctttctcttc taattatttt acaaatataa agagcatctg taacacaatg aagctgtttt5341ccactttagg aaaagacagt tttgaaaatg tgattaatta tttgttgcag gttaggcttc5401atacagtcat attcccagtg cacattgtcc tcaagatctc cccagtttgg cactgaagcc5461ttattgactc tgtctctgaa agaggcctta aatgatcccc cttccttcta atcctcactg5521aaattccctt aggttaagcc caatttatcc aagggctatg gtcttctact tgatgttctg5581tttttaatcc ttgatgctat ccttctcctt ccatacaaac agtagataca catattttca5641aaacacagac tttcttgtgt tctctactta aaaatctgtc tagctttcag atacataaag5701gaaaagcaac ctggttttaa gagcatgcaa tgYttcttct taaatttccg atccctgtcc5761ttgtctgcag atttatcact taacattcct ctccttgctt cataatacta cacacacaga5821catacacaca cacaaacaca cacaaacaca cacacacaaa cacacacaaa cacgcacaca5881caggcacaca cacacacgca cacacaaaca cgcacacaga gacacacaca cacacgcaca5941cacacacaca cgcacacaca gttccttgat attgcagtca cacagaattg ttcactgttt6001cttgaaaata atcataaact gcatttgctc atgttatttt ttgagatcag agtgttcttc6061cctctttttt ctgctttaag gttttctctt tttttgcaca gctattaaaa cttggccaac6121tattatattt tctctatagt tttccctgat ccttacacat cttcatagct ccttacatgt6181aactctatta ctgtgtgcat catatgcgat cgtgtttatt ttccctgtgt gatttgtttt6241ttagactatg accaccttga agacagaact gggtcttatc tatctttaca tctcctagtt6301gtttgcatgg ttcttgacac atagcaaatg ctcataaact tctgatgaac taaattactg6361taaattaaag tcattgatac atttaaatgg cacgatttac ctatatctgt tttataatca6421tagttaacaa attaagcaaa atacttctag gaccaggaac tcaatatgga gacactccat6481tgtaagagag aaagatgcat tgaatcgttt attcagaaag aacttattat gtcactgtag6541gcactgcaca aaggctaaaa atcccaaaat agaattgtta aaaaattagg gtttaagatt6601aaaggcaaag gaaatcatat ttgttgagac tattagggtt gcttgaagta aactaatgcc6661aagtttaagt aaaaagattc ctgctatatg atataattgt taagcctaag agaccagcag6721gcaccaggta cagttacatt cagatgctca agcaatgcca ttagggaact gcccatgttt6781agccattact gtgttctgtt attccttttt tttttgtttt gttttccctc tcaggcagat6841tctactcatg tggtaacaag actattattc tagatactgt actcatattt aacagtctca6901gggaaagagt gaagcctttt actcaatcgt tccagaaaat atctaatgga tgaagggaag6961gctctaactg gccttcgttg gaccacttac atttctttga accaattact ctggtcagaa7021gatgaacatg tctgatcttt caggattaga ttcacatgca aaataatgtt acaattcaaa7081ctaggaaaaa taaattatat atttttaaga gactggatga aaatactcca tacatcacat7141gtgcttttct ttttctgtat attggtatat acataatcac tatttctttt tttttttttt7201tttttttttg gagatggagt cttgctgtgt tgcccaggct ggagcgcagt ggcatgatct7261tggctcactg caacttccgc ctccaaggtt caagtgattc ttctgcctca gcctcctgag7321tagctgggat tacaggcacc caccaccaca cccggctaat ttttgtattc ttagtagaga7381cggggtttta ccatgttggc caggctggtc tcaaactctt gacctcatga tctgccagcc7441tcggcctccc aaagtgctgg gattacaggc gtgagccact gcccctgacc caccactatt7501tcttttgtaa ttaaaaagta catatacact ttatattttg atgtagatgt aagaatagcc7561tctgcttcaa agacctcatt ataatagtat taaagacaca caagtaaaca aaggtaacaa7621taaaatagta atacatatca aatattaagt atctcaggaa taattattcc ttctaaggaa7681tggcaaagaa atttttcaca ccacaaagtt aattttgaat tgggtcttca aggaacataa7741caatttgaaa agacagagag gactttccag gaaaatgtaa ctacatatgc acaaatgaca7801gtagggatta tagtaaKWac acttttatta ttattctacc tcttcactct attcaatttc7861cctgactact acaatgtccc catgttggtt tctcctttct tgtattccaa gatattgtgt7921cctgcttttg cttattattc tctacccctt aagcttctca ttgcttcctc cttcttttct7981cttttttctg ggcctccctc tttgttttta cgatccctgg gaggactcat ttaattgact8041cctaaatggt ttctgtgtct ctagtgtctt gtagacatta gaggcacaga aaccattttt8101cactgtctat tttccactcg gcatccaaac taattttcca taaacattgc ttccatcatg8161gatatgtgct ttaatagcat tggaatcaga cagatcttaa gcacaataca atagtatata8221taccagatac cagttatatg actgtgagaa gatagtaact tctgagagtc tcactactaa8281tgcccaactt gtaagataat tatgaaaata tgtacaacat atgtatcact ctcagcagtg8341ctagccacta gatagatgtg caatatataa gtagataata cttttgtggg tatctatatt8401actcctttgc ccataaccaa cagtgaacca tcatgttcct ttttaagctt ggtggtggat8461acaggtgttc actttaaaag tctcagtctc agatttcaag tcttcaaccc atctcctaag8521ctgtcagagg cctttacaat ctttacctac ctcctttatt cagtcttatt tcctatcatt8581tccccacagg aactatttgc tggcccttta aKttctccct tacctcagaa cttgctaata8641tttatcactc ttaaatatat gtttttgctt gtgctgttcc tcaaactaga atttttctgc8701catcttttgt tatcctctct cttcttttag tttaaatacc ttctgttctc taagtttttt8761ttttccagga caacctagaa aaaaatatct ctttagtttc tacagtggca gaaggtaatg8821tgatttacca atttaattac ttcatattac aatatagtga ccatttatat cagtgtatag8881tacaaatatg tatactgtgg tcttactact gattatctta ttcttattta ttgcctctcc8941aacaagatgt tatcacccat agacaagaat catattttat atatctttat aacccaaagt9001gcctttttaa aattaatgta tcatgtttgt tttcctggaa caggaactga aatagagagt9061atgaattcat ttgtaactga atctttgctg taatagttat ccccagcatc cttgctaata9121cagagaatga agccttaata cctaaagcag ccactgtRtg tgattaatta acttctctcc9181tatgcatctt gacaggtagt ggctatgtgc cattcttggg agaactggga aaatggtcac9241tgaaatcatt tttgttgttt ctagttccaa tgagaaatgc cagcYgggaa aggctgctac9301agtatgtagc aaggtgcttt tgctgaaata ataaaagtat ttgcaaggaa atacttgaaa9361taagtgctaa atttccaaag attgatctac actacagaag gcttattagg gtatattgat9421actagtatgt gttgtcttaa gtggtacatt gtagtttcca tgccaattct tggtttaaaa9481cgcagcatgc atctgttata tgccactttc cacttaaatg cctaagacag gtagattgca9541ctgtcaagtt aggtcattat aactccaaca gatgttgtca tgtagatgaa gaaaattcat9601tttaaatgat atcatttata aaatgtgttt ttctttgtac ctaaaaaagg caataatatg9661tcatattagc tcttcagatt caggttgcaa tcagtatggc atgttttgat taaacacttc9721acaatttcaa aatcagtgca ggataatgat ggagcacatg tgaggaaaca gcaatagcag9781gggtgtttac agtatcccag ttgtttcaag cttaataaca cttcatgtta tcaatcagtt9841acaaaggaat aattggtgga taggctgagg aaatggtaca gtaagaaatt gtacttattc9901taaactatag ggatggaagt gcagccaggt caatacttat ttggttagta tattgtaact9961aatcatttga gttttgccag ctggtatctt atttttgctt atttgtttaa ccgcttttaa10021ataagtatat aattttaaca atttaagtca gttgaaatcc cccccataga gctctcctcc10061aaatgcatcc ctagctacat tcttctttct ggagattaac cagaaattgg tggtttcatc10141ctgtttatat gaatacattc ctagaagata aaatcatatt gtagatattt gtgacaaaat10201tttcctcaca actatatgaa agagaacgaa ggaaggtgtg tggttaggag ttagctgtca10261ttaaaagtgt gtaaattttg cacgttccct acatttattt tccagtaaat tttactagtt10321tctttctaat cagttgggac taaagtcaat cgacctgtct ctgcttcttt caatttcatt10381tcccaaaaga attttagtgc ttctctatta ttcttaactc tgccttgccc caatacatta10441atcaatgctt tgggtaacaa cattagattt gtacagggaa ggaccaggga atggcattcc10501aaagcaacac atggaaaggg caagagctga atttcataaa ccgtaaccta atccatcact10561gcagctttcc gttgcctcta cccagactgc agccaaacat actctaagct gccactttag10621agtatcttta ccctccatgg gagtttttct ttttttccct tttttttttt ttttttgagR10681cagaatctca ctctatcgcc caggctgaag tgcagtacag gatcttgtct cgctgcaagc10741tctgcctccc gggttcaagt gattctcctg cctcagcctc ccgagtagct gggattacag10801gcactcacca ccacgcccgg ctaatttttg tatttttagt agagatgggg tttcaccatg10861ttggccaggc tggtcttgaa ctcctgacct cataatctgc ccacttcatt ttcccaaagt10921gctgggatta caggtgtgag ccaccgcgcc tggccaggag tttttcactg tgatgttgtg10981taggtctctg gaatgtatgt ttccctctgc agtttcccca gtgttgattt taagggagga11041agccagagca cttgctattt caccatcaca cttgtttgaa gtgtgagtta ccatgcaatg11101tttaaaacat gagttacacc tttttggagg atgctgtaga ataccgattt attttttgtg11161tgaaaacaaa ctctacctca ggttaatcaa ataattactg aagaaaaggt ttttctttat11221tcaaatattt cagcacatga atgaagaaga aatggtaaaa gtaaaacatg aacatttggc11281catcactaat tatattagtt tgtagaggct actgtaacaa aattccacag accaagtggc11341tgaaacgaca aaaatttgac tgggagttca aaagcaaggt gccagtggat tgggttttcc11401ctgaggcctc tctcttcagc ttgcagatgg ccaacttttc cctgtgtcct aacatggtct11461tctttgcacc cgatggctct ctttatggtc taatctcctc ttcctgtaac tacaacagtc11521tgattagttt tgggcccacc catatgatct cacttaacca taattatctt ctttaaagac11581cctatcttca aatgcattgt gaggtactgg gggttagggc gtcaacacct aaatttgggg11641aaacacaatt cagctcatta aatgaatgga agtcatacct gaaatcaatg acggatcgta11701tgactacaaa aaaaggagac aaacattata cacctgctgt ttaaagtata caacacaaaa11761ttattgacaa atattaagct gaattaggtc aatcttctag atttaccaat ttgcaaataa11821tgcaatccac agagcaagat gtggatatgg gggattcaga cagcaYaatc tagctcggga11881aactacagaa aaaaaaaatg acccattttg tgacatataa ttgaaggaac aaatgaagat11941agatgaatgg agaacccRta aataaagcaa ttcaagatac acatgaactc ataaaacata12001ggtcctaatt tgagtaaaga aagaaaattt taatactgac tggWtatttg atgacactga12061gaaactattc taactgtgca gctatgaaaa ggaatgagat catgtccttt tcagggacgt12121ggatgaagct ggaagccatt atcctcagca aactaacaca gaaacagaaa accaaatgcc12181acatgttctc acttataagt gggagctgaa caacgagaac acatggacac agaaagggga12241acaacacaca ctggggcctt ccccggggbg gagtgcagag agggagagca ttaggaaaaa12301taactaatgc atactgggct taatacctgg gtgatgggtt gataagtgca gcaaaacacc12361tttgcacaca tttacctttg taacaaacct gcacatcctg cacatgtacc tgcacatgaa12421ctaaaaataa aaataaatta ttctaaatct tgggaagtat gataatggtg tcatgattat12481gttttaaagg acttcttaac ttttagagat atataccaga atagaaataa tattgtataa12541tgtctgccat ttgtttcaaa tcaaatctga ccaaagtagg ggcaagaaag agtaggcgca12601taaataaata actcattgat aatgagttga taattgtttc agtaggatga tgaatatttg12661agtttataat tttattctat ttatatattt gaaaattttt atactgaaaa gttgaaaaag12721ctttatattg gtattttaaa ctttgtaaat gtKcactaaa agaagatatg tctttttagt12781tgttttgcct gagttatgat gagctttgat gagtcaatca ggctgcctct tgagttttcc12841ttgtaaggtt aattgggtgc actggagagc tagctgaggt taggagagca ggctctggtt12901gaaggacagg gtttcggctt ggcagactaa ctaccttctc tgattattaa actttgatgc12961cacccacatt agcacagtat tctagtcacc tgtgataacc tgtccagaag ttgctctgat13021cgtgttcagc tcaataagtt tagacttcac acaatagtgc ttgtcatttt ttaccctctt13081gtaccaaata tatttcaaaa tatgtccaat ccagctgtta atttgactga ataaaatatt13141ataataacac ttctgaggat tgagatgatg tttgaagttt ttcaagagtc ttttccctct13201ggattagaga acatctctgc cagaatcaaa atgagtctca aaattgacag tttttacttt13261acttgctaca gtaacctggc attttaaaaa gcattctgga aaaaaaaaat gaatcttctg13321attgtgtaat aaaagaataa gaatagaaac taagataaaa tgattctaca tgtatatctt13381gacttatgtc tatattttat aatttcaact tttacgtcaa aaaattgtaa aatgtcacta13441attttataag gtttaattta acagatcaaa gctcatagga ctttgttgaa aacaatgaat13501gcaaatcctc agtacagttc caggtgtgtc atgagccctc caaaaatgat agttacaatg13561actgtttcaa aaaatttata ccttcaacaa aactttaatc ctatttttat atgcctgtct13621gctctgaaaa taatttaata tgtttaaatt cctagaataa atcttacttt aaccaaatta13681ataattctta aacttaaatt tagatttcaa tgaatcccca aaatggtttc cacataaagt13741aatgcagcta atatcagcac tgctaacaga ttacacagaa aggtctatta taatgattga13801gtaaatattc ctgggaaatc aaccttgtta aatctatatc ctataaggaa aggtgcatat13861ctgttttttc tagtaaagat tccgtaattg ttattacaag ttaatcagct tctcccaggt13921tcatttactc tggattttat taatttatta caggaaatta ttgggtaagt aaaccacaat13981tataataaaa tctcatacat tttattatat ggttcacaaa ctttataaac acctgtgatg14041ggattctgct attgatattt aagtggatat ttattaagga actagagata cttctcagta14101agattagctt agagaacggt cctgtttttg atctcttaag attccaaatt tttattccaa14161attttctgat attgcccaag tgtcttttct gaatctatgt ctttattatt tggcttaaaa14221cctttgtgca tctggtgctc tattctgctg tgactttgga gaaaggttac agtttgtttt14281tgctgggagg aataacttct tgaatgatgt cccaactgaa aattattttt ttggttggat14341agaacatccc tgtacaaaac ttcctctatt atcccttgga taattcctgc tgtatataga14401ggtccaagat tgattaatga ttttatcttc agtaacctgt gatctaaatt accattggca14461agacaagagt gatacctgtt tttttattct ctacattaat aaaacatgcc ttaagaaatc14521tatatacttc atatagagga tatgatttgc cactaagcaa actctatgaa 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cagtggtttt25561caaccttggc tatacattgg aattacctgg aaaggctttt aaactactga tgccttggtt25621atactcctgg ggattctgac ttaattgtcc tggggtttgg atggagcatc agaatttttt25681aaagctttcc attctaatag tcaacaaaat attctaatag tcaacaaaag ttgaaagcca25741cagttttaag ggcatgtttt atcactcaga ctactaagtc acccgaaaaa tgagactgag25801caaggaacaa aagaattctg attatatagg aaaaataata acaaacattt ctttagtctc25861agtgtgtcat gaacacttct aaacacttaa catattttaa atcagttagt ggtcccaaaa25921actgtatgag gaagtcactt ttactattcg catttgagag atgagaaaac tgaaacccaa25981cagcacacgc aaagtaagtg ttagaacagg tacttgaact caatcagtct tcttctagag26041cttcttatct gaactggtat gctatattgc ctctaaatgt agtgtaatgg taattttata26101ccagaagaat tataaaagaa aggaaaacct ataaaaatag gatatcatta aatcagttaa26161atgctagttg ataatagagt gattattatg actgcataaa acatctatgg gttatacata26221tgtgtatata gacatatata tgtatatatt tattcaaata tgtctatata tagatatatg26281tatacatatt tgtatatata tgtgtgtgta tatatatgct ggttctcatg ttttcttcat26341ttgtaggaat cagttaacaa gttcttgtta catagtatga aggttctgtt ttcagtagtg26401aaacagggag ataaaagtgg ttgaaccatg tgattttttt tctgactttt caaagacatt26461ttctcctgaa ggaagctcaa gtgctaaggc tattccacat aatctcaaga acgactacta26521ctttatagta atgaccaaac tgtagtaata gaatcttagg agcatataat catcctctag26581ggaacacatt ttacaaattg aacctatctt gcaggtggaa ataccataaa gaaaatKatc26641attggagaga ttactggcac actgcattca ttcacatgtc aaagtggaaa acattccaat26701ttacttctat aaaacatgta tctgagtcaa cctgccatat gtatttttta cactttctat26761ccccttacag aatatctacc aaataaatgc tgcacatttc taagtggctg gcttttaagc26821tgctttgcct atggcttttt gttccctctt tttctcagct gagaaatcaa gtaaacaaaa26881cattgtggct ggtagcatag gtcctcagtg cagtggatat tttgtgtccg gcagctggag26941cattggtcgt acagatgggc ttcatttgtt ccatatgaat acaagttaat aaatggagag27001aattccattt ggtattcaat taagatctcc cctgactcct gttattaaag cctacaaact27061attgagcata aaattaaaat cgagcagttc agctcttttt gacattataa cactgcctga27121aaaataatgt aaaacccaag agtcacaagt cattccttac agcccatggc aaataagaag27181tggaaacatt gaggaagaaa gagtaaatat ttaaaacttg atcattagta cacatgttag27241gagcaggcta ctgtgctcat gcaaatacat caatccagtt tgttgaacac aagatattac27301attaatttta acagaatgtt acaagattat tattgccaaa gctccaatga aggaaataat27361taaagcacta ggcattttaa ggtcttaaaa tgacagaaaa tactatagga aatcaataac27421cagaaaatac tatagaaaat caatatactg taattgaaag gaaattgaat tgggtttact27481ttttttatcc cgtctaaatt ttcttcagat tgccagacca ctgaagatag tgaatcttgt27541tttgccatca gcagtgtgac tttctctaag tctcatgtgc tgcaagggcc atctttattg27601ttttttattt aggaagcact cagctgaata gacaStatga gattttgtgt gtgtgttctc27661tttactagtc ttggactcat tgttaaaaaa aacagaaaca aaatcaaaga cacagcagac27721aaaaacaacc acctccacat aaccagagaa gtcaaattaa tgagaattca gacatcgaaa27781ccagaggact tgttagataa gcctcacact tgaacctaag tgaaattctt ctagttttta27841tcaaacacta tgcctgtcat tcttgctatg caataagaaa cattaccagt tgcagataca27901aattcaattt gaatctatat gaatctaact cattttcatt gcttattatt ttaaaaagtt27961attataatca aacaaaaaag cttgaaatga acctcaggga ggtaagtgga tatgaacaga28021aattaaagaa tgttaaaatg agaaatccag actgggtgct gtggcttaaa cctataatcc28081cagcattttg ggaggctgag gtgggagaat cccttgagcc caggagtata aaacaaaaca28141cttaacaatt ctgagtctca atgtcgttga ctataaagta gaaatatctt cccttcctac28201cttaaataga tcacatttat gaaaaagatt cataagttat aaaacaacac ctcaatgaaa28261aatgctgtat ctggacttta aaaagaagtg aattaaatac taattttacc tcttagtata28321tatgtgatct taatgaagtc cttagttttc ttgtctgtta aataataatg gtaagggcac28381cttctcatat ggtcattgtg aagcttacat gtataaaaag ctcagtacca tggctgacac28441atagaaagta tttaacagtg ttcaaaaaca taatcaatat aggaaataag tattatttta28501tttccttaat aatttcttag ttatacccca ttatcatatg tgataagaga atgtacttta28561tttctagttt tccagataat ctgtatccta aacattcttt actcccaaat tcagtctttg28621agcatcctaa ctcttgacat ccacagctaa tatttaggaa acattaaaat ttgtttgtac28681atttgaagga agaactaagt aaatggaact taccaatcct aaaatccaga ctgctgttat28741taagaagaag aacaactgta caaatgctgt taYcaaagga tgtatgagtc aggcggaaaa28801aaaaggagaa cacagaaagg tgaaaagtct ttgtcaagca gaggagagaa attattgtct28861tgtaatatat atgagagagt ctagccaaat attaaacatt tttaaaatga aaagaaatat28921tatacatggt atgaataata tttaagtcat tgcctaggtt agaagattag atatatttac28981ctattctacc tacttcaaat gcttttttgc tgtcattgtt tggaacctcc aaatactaga29041atgctttaga attataaaac cattgaccat gttcagttat gtttaaaaga aaacatcatt29101ctgaggaaac tggaaattat atatttataa atgtttgtcc atagcattgt tgaaacaaat29161ggctcaggtt tcactgttaa tccagttgct gatatttttg actactcaat acaccaaaat29221ggtacagtca agttggtgct aatagatgtc atttatttac acaaactgac aataggttca29281ccaaagttaa gagacgaatt taagggggac agaaaagaaa ttcctgtgtg tgctttggca29341gcttagacat acttaccacg aacaagatta tatcttaaaa gctattcgtt aagcttaaaa29401ttaagttata tggttgtaat atgtggagaW agcacattgg aatagctctt cacttaatgt29461tatagatcac tttttccacc aatattattt ggtctaggaa agtaaaatcc tcttgaggaa29521gtaattagaa aaagcacaca tcagggaatg taattgaaga tagacttttg ttgacctcag29581aagagaaaag ctcaaaagaa atttcgtaaa gttttaaata tggcaagagg accacaatgt29641ctttgataat tagactttca acacatttgg atttgctaat tggatctaag ttctaattag29701gctttttatg taactaagaa tgacatatca ttgtatgaat ttaatgtgct tttacagttg29761aaactaacaa ttagcagcct tttccaaatt attttaataa ggaaaaagct ggctctgctg29821tttatactgt gacattccct tctcttaaga tatattatgt acattttcat tttctWaatt29881aaacaccttt tggggagctt aaagggaaac ttgggtttta ataggaagca cctaaattgt29941ttatttgtgg gggagacttg ccagccagta tgtagatgac tttggaagct acagacaaac30001cgcaataaaa agaaataaat cacaatcatc aggaggaaac agcacaaata accatttgcc30061cctatgacca ttcagttaat caaaacagtc tctgaatatg atgaaagatc tgttacattt30121ttaagtgtgc acatgcggaa tatgttccca aatgtgaagg ctcatggatc tgctttcagg30181atgaataata ggaaatttct tctcaagatg tgcattacaa cattctctct ctctgtagcc30241ttgttctgta aacagttatc tgctaattca agtcaaatca tctctttctt tctccatatt30301tttgattgag agtcatcaat ttttatccca ttcagatata tagacagtaa tttaaaaact30361ggtRgccctc agatttgtac attccaagag ataagaccta tataacagca taaaattaaa30421ctactatttg ggtgagtaaa gagcagtgag tcattgcaag actttaaggg aaaggctgct30481gccaaaatat tccaagcaaa ttgataacac tgccaaaaag gcaaattata ttgttttatg30541tgctatgaat actttgaaaa caaagacata cacatgattt ttttcaaata aaagcagttg30601cccttctaac catattaaaa atagtgtctt ttttcccagt aaaagccata taagatcaaa30661ttaaaaccat tgaaactatt agagaatcta acttacagta attgatatat taaaaaagac30721attatgttag agttatatgt gctattattt ttccaattag tacattactg ggactgagtg30781attggtgtat acataagtcc tcattaagta aaatgtcctc aatgagcctc ctaaagcaca30841ttgggtactg tcatgtgcca tataatgata tttaagagca agaaatggca tatctaataa30901cttcatttcc tatttaaaaa gaaaacctgt gcagtactct ttccatacca attattctaa30961gagctatcac atagttctcc ataaagacta tacagaggtg atgggactgt tcttcaggca31021gaaaaatgac caaagttgtc ttatctttca gcttggKtgc tggaatcctg tcacaggtct31081gaatgggtca ctgactgaca agaaattgga gaataacatg cgtggagtgg ttctacgtgt31141agtaactgtt ctggtaagta ttatctgagc ctcgtggttt tgacttttgg aggttacttt31201atcctatatt tctttcttta ttaactgatg acataatctt aaaagagatt ttaacaaatt31261ctaaatacgc tttctaagat tttttaatgg tcatatttca cagccttcaa tttacgtgga31321tcaggatcac agttttgcag acttttaact acagtgtatg tgttaggaat tttcttagaa31381attttaggct caatttccat cctacagttt tctacacatg acaaagtaaa ggtatgtctc31441aggccttctt tcattaaaac tgtagtgaac atagatagtc aacatatagt gaacattgaa31501actataaatg aacataaccc tgaccatgcc aaacaatggt agatttggta aaatgtacat31561tctctaatag tgaaatatta acaaactaag aatctttttc tcgtaagaac ctacttcaaa31621gggaagctgt tgtttaatag gcatctactg tcgactgtat tccaggctca gtgctgatta31681ctgagaacat tgacaaataa aatgacagat ataattctgt cttgatagaa cttatcatct31741agtgattctg tgaatgttga ataggattac agtagtttcc cYttatctgt gggggatgca31801ttccaagacc cccagtggat gcctgaaact gtggatagtt ttgttttctt ccaacacaat31861cacattgtgt agggcttata ggttatagag tgtggatatg ctggacaaag ggatgagtca31921catccagggc atgtcagtgg gatggtgtga gatttcatca tgctacttag aacaatgtta31981aattcaaaac ttataaattg tttatttctg gaagttttca tttaatattt tttggaccat32041ggctgattga ggagtaaccg aaactggtga aagagcaacc atggataaga agagtctact32101gtatacctgg gaaagatctg ttacaatttc atttacttat taaaaagtca ataaatggta32161actgttataa ttctatacat tatagttttc tttcctaata gatacataca ataagatgtt32221aatagaaata ttcttaaaca gtaaaatact caaatgggct ctgtctaaat agccataaac32281cacgaaggca tacattctcc tttgctattc caatgtgttt aatcatgtgc tagtttatag32341cctgtttcaa aacgtaatag tccatagtta gtactttatt tttcttcaga aaagtctact32401tgtttttaat tttgaaaaag attttcctat gggctaggta aattgcagaa ttagtaaata32461ggagaggaag actttttgat acgttgatgc taattggatg ttcatcaaat tttataacac32521cagttgctgc cctttgtaca ttgtttacta caaattaaat atatgcaatg taattttatt32581gtcaaaaaag tggatttgtg catattttct atgaaaggac attcaagtga gtgacctatt32641cttctttttt tgtggcccat aaattattcc tagttattat ttttaaaagg gcttaattgc32701ttttggtaaa taattgtaag tatttcacaa cttaaatgtg aattcgcttc tgtatgtacc32761taagggtatt gatatgcatt tacattgatg cactaatatt aaaaaagaca gatatttaaa32821gtacagcaaa ttattaatag tctttcctcc agtgattagc atgaaaactc cagtgatgat32881tgcagtgaaa gacggtatat gtgctttgtt ttcctttgag aaaagaaagc aaatctttaa32941gtccaattaa cctcagtcag ttttaagcaa atagttattt cgcaattact atatgataga33001ctcagtaatg gatataagag aaataatata cagaccttgt cctcaaagta ttcatagaat33061cttgttaggt tgatgcacat agagaaaaac agctcagatt gattaaatat ggttgaccct33121tggtgtctgt gaggcattgg ttccaggaaa cccccacacc aaaatctgca aattcbtaag33181tttctgatat aaaatgatat agtatttgca tataacctat gtacctcctc tcatatgctt33241taaagcattt tagattactc ttaataccta atacagtgta aatgctatgt aagtagtggc33301tctaccgaat tatatattta tttttgttat ttttattggg tttttttcct aatatttttg33361agcctcagtt tgttgaatct atggagttga gtctagatgM agaacctgtg gatatggagt33421gttaactgta cttactatgt gcaagctact ctactaagtc ttttgcatgt attgtcttat33481tttgtcctca caatattctc aagaaatagg taatattctg atctcaagag gaaactgaga33541catccagaag ttgaaataca tacatgtatg tgtgtgtgta tatatatata tatatatctt33601atcattaagg gaaggggtta aggtctagaa tcagacttcc tgaatttgaa tcctaactct33661gctacttact atctgtataa tgttcataaa tacatgaacc tagaagaaat tgaagaataa33721catgcaagga gcgattctac gtgtggtaac tgctctggta agtattacct gagccttgtg33781gttttacaga cagtaagtag cagagttagg attcaaattc aggaagacag attctagacg33841ttaacccctt ccctcttaat gatacattat actgtctcca gtcctactgt gataagtgtg33901agaactgagg tgtctataga attttgtttg acttgagagt tgaaaatgct tacgtctgaa33961taaggtgaaa gtgagtttta ttgggaagga ttgtaggtac aatcatgtta aattcatttc34021caggctgaat aaaacaattg ctattttgtt catgaaatag tagcacttca cacagtgtta34081acacctgcat accccaggtt caccttcatg actcttaata atctctattt cctgcaagct34141tagccctgca cagatattga atatggtttt gtgactggag acatggaagc agtgtttttt34201tttttttttt tcaagtcttc tatgatggac ttatcagttg ggtgccagtt gagtaacagg34261ttgttatact tattacatta ctacaatata caatcattgt gtttaataat tttgcatgct34321tcctatgtct ttctgtaact actctgagaa tggaaaccag tcattccctt cttatttatt34381ttctacaagt gccttttcag gtctagctct tagttatatg gccttgcaag cttcttctac34441tcaacactga gaaccactct cccctcaccc cacccagcaa ctcccgaatc ttgaggcttt34501acctcactaa accctgaaac taggatttaa tctatactca acttgatgtt gtcacctaaa34561cgcaacctcc caccccctta tattccaagt atttacgtcc aacactttcc agaagagaaa34621agggaaagga ccaatgtgta catgggaaga agctatttcc tcctttcttc tattgaaact34681gaaatctagt cttagctcta cccactccct cttttcttaa gaaattttat attatcaatt34741acaccaggtt aataaaatgg atttttctta ccaaaatttt gaaattccca ttcttatgac34801tgttgatatt ttattgactt gaaagaaata acttcatatt tattttaaac tacacaattc34861agcactctac tgtttgtgat cccatgggca aataagtggt gctctcaaac atttcattga34921agagttaaat agaggtatta ttgacgaaga tgtaaatagt gttaaaggaa tcaacaagga34981gtgttgaatc accagaacct acctagatga cttacatgaa gactgataag gcatgggagg35041aagcattatt actagacaaa gcaatagagc catgggagag agaccatcac tcatagtagt35101agtgagctac agtgcagaaa aagaaagaga atcactgcca ataccaaaat caggctatga35161ggaactggga ataagggata cactgatctc actcctctta tctatctctt ttcatggtct35221ccaactgcaa atccaaccag aagtcagagg ttatgggagc ctaagtaagg aagaccatga35281aagttagtct ttcaggacac agaggaaggc agtgaagccc tcagtgaatc cagaagaaaa35341gtagagaaaa accaacacga gcatctacca tttgatagga cctattataa gaaggttata35401tatattaact tatttaatcc ttataaaatt tcatatgagt ggcactaatt acattataag35461gataaaaata gggtacataa gagttaacta aatttctgcc tccatatagc tagcaggagc35521cagacataaa tttcaagatc agagatcctg gttccacaaa ccatgtcctt agccactctg35581ataatctKcc ttctgaatca gaatggactc atgttaggta taaatgaaat ttgatataat35641tattgagatg tgaggattgc atatgttgga ttgataactt aggagaattt tcctaaattt35701cttcatatat agatttcttt gtattcaacc atcaccaaag ccacagaaat atgtcttaga35761aatggaggaa aagaaagaat gataataaaa gcagtctcta ctacttggtg tctcttctaa35821tctctttgtt tccataattt gcccactgat ctttacttct taccaagtgg tccaagtgta35881ttactacaaa ggaattatga agattttccc gtttttaact tcctgagtta tgcaatgtag35941atagcaataa atgaccaatt aagtcattca attgttttca tggtaattca tgaaaacact36001attggaaaca ttactgagtt ataaacataa tcataatata tatgataata aaatggaaag36061gaattggtta caaattaaaa gaaaggcgtg cgaagctatg ctgcaacaag tataagatat36121ctgagaacca taaattggca tttgggagga gctcactgat tagtaattct tatttaccta36181ctttgattgg ccttaaaaaa gacatataca ttcctaataa acatacattc actcatgaat36241tcacacaaaa cagtcaaaga tcctgacttt agagagtttt tttgttgttt gtttttattg36301agacaggctc tcactccttc acccaggctg gagtacagtg gcatgatcat ggctcactgg36361agcttcaaac tcctgggctc aagaaatcct cccacctcag cctcctgagt agctgggact36421acaggtgcat gccaccgtgc ctgactaatt tatttttcgt agagacaggg gctcgctatg36481ttgcccaagc tggtcttgaa ctcctggcct caagtaatcc tcccaaagta ttgggattac36541aggtatgagc caccgcaccc atccagggag tttgattctt gcaagatatc ttctaaagct36601ctcaaaatag tcttgaaaaa ctgcagtgca gttgttctcc attaaataca caatagagca36661tttttttgcc tagaattacc ataaaaataa ttcaatatat aaattgaatt catatataaa36721tatatgactg gaagtctata gtaaagactg tgatagtgat ttttctgcat tttataaatt36781aaaaaacata gtttttcata ttttaatctc tctaaaatta ggatgcatcc ttcaacttct36841atttgcaatt gtaattagca ccatgtttgt ctttattagt gatgtgtaaa atagttgcac36901atcttacaat aggaaacatt ttagattaaa taatgtatgg tatttttaca aattaagtta36961atggatattc ctggaaagtt aagttaaacg tcactgggca agaagccaca taaagagaat37021aactatttta aagaatacct ccaaaagaaa aggcagtagg aaatatacca attagaaaac37081ataggacagt aatagcaatg agaaaaatta ctgtctaaat taaaactgtt gcctcaatca37141tagaaggata tacacagaaa taggaaatac acagagatag cttatcttga atcattacca37201caaagcaata tccaaaatat ctattgagag aatggtaggt ttttctaagc aactcaccaa37261aggaaggatt gtttgcctgg ctgcagcaga cagccaccta ctgagttatc attttgagta37321atttcttttt cctaaaaaat atccatcatt agtctcactt tttggaattt cttttttttt37381ttttatggag attgtgactg atatatgggc accagagtct taatttgtac aaaaacaaaa37441aaaaagtatt taggttagat ttagttattt atatacatca gcatgaagta aagcaatgta37501cttaatttcc tcttaatata ccttttaaca aaggaataaa taatatataa ttcatttttt37561attcaaagta cttcacacaa ttttgttgcc tttatttcac caagtctcct ctatttaata37621cacctatgct aagaagcttt ggcacacact gcaaaaagca ctSaacttgc agtcaaaagg37661tatgactttt agtatcgtac tagtttttct gcttaattga tctttgaatt tatggaaacc37741aagacgctgt tctgaacttc aatttttcca tctgtaaaac aggaataata aaaccaatca37801caaagggtta ctactatatt aactggatga aactatgtga aagcaggtag caaaatgaac37861agtgYttcta catacattat ctctgcagta aaactatgat gtgtaaactc agtaaagaaa37921aaaaagcatg agtgatcata aaagtctaat tattcattgt catcaaactt cagatttttg37981tgggagattg gaggactcta agggagacaa acaaatgtaa actgcagaat aatgagtttt38041aggccccgtc actgttacct caatttgaaa acctgctaat gaggaccaca ggaactcttc38101tgccagtgaa gctggtactt cctagaggaa aaatgcacaa aaaacaccta ccaccgaaaa38161caaaagcacc ctgaattatg attttcaaaa atatctagaa gtttatatat caattatWtt38221atctcatata aactgtgttt gattccaggc tagctttaaa tagactctat attttaatat38281ataactaaac aaatgcctcc agtgatagtt ctgaaacgtc attgtcctta aattttttgc38341taaggacatt gtccaagtgt ttgctactta gagactttca gaattttcat cgctacctca38401aagttcaagc ttttctgagg tcccagcgtt tgagcctctt gaacctggag gcaaggttag38461gggttgggaa agtaaacttg tcaagagact ctactgggca agccctcaca gcaaggagtt38521gggaagagag ctgacagcaa gctctggtgg ctcccacagc aatgtcttac gagggctcct38581tcggaggagt taataaataa taaagtttgg ttcaggactc caggcaagaa tgacaactct38641ggctgaggaa atttccaggg gctgatatct aaaataaact taaagtcaca ataaaatatg38701ataagtgcca tgtaataatc ctacaatgga aatacacagg atagcattgt ggttaagaac38761acagttccca cagtttcact tctggggtgg caaatgagga gttccatgga cccactcccc38821agcaaaataa gcagagatgt caaaaatgaa aaagaaatga acaaaaaaca acactaacaa38881aaaagtttac attctctgga aataattgca aatcatatat ctcataagtg atatttagca38941tatacaaaaa tattataact cagtatgaag aaatataaac aaaattaaaa aaaattaaaa39001tgggcaaaga tctgaacagt tctgcaatga agatatattt atataaatgg tcagtaagca39061aatgaagaga tgctcagcat agttttccat caaggaaatg caaatcaaaa ccacaatgag39121ctatgactac aagcccacta ggatggctat attcaaaatg acagataata acaaatgttg39181gcaaggatgt tgaaaaatca gaatgctgat acattgctgg taggaatgta aaatggtacg39241actccttcag aaaacagtct agcagttcct caaatggtta aaagtagagt cactacatga39301ttacaaattc cactgtatat ataatcccaa gagaaatgaa aacatatgtc catatgaaaa39361cttgtactca aatgYtcata gcagcatggt tgattgcagc caaaaatgga aacaacccaa39421aggtctatca actggtgaat ggatacataa aatgtagtat accataaaat ggaatattat39481ttggcaatag aatgaaatta catgttgata acagtgtgca gcatggatga accttgaaag39541catgctaagg gaaagaagYc agacacagag gatcatgtat tatatgaatt catttctgtg39601aaatgttcag aatagacaaa tctataggga ctcacagggg caaaaagtaa ttcgtgattg39661cctaggtctg ggaaagtttt ggagattggc agatgacagc taacaagagt ggcatttttg39721agggggagct ggtaataaag ttctaaaact gactgcaatg atgattgcac atatttgcga39781atatactaaa gctattggat tgtgcacttt ggatgggtga attgtatatt atRtaaatta39841tatctgaata aagctacttt ttaaaaaaga gagagtctgg ttccccagac tgcctatgtt39901taaatcccca cctctcctac ctgtgaatgt aggccaggta tttaaactct atgattctgt39961ttcttcatct gtacaatgga gataatataa attacctacc tcataaagct gttataaaaa40021ttcaaataac tagtacatgc aaagaacaaa gaccttctaa cagaacctgg cacatgaaaa40081gtgtgatatg tgtccattct tcttatgcac agactgttaa gggagagcat gaaaRaagta40141tccaacttat gggtaaggca gtcggcaagg cttaaaggat gatatttaaa ttcatcttga40201aagatgagca gggattatca aggaatagat aagagggaag ggatatccag cattagaaag40261agtatatgcg gaagtatgta gatatgatat tctatcaaga atttaaagta tcctaaaagt40321aaattcaaat attttctgaa gtatatgaaa ttgaaataca gaaaattcca gcaacctatg40381tgtcatgtct tctctttttt aagagttcct ttagagacaa ttcagtaaga aatttctctg40441tgactatgaa ggtaatattg tatgatgtaa ataatattca ccaagttaaa aataacattg40501ctacaactct gatccagtgt aaagtttagg taaaatagta ctcattttta ttattgaaac40561agtgtaatca gtagacatag ctctgtgttg tgtacatatt ttgttttgtc tcttcttctg40621agtgtactca tcttaggtga atggggaaaa tatgattttt ataaacagac tcttaaagaa40681aaatggccta tgcaaatgat gtaatttaga gcaaccatag tatatgtgtt cacttcagcg40741ctcactaaat aaaatcacca taagaattga tgcatgacaa tggcttgaca atttcttatt40801cttttgtatc acaccaattc ttgaaatgat agctgttgca cagacatgtg tgagtattgc40861tattgtatat gtggtagcca tgcatgaccc tacttttctc ctcttggaag ctggaacctg40921aattcttaga ctaatcaatg agtaaatatt tcagagatgt gttatctaat ttacttctga40981aaaacagatc tactacttgt ctctagacat ttagaaagag attgacagag tcatttgcaa41041attcaaagat ataaaaacag taggtagatt gacttccata atcaaatcaa tatttggtta41101gaacatttca caatattcta accgaaatta catgaactac attatatact ttcagaaatg41161cagtgtacca ctccatctga acaaaaacat aatgttaagg tgtccttgaa gctttaagtc41221atcttttggc aatgcagtag tttcaacata atcacaagac aaaaccagtt ccacataaaa41281ttcttcagaa atgaacatga atataaataa aaacttgaga gatgctactg aaatagattt41341tacatttcag agttacaaag gaacacatta gtagctatta aagcttacag ataacattac41401catctagctt actaataaat ctcattgtta gtattttctc tagtctttac tgaaccttta41461agattattaa tttttttcat attttattga tatggctagg atagagttat taaataactt41521cttcaagtta caaatatgct aaaaataagc attgaatcct tatctatcta atttactccc41581agccatgatg attctaacaa ggactggcct aatttcctgc cacaaaaggc tataaaactg41641agccaagtat ggaaaaacct tttcagacat tagtcaattg gtagaaatgg actttgaYac41701ctaaaaggtt ggaaacaact aaatgatccc aacaattatc ccagctttct tgctgctggc41761agtttccata ctggagacat gaaagtatgg atccaaaaca gaacttgtca gcctcactga41821gtttacgaag tagagatcag agggtgagaa agctgatgtg gttggcgcat attatctcat41881ttttgagata tgttgtaaat tagagggagc tgagcaggaa aatatttaca gaaatgtgaa41941tcttgcctga gtactagacc atcaatgcta gagagaaatt ctacaagtgt gggcaaagaa42001tgacaggaat cagaacaatc gccagagctc acacatgatt tttgagaaag gtttcatttg42061gggagatcgt attgtatcaa gaattcaaaa gaaaatgtag aaagtatgta tttatctttg42121agttgtgtag tgatcgatag aaatttaggt gaatatctaa atatctatat agatataaag42181taggatactc ccacacacct tgctatttct gtgttttaca tatttccctg acctcccaaa42241atgtccagYt ttttgttagg aagctgcacg ctcatcttcc ccttctgagc tccaagagca42301tgttgatgtt cttgctgttt catagctgat ataaattagc attgggtaaa cgacgaaaaa42361acgtcacaga aagtttttct tgttcacatt ttggaaatct tccttctcag tagagaaaag42421caaccttaaa gttgcaacat catgattgga tttcagttca caaaagaaaa taaattttga42481caaatcacat atgcttttcc tgtccctccc aaaatgctgc agtcttccat ggcagcctta42541ccaaagaaaa aactaagtcc ctaactggaa Sttggattct ttcaaaggca cagtaagagg42601ttttgaccaa tagagaagca ttgatcaaat cactatccac tgcattacat ggtactctag42661gagagtctga aatgagaata gatatcttca aaaagcatcc aaatctgggg ctggtttact42721catctgtcag cttctggaat agtgaacatg ctattaaaat tcagctcctt ctgggaggtg42781ggaagataat caaggggaga cccaccatac tgcatggaag tcccagaaat ggaaaagctg42841atcaaaggaa ggaaggtaat atactttttt ataatatgtt ccttgggatt tttaatgatc42901ggtcgaaata cagaggtttt ggttttaagg tgttattttc acagcatctc caggtaaact42961tccaagtatt atgttaRcct ggatagaaac aaaaaagtcc ataatgcttg aaactgaata43021tgtgatcctt gcatcatgtt taaaattgtt cagcaaggaa tttcagtttc tctaggtgat43081ggaagttagc acgagcaaag gaactttaca atttttcaga attttttttt tttcatgttt43141ggaaggtctc ctcctcctcc tcctccttct cctcctcctc ctcctcctcc tcctcctcct43201cgtcctcctc ctcctcctcc tcatcctcct cgtcctcctc ctcgtcctcc tcctcttcct43261cctcctcctt ctcctcctcc tcctcctcct ccacctcctg cttctccttc tcctccttct43321tcttcatttt tatttttaac cattgctagt ggtatgattt ttgaattggg aaaacaaaat43381attcagacta aatattttcc caatgattct tatgtagagt aatgtacttt gcaattcaat43441taaaaataac aagctaggat ggtgttctga gccaaatgta atctccaaga ccatggtcag43501taaagtactc aagaaaaaag tattgaggcc gagtagtctg aagtctaYtg gggaataaag43561aagcagctga ttagcatttg aaagcaaggt ctttcactgt tttaaaagtg aaggagaatt43621ttttaacaga Rcactcatca aaaacaaagc gtttgaaaat tacccctcct ttgttttatc43681agtctcaggg aagatgcact tcgaYacacg tctcaggaat taagatgcat ttcgatacat43741gtaatattac atttggtgac actgctggaa catatgctga gaaatgcaag aataaatagg43801actaatgctc attttcNttt tttttttaat cacttgcaag tgacatttgt ttcatctagg43861caggaaagca ggatcttata ggcagggtag gtgtaagggc tgattttagg tcaagctttt43921caatttatta tgcaataaaa tatagcaata aaaatatgca tctttatatt ttccagtaaa43981tbataggaat ctccgtttaa ttttttatat atgtgctaat aattaattca gtactacagt44041ctggatccac agtccttttg ataagagctg gcacagaggt catttttatg tgccttatta44101ttaatcttaa taatatgtag taatattcct ttatatgctt attgtgacac acagaaactt44161aaagcctttg tagctttaag ttcagatgtc tccacattct tttgtaaatc cctgcagatt44221tgtttcttgc ttttaaatat cagcaccttt ctgctgtcta ctcttaggtc tctgccctct44281atgcaggaga tcttttcttt taagtttccc accgtgcttc ataataaaat caaaagaaaa44341aggtacatcc ctcagaaagc attcatctca ctaKaaatag aaaacctgtc accttattct44401taaaacctta gatcagccag gccagtggct gaaatagtga gggtagtgtc tacaaagggt44461ataKagtagg ggtagcaaaa taattatgta ccttgttctc tccacatctt ttagggaaga44521gactctttgc tctggaaaat gacttaatac cattgggagg aaaacatttc ctctacccac44581ttaggttcct atgtttaggg gcctgtgaat taactgataa tagacagatt aacaggagaa44641aagaaaaggt taatctacac atgcatgtga agtcactcaa taatgagtcg tttcctgaat44701acccagaggt aaagattggt atagcaactt aaaaaaggga agggaagtgt ggctagggca44761tcaatgtgta gttgatctcc ttcctggRat tagcagaaag ctcttggagg agagttaata44821gcagctgtat tgggggtagt gtcagcttta gttaggtaag ggaaagtcag atcagatttc44881aaatattttc actttaatct ttatgctaaa actgtgattc cttcaatatg ctgatgaaag44941ttgaagtgtg gcttggaaaa aaagagaaag tataagtaga tttattctag atataaagca45001ttttttaggt atagtagaaa gagagaaaga gaaagcaaca ggcacacaca cactgagaga45061gagattttga cacgaccatg tcaaagacta agagtacccc aagttcttta tcaaccatgt45121agtttctgca acctgcagta tacacacatg catacccata tactgatgga ggcagtctaa45181attaatggtt aagaatatga acttcagcac cagagggcat tggattcaaa tttcaatctt45241tcttactagc tttgtaactt caaacttttt tcctcttgga agctggaaac tgcattttta45301gattaaacaa tgagtaaata tttcagagat gtgttataca gtttacttct gaaaacagat45361ttattacttg tctctagaag tttagagaga gatcgacaga gtcatttgca aattcaaaga45421tataaaaaac aggtagactg actaccataa tcaaatcaat attggtttag aaaatttcac45481aatattctaa ctcaagttat gtgaactata ttatatactt ttacattatt tatctaccct45541caagtttcag ttctctcctt tgcaaatgac aataacaata ccaaaaaata aaaaaactaa45601atgaggtaat gaacgtaaag tgataaggat gatgacaggc ataaagtaag ctttttattg45661tttttatttg ctttttcctg tagcctgaaa atatgttcaa ggtaaaaaaa agcattcttt45721tgctctgaat ctcctttatt ctaccaattc ttttctcgtg taagtgtctc agactcttca45781gttgtcttca ctttgtcatt tatttttatc ctcaaatcat tgatatttgg cttctatttt45841cacttctcca aacaaattgc ttttttgtct tcatgatctt ctacgtgaca aattaaatgc45901atgctttcag accttacctt cctggacctc tcacctccat tggaatccac tggcaattta45961ctcccagaag ccctgtcctc tcttgcatct tcaacatctt ctgattctga cctctctatt46021cctttgttta tttgtttgtt tgtttgagac agagtttcac tcttgttgcc ccaaatggag46081agcaatggca tgatctaggc tcactgcaac ctccatctcc tgggttcaag tgattctcct46141gcctcagtct cccaagtagc tgggattaca ggcatgcgcc aacatgcctg gctaattttg46201tatttttagt agagacaggg ttttgccatg ttggtcaggc tgatctcgaa ctcctgacct46261caggtgatcc tcccgccttg gcctcccaaa gtgctgggat aacaggcgtg agccacagtg46321cccggcctct ctattccttt tacctccttc attggattct cttcttccag agtttcatcc46381ctggccttca ctatacttta ttgaatgact tcatttactt tctagaaagt tataaacaaa46441tttttatttc caaccctagc ctctctctcc tgcttcagac tcattatcca cgagtactat46501tgaaaaaagt attctatatt taatgacaaa aaaacagaaa atatggaaaa caaaaattaa46561cagcaaaatc ataaataatt cttccatcaa aagttacttg ctaatatttt agtgtctacc46621actagctaaa cttaactaca tttccttatc tataaaattt gaggtaattg aggtcccaaa46681ctcataaaac tattgagcat gaatacacaa aaagttttta aagtacccag cacatactaa46741gttccatatg aatatttgct gctattattt ttttcaattt caaacatgta cacacatgtt46801tcaaattcaa aaatgtagct ttgtacattt tcttcccatt tagcaatatg caaatgagta46861tttttaattg aatagatttt tttttttttg agacggagtc ttactctatc actctgtcac46921ataggctgga gtgcaatgcc gtggtcctag ctcactgcaa cctccgcctc ccgggttcaa46981gcgattctcc cgcctcagcc tccagagtag ctgggactac aggtgcatgc cactacacct47041ggctaatttt tgtagtttta gtagagacga gtttcactat gttgtccagg ctggtcttga47101actcctgacc tcgtgatctg cctgcctcgg cctcccaaag tgctgggatt acaggcatga47161gccaccgtga ccagctgtga atagatattt ttaacagatg tgatcagtag attttttcag47221ccacttagtg aataatttct acagctgcct caaatgtcta ttaatttatc tagggttgta47281tgtaattccc agccttctaa ctgttgacag ttttatttct cattccctga actatgttga47341aatgcaaatt aatgtcttta cagagatatt tttgaatctc tctattaaaa aaaaaaaaag47401aaaaaagaaa aaaacaaacc aatcccgaac ttcaaaatgc tattcttggt tttttaaaaa47461atgacctata gtccaactct gtgtagataa ttatgtgaca gggcattgag acactgaagt47521tgacagccca atgtgctgtg ctgtgtcata cagatagact taaaaaaaaa aagccccagg47581ctgggttctg tggctcatgc ctataactcc agcatttggg gatcacttga ggtcaagact47641ttgagacaag cctgggcagc atagtaagac ccatcccccc cccccaaaaa aaaataccag47701gcataacagt gtgtgcctgt attcccagct actcaagagt ttgaagcagg attgcttgag47761cccaggaggt tgaggatgta atgagccgtg attgtgccat tgcacttcaa cctgggcaag47821ataacaagac cccatatctt aaagcaaaac aaaacccatc tctgattgta gcgtatttag47881gttgttttca acttcttcct agataacttg caatgaacgt tttaaaaata tatacttgtg47941cacatttatg ctcatttatg attatttaga tgtacaatta ttagatgaga taatataaaa48001aatttacagc ctttcacttt tatttttctt tttcttttat tttactttaa gttccaggat48061acatgtgtag aatgcgcagg tttgttacat aggtatacat gtgccatgtt agtttgctgc48121acctaccaac ccgtcatcta gggtttaagc accacatgca ttaggtattt gtcttaatgc48181tctccctccc cttgcctacc ccactaacag gccccagtgt gtgatgttcc cctccctgtg48241tccatgtgtt cccattgttc aactcccact tatgagtgag aacatgaagt gtttggttgt48301ctgttcattt gttagtttgc tgagaatgat ggcttccagc ttcatccatg tccctgcaaa48361ggacatgatc tcattctttg ctatggctgc acagtattcc acgatgtgta agtgccacat48421tttctttatt cagtatatca ttgatgggca tttgggttgg ttccaagtct ttgctattgt48481aaatagtgct gcagtaaaca tctgtgtgta tgtgtcttta tagtagaatg atttataatc48541ctatgggtaa atacccagta atgagattgc tgggtcaaat ggtatttctg gttctagatc48601cttgaggaat cgccacactg ccttccacaa tggttgaact aatttacact cccaccaaca48661gtgtaaaagc gttcctattt cttcacagcc ttgccagcat ctgctgtttc ccagcttttt48721agtaatcacc attctgactg gtgtgagata atatctcatt gtggttttga ttcgcattgc48781tctaatgatc agtgaatgtt gagcttcttt tcatatgttt attggtcaca tatatgtttt48841ctttatagaa gtgtctgttc atatcctttg cccacttttt tatggggttg aggctttcac48901ttttttattg tgaatttgtt ttctggaaaa cttttaccaa ttttaattca cataagtagt48961gYatgagaaa gtctactttc tcacatgctt gcKgataaat gttaacattc atttttatcc49021ttgccagtca gataagcaat aaattaaata gttcttgtta ttttaatttg tattccccaa49081aggtatgtta agagagcaaa acaataaatR attcaccctc aatggttgct gttaaacttt49141gtctttttaa aatttaagct ttaaagatta tgactttaat tattttttct tctcataaat49201aatatttctc ttctaaataa ttctaagtca caattatgta gggataaaaa agaaagtata49261cattttaatg ctttcctcca ttaaatttga atgtgtgtta attttgtatt cagtgctgca49321ggtttttaca gaatactgtc tttggttcca tattgaacat tcaccttgag gactttagtc49381tattgattga aagctttagt tcatctaata gaattattat gacacacact ccaRctaaaa49441atcagtcaag gacagtccca gaagttaata ctcttccaaa gactgatgcc tccactgagc49501acctctagga agtatgagat ggKgttgcat cacttctcac taagttctta taaccccaca49561tccaatatat caacaaattt catcagctct accttcaaaa attacctaga atccaattat49621gtcttattaa atccatttta ctgccaagtc acttctgatt tattgcaaaa ggctcctaat49681tgatctccca gcttcttcac ttgcctcttc cagtctattg tcaatagtaa ctgtcaactg49741tStagtaaac tgtgaaaata tatctgatca tgtctctcct ctgctcagag cccatctggc49801ttcctatctt agtcaaagta acagctgaca tcatcatagt ggcctaaaga ctctagtgaa49861gctctgcccc atccaaatac attgcctctc agatatttac taatatStgg ctctagcttc49921cttggtccta gccacgctag tgtctcttct gtctcttaaa caagtcagag actcttaact49981gctgtattta tacttactct ttcttctgtc tgaatgctgt ttctacaSag gtgctttcta50041attgaaggta caatcatttc tcacatatgc cttcttctca ttatttgtKt aatttctctt50101cacagcacct atcatcacca tctgacattt tatatatata tatatatata tttccttttt50161tgtttgttgt ctgtcactcc cactaaaatg taggtctaga agaatagaaa tgttcgtttg50221ttgtttgttt tgttcactgc tgtattctta gtgtgtgcct ggcattaaca ctcttttgaa50281tgactgaata aatatctgaa tttctgctat ttccctataa gtaatattat tttggataga50341aatgccacta atcctgaaac attttcaagt tttatatggt ttttatcttt aatatttgtg50401tggctttctg ctacattcca atatttaatt agctttagtt tacatttatt aaatgcttct50461atatccagat aatgtcatat cataagtttc agttgacatt tattaacatt actacttctt50521ataatatttt aacagaaata tgattcatca actccagtgt ttgtaaatat Oatcaccatt50581ctgaagtcaa atgttgccaa agtcttccat taaatacttg cagacttctc tcatttggta50641cagccagtca ctccttacag ctgcaatatg ttatatctcg aatgtatttc ttgatagctt50701tctttaagat aactgcactt gcaaagttct ttgtacctag aaaactttca acaaatattt50761agagaatata atttactcat gcatgtggat agacacatgt aagattcact taagtgtcaa50821atttactaat ataatgaaaa cttggaccaa acaagcaaca aaaaatatta tccagcactc50881atactcaaaa cgcagtctga gagtttggta tttttcagtt cctaaaggtt gatcatgtgg50941ttcataaaat cttagtctcc aaaatgtatt ttcaaatgaa tgtcaggcag aaccaacaaa51001tgagaactag ggtacttagg attattgtaa ttgcctaatg tgtttggtga ccttgtattc51061ccacttacag caacttatgc ttctttcaaa ttcttttgta caaaaaaaat tgtcttgtcc51121actctccact tagcctttaa gtcactaaga tgtggctatt tcattagttg aaagcaatgt51181ctaaaataaa atattttatt ttaaaaatca atcatcttgc ataataatag ctttaacttt51241atgctcaatt taaaatattt gtatttaaat aattgcttac agaatagaaa tagaaatgat51301atataagata atatagaaga tgtaaggatt taagaagtta ggatgacagt atttttattt51361acttttatca tttgtaattg tatcttattg tctggtaaaa acatttaagg aaagattaaa51421atctaagttt aatgtattat ttataaacat ttgctccttc ataaaatctt cctgcaatcc51481ctctttttaa aaatgttttc attgcatatc ccgatgatct gcttttcttc tctccatgaa51541actcagatac tagttttctt tacaacacct ggattgtttc ttcctctMct gctgttcctt51601attttgtttt tctattctgg tgtcttgata tctcctttta acaaattcca taccattggc51661cttcctaact tgtgaacatt tctaatactc acatatgctc tataaaaaaa agtgaggttt51721ttccaagaag aacagtggcc attaattctg catatatcaa aatggaatgt gtcatctttg51781agaaaaatat aagctcacac catgcataaa gacaactatt gtttgcttca gccaggagta51841tgttttaggg aaaaaatatt ttaaacaagc cattaagaaa tagtctcttt tttctttaat51901gtctttgagc tacatatgtg agcagaatta taaagaattt ccagtgactc attcttagtt51961ttggccttcc tggcattctg tagtcgtgca tattaaaacc tctaaacagc tctcagtaaa52021gccttggcag tagagcttgt agcttgtacc tatcaaaaat gtcagatgct tttttccaac52081gccatcacta gcaaacaata ttacttagtt attaacatat aggaattaac ggcaaaatct52141gcaagttgca aacagtgttg taaatcaact aagcatttat catgagattt tttaagtgac52201tgaatacaga ttcagaatca tgaagttatt atctaataac ccaacaagtg atgtgaataa52261atccttgcta atatgaaaat tatcagccac tgaaacaccc ttttctacaa gcaggtctgt52321ggatcctcat gctaatgtac ttagattgat aaaccacaga cattctctga aagcttcgtt52381tgttccagtt gctgaggctt gtgcttagag catctgtcat gcaaatgatc agcaaatcat52441aacctgtaat ttgttttcat ttaataggca gacaggtttt caccaattta gactcaagtc52501ctattaatac tctttgaaac taattgctgg aaaatgaatt ttaatgacag gattttatca52561tttattattt tcccttctgt ccctataaag gaagactcaa agccatctac tcacactttg52621aaaatatatg ttaaataggc acaagccata atctcctgtc atctgggctg ttgcaaagga52681cccctaatcc cctctcttgt aataatccat tctacactct actcttaaaa ttactttctt52741actatcccat ttcccttcca caaaatcttc aattccctgt caagtaaata gcagacactt52801taatatggct tcgttgccct ccattatctg tttgcagttt acatattttt atccttattt52861gatatcgcaa tataacatgt atacagaaaa aagcatgaMa cattaattaa taagtagtaa52921agtaacatcc agaaaacact actcagagca aaaagcagac gattgtcatt accacagaaa52981ccacctcccc agtgcatctt tctgatcaga cccttcccag catcccagag tctaaccacc53041cagagataat cacttcctct attttcttta gattgtctcc agctacgtgt gaattcttaa53101ataatatggt caatttaccc atttttgaat gttatgtaaa tggaatcaaa atctgctttc53161tttggctatt gcttttttca ctcaaattat tctcttaaac attcattcat tttagggtac53221agcttcagtt aacttcaatt ttaagctgtt tagtattcca ctgcatcaat gtaccacaat53281atatttatct tttccatgtt gatgggcact tggattttta gattgtttcc acatttgagc53341tattacagac aagggtgcta tgagcattct tggatgtata gtttggtgcc cagtattctt53401ttgtattcat acctaaggag tggaatttct aggacttagc catgcatatt catactagat53461aaatattgat gtaatacgta aaaccaagta atattaactt gtatataagt agctctgtat53521gctactagac aagtcaaaat atttttcaaa atggttgtaa atttatatat cgagcaggag53581tgaatgctat tcactcctac ttctatttcg acttctagaa ataggagcac ttctatttct53641ttatatgctt gacagtactt gggattatca gactacctca ctttctgttc ctcctctatt53701tattcttgct ttaggatttt ctatcctctt gtttattctt ccttcaccct ggatattaat53761tctgacctat tgcaattcat gaattctttc ttcatctgtt tctaatctat taatgactca53821gtcatatgtt aactttggta attgtctttt ctaattctca aatttgttta gttctttttc53881aactgcgtaa caacactcct ttgtagtttc cagtttcctg ccaattaaaa aagcattgcc53941cttcatttct tcaaacacaa taaacataat atttccaata tgcatctgaa aattctagta54001tctaaattct tgaggatcaa tttctgttcc ttgtttcttc tgcaggttct attattgaag54061aattattatg ttggtgcaaa agtaactKag gtttctacca ttacttttaa tggcaaacac54121cacaattact tttacactaa tctaatattt cttttcacca catttctttg atttttgttt54181ggacatcata ttcaaaaatt atttgaagga atcatgttac acctaaagta atattacctt54241tttctagaga ggattgtgtt tttctctgtc aggaatctgg agcctccatc agggtaccac54301cataaattgt gttaaaattt gagattaaac tatgcagtcc tggattttaa tccataggtg54361gaaaaaaata gagtttcaaa gaggtaagct tcaattaaga cagattatga tgcctccctc54421ttctgtaaca tattgtgtga ctttgagttg agattcttcc taagttttct gatctattaa54481aaaagatata gctggtaatc cccaaaatca tgattttcct tttttttttt tttttttttt54541tacagtttct actgtatttc tttgttgtcc tgtcagtacc agttatggtg tgtgttgctt54601tttctttctt tatatttttg ttgagcacag tgattgagta catgccccac taatagggta54661taattatttt gagagtaata tctatgactt aacaccatat ctctcactat attgagtgta54721gtaccttgat gcagtagcta gctgctcagt gaatgttaaa tggataaatc aatgactgaa54781taaattttag agataggtac atagataaaa gtgatcaaaa caagctaagt attactgcag54841agaaggaaca agtatctttt ctattatagt tcccaaagct tcaaccaaat ttcttttgct54901atgtttacct gtccaatata ttggctggtt gtactcatag agtactagtc ttagttagaa54961tttatgagta atggtccaaa tccgtaatag agcttaaaac taaagcttta aaaacattga55021tccagatgaa gaatgatagg atgcaatgaa agtttattta gggcataaaa tttaaaaggt55081atgttatcaa taattcattt tgaaagtccc cttaatatag ccatttctat tctgtatctt55141taaccagtta taggtgacat tgctaggaac agattttgac agcagacttg tgcaagggat55201ctgtttgcct agagatttac ttaaaaggta gaattaaagt catttcaaga aagaaattta55261acataagaaa atataaccat ttagtacact aaataattgg tctagctagt tatgagttaa55321aaatgaaaaa gaattaatag tttttagcaa catatacatt gggacagtat ttttgccaca55381tctatcattt acctatgcaa taattaaatt cataattttt taagtgtcat atcgaagagt55441gttattcaac ttcctggtga ttaaattact gataaacata gccgattttt tttggttttg55501caggtcctga aaaatagaga atgcatatga cttccaaata ttggtagaag agccagtcaa55561ataatatctt ccatgaatcc tcttacaatt aatttgctga ttgatagatg ttcaaaatct55621agaaatgaat gagttgcatg taaggaaatc agtacatgct tctgctgcca tcatatatca55681caatacaagc attaaaagct atattaatta tagaacttta tgatcttatt tacatggtct55741gtgaatttga tctttatttt ggaattcctt taatccattc tgattctaat cacctcagga55801ccaactttag tgtatttgta caaggcgtaa tcattggcta gctctataag ttgtccaaac55861aaccaaatga gatgtcgcaa attctgccaa ttgtgtaaag ttttattatg tactttaaat55921atatgaatat ttggaatatc aagatgtgtt gtattttacc aataatatta aaggtttgct55981tgttcacttt tcacttgtat tatgatgtca tttaaacaag tcagtattat tagaaatctg56041attcattctg aaaacctctc atctactgat ctaatgatct tcaatattca ttaacatgaa56101atattactat aataggaaaa aaatcggtac cttaacaaaa aatatggaaa tttatttgtt56161tatttattat ttttacttat ttatttattt atttatttat ttatttattt atgtttttga56221gacagtctca ctctgttgcc caggctggag tgcaatggtg tgatcttggc tcactgcaag56281ctctgcctcc caggttcacg ccattctccg gctgcagcct cccaagtagc tgggactaca56341ggcgcctgcc accacaccca gctacttttt tgtattttta gtagagacgg ggtttcacca56401tgttagccag gatggtctca atctcctgac ctcgtgatcc gcccacttcg gtctcccaaa56461gtgctgggat atttctttct ttctttctta cattctagag ccttggcgag ttggcccaag56521tgttgtacag cattttcRgt gtcagggaca tagacttctc tcctttctct gctgtgtgta56581gtctcagata gttaccagag caccagccat tgtatgttct ttctagtttt caggtagcag56641aaagaataag aaatgttgca caaaccaccc tgtttacatc acgttggcca gaattagtca56701catggccatg aagcaagcca ctttgcctga agtaggacta cagattgtct ttattctcca56761tagtggtaaa atataaaaaa atataattag agaagaagag aactcctctg gaggacaact56821agcagtaacc tactctacta actgtccatt tactagttca ttttgctcta agataacata56881taaacagtga aactaaaata tgttttcaaa attagaaaat gtaagtacct tagataacca56941agattaaaga aatgttacaa ataccacaat atcaacatag ttatagatga acatcaaact57001tagtactgat tttctgaata tccaaaatga aaagaaatac ctcaataatt ggttacattg57061ttttttatca ttttgaaaaa ggcactactg aggcaaatga agctctttga ccctgaacaa57121ttacaaaatt tatctcatag caatttttag ggagaaaatt gtatattata gttgacaata57181ttcctataac aggtgcagtg attttataag ctacttacag tgtctttgaa taaaagccaa57241aatgaaagca ttatgaaggc tattttgtga atctctgagg aaaaatcatt caaaaaaaaa57301aaaaaacctt tggctattct ggcttatata caaggagaaa ttttagcctg cccagagggc57361tggatggact acatacacca tgaatggtta tctgtaaata ttactgttgc tgaaagattt57421ctgaacaaat gtagaaaatt aaggaataga ttatctagtt ttctgtagtc tgccagcatg57481tttcaaatca atcgagcttt cttaacacca ggtgttctca gaagtgaaag gggcctattt57541gttagcttta aaaagacaaa aatgggaaaa gataaaagag gtggaagcag aaaccaattt57601gctaaattta ctaaattaga cagtttattg aaaaggtaag tgaatttctc atatcagtca57661taaagaagct atttttccaa tgaaatgtgt gtttatatca aagtcacaaa attacttagt57721gaataactcc cagtaaatgc gatattatta atttcagcta aattatatgt tcttagaatt57781tttttatctt ttcagattgt tttatgtaga ttatagctgt taaaatttta ttggatgtaa57841tttacatggt ttacaaacaa taaattcctg agaatagata cgataaattt atagtttgtt57901gaatgattta ttattaagga gtctcagatt ggtcctccga ggacaggaaa aataaattca57961tggaccctaa gttttttagt tacttttatc taatttttga tatggtaata attaaaaggg58021agatgataag aaattgaatg attaagcatt gttaaataat atgatgcgtt aataatgcat58081aagttatatt cctgagttga ttctttcaaa gtataaaaca atttttagat ttaatcaaaa58141ctctttaaag aattaatctt tgcttttagg gagcactata gattgacatc agaaatttct58201cttatttcca tgtaggaaga accttttgtg atggtctctg aaaatgtctt gggtaagccg58261aagaaatacc agggcttctc cattgatgtt ttggatgcct tatctaacta cctgggtttt58321aactacgaaa tttacgtagc accggatcac aaatacggaa gcccacaaga agatgggaca58381tggaatggct tggtaggaga acttgtcttt aaggtaagaa ttactttatt tatttgtctc58441atacttaaag gttcaattat ttgtctcata cctaaaggtt caacagtaac accttgaagc58501tgatttcata taaaataagt gtgatgtatt taggttggtt aagcattagg tggtggaatt58561gagtacaaaa gtctcactca atactatttt atgaactttg tggaaagaaa agtagttgac58621aaaataaacc taaatgttaa aatatatcct gtaatagaaa agggtttaga agaagacctt58681ttctttgctc aacttatacc ccaaaaacag aaagtgtata tgatacgtga tgaaatcaca58801tttttttttt gagacagagt ctcactctgt cctccaggct ggagtgcagt ggctggatct58861cggctcactg caagctccgc ctcctaggtt cgcgccattc tcctgcctca gcctcccgag58921tagctggact acaggcgccc gcccccacgc ccagctaatt tttttgtatt tttagtagag58981acggggtttc accatgttag ccaggatgga ctattgtttt ctttttaaaa atgtgatgtt59041attggaaaaa attaaaacat tcactgctta Raaactaatc atttcattct gtaatctaat59101caagataggK atgtacatat gtatatattt ttctttgttc tttcaattct cagaaaggtg59161tttaaaacct ctatgtcYtt ctttagtcct gtcagaatct gcttcagttt tttgaggctc59221tgttattagg cacatagaca tttataatta ttacattttc ctgataaatt attgaatagt59281tgggtttagg tttataactt actgtttggt ttatatgtat accatttttt tctctgttgc59341ttcttttcct gtttttcttg gggttaatta aatatatttc agtatttgat tttattgctc59401ttactgcctt tttagttgtc tccctttgta tttttgttcg tggttagtct aaaggtcata59461atatgccttc ttaacttact acattctatc ttaagttaat attgtactac ttcacataaa59521aagtaataaa ttttcagcaa tataatttta tttgtactca ctcctttttg atattgtgtt59581cacatattta tattttatta acctcatacc aaatatcata gttttttatt taaatattta59641ttgtctttta aaggtacaga aagaaaaaaa aaaagacagt tgctgggata taatcactta59701tctaccgtgt ctggggctct ttattcctta catatatttg agctcccatt tggtataatt59761taccttcaac ctgaagaact ttctttagag tgtcttgaag tgcagggcta cgtaggtagc59821atatactctc aacttttgtt taccttgaaa tgtctttttt aaccctcatt tcaaaatgat59881attcttactg gatatcaaac tctgaattta cagggttttt taatgttcat cattttaaag59941ttgtgattct atcagttttg ccatatatta tttctgatga gaaattagcc atcatctgta60001tcctgattct ttatatgtag tatatttttg tatgtgttag tggccattct acaagtttct60061cttcattttt tggtgtttag aaatttaatt atgatgttct agatatgatt ttctttgcat60121ttattgtgct gagagttcac taaacttctg ggataggtta catttagtaa atatagagaa60181ttatttcttc aatttttttt accttctttc ctttctcttc ttgatttgag gctcagagaa60241tattcaagtt agatcactta atgttgtctc ctaagtcact gaggccttgc ttgttttatt60301aagatatttt tactccctga ccttcagatt tgacaatttg tcttgatctg ccttcaagtt60361tactgatatt ctgccacctt caaatttttg ttaagtcctt tcagtagctt tttcattcta60421gattgcttat tttttctttc cagaatttca attttttgaa ataattttta cttttctgct60481gagatttcct atctttttat cagttatgac tttcttttct taaaagttca tgatcacatt60541tataatggct tctttaaagt ccttgtttgc taaaatttca acatcttatc atctcagaat60601acattgcatt ttcctggttc ctcacatttc tggttacatt tgattatata ttggacttcg60661tggttgatac attgttaaga cttgggatta tgtctctgaa attgtatatt ctgaaaagga60721ttgatttttg cttcagtgga tagttaaatc actatctgtt ctcttgaatt tgtggagatt60781tagctttaaa cattgttaag gcaggtctat ttgatgtaat cttggtccct agggcaaatc60841ccttggtttt cgtagtccac atatttctaa gatataacct tctggagttt ctggggaaag60901cctgtggttc tcctcaagcc cttctgactt aaaggaactc aaaattcaat ctgtatcttc60961cctgtcatag gcaacagttg taatcccctc tttagcacgt ttagccttct agccattact61021ctttgctaat tttcctagga tctctcccat atatgtgcag tttaggggtc agctaaggat61081tttagaRagt ttatacacag attttggggc tcactcctct gtggcatcct ccttcttgtg61141tttccctttt caatttctgg caaccctagc tgattcaaac tccatcctct gacaagttag61201ttaataagac tgactttcta cttgagctct gtcgacccca tccccgctga actgaagtgg61261gtcctcaatg actaagccta ataaaggagg gctctacccS gtgcagttat tattttcaag61321ggtaccctgc agtttctgcc tgctttgggt tgctctccag tcttttctat atattttttt61381caatttgatc ctgaattttt aatttttatt ctgatagggc tagtccaata aaagctagta61441catcattgct agaattggaa taatttctca aatgctttaa agtactcaga aggctagagg61501atctaaccta aattgtttgt aaggaatgga gaagagtaga aataaaaggt ttcttaaggc61561agtggtaggg aaaataataa agctatttct atattctata aaatcctaat gaatttggtc61621tatttaatac ataagttaca tatagaattg tattggaaag cattaatatc gttattttta61681atacaaaatg ggcaatcgtc agtcctcttc cttcttatta aaaccgtgcc ccttcatctt61741ctattctttt aaaagtcaca aattcagtgt tccaccttta tctttctaag ggctgtttcc61801tgatctgaac ccagattagc aattacgtta aaattagtgt aaagaaaagg cattatacaa61861atttattcta tatagatagt ggttaaaatc cttaatgagt tattatgcta ataaactaca61921cttgctagat gcaaattaaa cataaaaagc attcaaatta gtatgttgat gttgttttta61981atttgtttta tgtgcttaca ctagttagtt taattttgga gacttacttt ttcacctata62041aaaatgagga gtccaagtat gttaatggta agatcacttc caaatactat gttttgaaaa62101tataagttta tcgtatagca atcatacaca agaaatagaa tgttcttcat aaacaatcaa62161tttcaatgta Ytatttgcat gtaagagcat gtcattattg tatgataatt tatagtttag62221agggagtcct tttgcaaata aaaaattgag gcttaaagaa gcagacatat gatttttaga62281cagaaaaaat ataaaattat tcattggaac taggttttta ttttgttcaa ccggatattt62341agtcactctg actaggcttc aggaaaacta ttaagcaggt ggaggagaag aaacctacaa62401aaaagactta gttggagtag atagagagat taaaagaaaa ttgagaaaat gggttgtcat62461gaatgccaac agaaaataac atttcaagaa ggaaagagca gtcaacatta gaaaatgact62521atcaagttaa gggtacacaa cattccctta actgtattct gactgttatc agtagagatg62581taagttataa tttttaacaa ttacaaatgt taattcaatt acataatgat actttaataa62641aataccataa aataatttag ctttccaaga aaattcatca tattcaaact ttatgaggtg62701tatttacccc tataaaccaa aattacaccg ttgaaatggc ataaaaatgt tatgatggag62761ctccagaaaa gcaagcttat taWtgttatt atatcttctg ataatataca tacttttgtg62821aatctaagta tattttaaat aaatgttgcc actaaatatc tctgtacaag acagtaagaa62881ttttaaaatt aacaggatta actcgtgtgc ctttctaagg ggctaccaaa cttaaaagaa62941tgtttcacat agtgcaatta tatatatcat aatgattatg caYgtaccat cacattaaag63001aagagtcaaa gaagaaatgt tggaaagtga gctctgaatt catatgatta ttccacagtg63061attagatctc atgttagaga gctttctcat taaaaccaga agtcagtggt ccagtacata63121catactttta agagaggaaa atgcagtcag agagagagag aaaatgattg atatgatgta63181catatggagt ctatttaaaa actaataata tagtaaagtc tcctcaagtc cttctctgcc63241tcactactct tataattttc tgcaattaat gtgttcttaa aatttatgaa aacacaaatc63301tggccaaaag atatgaaaca gataaatgag agatatcttc tgcctagtac aggagaaata63361tttaagggtg agttaatgta actgagaaat tattttctcc tagtttagaa gggaagagag63421gcccacagag aactttcaat aagaaataaa aagtatatca agtttaggat agaagtacca63481aaaaaattaa aaacaaagat aactctgaat tagatacagt tggatgtttg atgatatagt63541ttcttctttg gctggctttc aagtcagaag cttttaaagt ggagtattta ggggtattag63601aagactttcc aagggcaagc cagtatattc agcacagaaa aatttcaagg tgttgagtga63661cattttgaaa tagaaactaa aaacttcctt tttcatatat taatttgttt ggaaaagatt63721tctataaagt aaaaaaatac agaaattaaa tcttaatgct aaactctacc tcatttaaac63781cataattagt actgacccat ggatatctaa attatttttt taaaaggctc tatccataac63841attgtaagct gcatttgtag taaaacttca tttttataga cactgaatcc atagatcgta63901tactaatYga atcatgactc aattcagaaa aaaagatttt atacctaaaa ctttatagtc63961actggttatt taaaaaggat tgtaatttta atttgtatgc atatttttga tgcaaaaata64021ctttggtgat caagaaaaga ctttcaaaca cacatttcta ttgtacttga attacaattg64081tgtgaggKtg gggcggaata taaatatagt tcaagcataa aataaaatga tataaatatt64141ctacctatta aagcatgagg tcaaatcact atgatattta gattctaaca gatatatttt64201taaaagtgac ttgacaatat tattttaagt tatcaatatt tacaacacaa tatacatatg64261tcagtgccga cgcccactca ggaaaatgaa aaccattcct aaaattttga aaagaggaga64321atttaatatt gtgggttgat cacaaaggcg ctagaaggaa tcaaagagca aaggatgaac64381agagtaggac attggaaaag caaaaagaaa aagtaaaaca cagatatcaa gtgttactga64441tgtgtcagtt gattgtatct gccagacgta tgccccttga tcagacctgg aattgccaaa64501aagttgctgc ccgtgcccta gctgctggga tcaagaatcg cctactgcca ctgctgctgc64561agccactgaa ataaccattt aaagcagacg gctcttctct ttctttttct gtctgatatc64621ttcagtggtt tccctcaggt ggaaattatg gagaagccag atggcaaagg agcctgggaa64681atctggtttg cagattccca tccctataag gctcacagta tatagcagag tagaaaatgg64741tatgtatagg tttaagagaa aacaggtaat gatcagtact gtctgcaaat tgcgcccttt64801acaattttct aaatgattgc aaaattaata tgtcaattat aaatgtagaa agatacatac64861ttaaaaaatt cctttggggt ttatatgaag aaaaaagctt gatggttatt acaatggaag64921atttatttta tataaagaac Wtgactggtc gttttggatt taaaaataat ctgttccttc64981agcctaattt tacctgagcg tttccaccac ctggaaatta aatctcttca tgctaactga65041ttatcaaatR ctaaattata tgacaagaat tttactcccc aaggaaaata gatccaaaaa65101tggaagaaag ccagaaccca ggaaaatgga aaaaaaggag gaataagtgg actaaattat65161aaatctgtaa aattaggata aagtactata cttagcatgt aagtattaat agtgatgttt65221ccatgttaaa atatagcacc attgagagtc ctatctctca atttctaaac ttctagtata65281acactaggct tttcttgtca ctgtgcccac ccacgtggtt tcatgagagt aaagaatgtt65341tttgaaagta gacatataat attggagtat aataagatac tatttagtaa ttataatgcc65401aataatgtca ttttctgaga aagaaaatgc tcccaagact aaacagagta aatcagctgc65461ttgggactac acagctttcc taatttttat ggttgacaca aagtttggca attctttagt65521tttactaggt aaatgaattc ctatgatggg tattttagtt catcaatgca ttaacaatag65581aaagcatata tttaccggga ggctttataa atattttatt ttattatttt atttatttat65641ttagagatgg agtcccactc tgttgcccag gctggagttc agtggcgcaa tctcggcttg65701ctgcaacctc cgcctcctgg gttcaagcga ctctcctgcc tcagcctccc aagtagctgt65761gattacacgc acccaccacc atacccggct aatttttgta tttttagtag agacagagtt65821tcgccatgtt ggccaggatg gtcctgaact cctgacctca ggtgatctgc ccgcctcagc65881atcctaaact gctagaatta ctggcatgag ccactgcgcc ctgcctataa atatttcaaa65941acatatgcca cttaacatgt gttaatcaca tgccatggtc aaagtgctat ggagggatgc66001aagtgtgaat aagacataga cattgatcat gaaaacattt tgttgatggt ctctatgtgc66061tatgcactgt gctaggcact ggagatacaa agataaataa aacatggttc ttgcccttga66121agagatcttg tcttaatgag aaacacagag gttaaactag acacttataa tacaatgcac66181taggtgcaat gatagagaag cactaagaaa gcaacaagga aggtagagta aaggtaaatt66241tcctgaagga ggagaaatat agcctgatga caaaataaca ggtagtaatt atctaggtaa66301agagggattg gcagaaagtg aaggacgtct actgacagac acaagagtag aagtaaaggt66361agaaaggtta gaaacagcat ggaaagcagg ccaaaattta tgagaatttt gcagctctcc66421aagcaaaaag tgatgagaat ctatcctacc atactaatgt tgtgaagaga atgaaagaca66481ggaaatcaga gataaaaagg aggtaggata aacagaattt attggctaaa gtgaggagaa66541gggagaagtc tggaataatt catcagttca tagtacaaat acataaaagg gtggttgtgt66601aactaattgg gacagagatt gctgaaaaag atttagagga ggaggacagt ttagaatagg66661gtgagttgga tatgtagcat tctgaagctc actgtgaaag tgccatagga ggtatacatt66721tgggagtcag caacctgtgg gtggtagttg aaatcatgaa agtacatcag attgccaaaa66781agaacacatg gagtaagagg atcactgggc taatcttagg atgaaaccca gagaaagctg66841tcacttaaga attgacaaaa taagaagaat ttatgaaaaa aaataagaaa gtttcaaaaa66901ataagctatg actagcaatg tcagaactat ttgagatgtt gatgataaga actgccaaat66961gttcactaga ttggccattt gggagttgtt ggttacccaa gccagaactc ttttggtagc67021atagtgggag aaaaagccag actgcaaaag atgatggaaa aacttggatg tgaaaaggtg67081aaaatgacat gcatatgtat tattttttca gaaattttag atggagaggg gaagaaagag67141ataataattg gaagggtcat tggttttggt agagtttttg tttgttttta agttaaaaca67201gagacttgag taaaattata agctaaggaa gaaaaagaaa gaaggaaaat gtaatataag67261aaagtcagtt aatatgtgaa ggataaatat cctggaacag attcaactcc atcaaaaatg67321attaaactga aaattgattt taatgaggta aagatgttac tttgatactg aatataatat67381aatgagaatg tgtatgttaa taatagatag gcaagagaat ggaaaattga caaagatact67441ttcttattcc ttcaaattta ttgataaaaa ttggagatta cgtatgttga cagtgatggg67501gacatgtatt atgtaacagt ctacaggaga gtggtgaaga ttgaaataga cattgaggaa67561agggaaagtg actgctaaat cagaacagat aaaagaatag atcagtggca ctaaagactg67621agtggaggtt tatatgaaac tgacactttt ttattgctgc tagtttacac aacagtgtga67681ctttcttcag ctgagattga gtgcccaagt ctaggagcag agatgaaaat gttcatatca67741aggttgagac atggtggata aacttggtaa gggaattaaa tgagatgaaa gaagagctaa67801aatgattaag gaagcatagc catgatcaga gacataaact tggataaaat tttggaaatg67861ttaattagaa gatcaaatga agttgaaaaa caggtgaagt atgagtgaag aaatgaaaga67921gtaggttaga aagacataac cagagactga aatacgaaag ttctagaatt tgaccttgag67981gttcatggca gagtgttaga gaaaacaaaa gaaatgagtt taaaatagct caaaatggag68041tgagggaggg agggatgaat agatgaagca taggggattt tcagggcaat aaaactattt68101tggatgatac tctaatgatg gatacactgc tgacattata cacttgtcaa aacccataga68161aagaatgaac tctaatgtaa actgtacacc ctagttaata atcatgtatt gatattggtt68221cattggccag gcaaggtggc tcatgcctgt aatcccaaca ctttgggagg ccaagatggg68281aggatccctt gaggccagga gtttgacacc aatctgagca acatagagag acctccacct68341ctaaaaaaat aaacattaaa aaaaattagc tagacatggt ggtgcatggc tctagtccga68401gctgttgagg aggctgaggt gggaggatcc ctttagctca agagtttgag gctgcagtga68461gctgtgatag caccaccgca ctctagcctg gatgacagag tgagatccgt ctccaataat68521gattgtaagg ttcattaact gtaacaaatg tacctcacca atgcaacata gtaataatag68581ggtaaattat tcacactttc tgctcaattt ttctgaaaac ctaaaactgc tttagaaaat68641aatatctatc tgaatcatga cccaaaatga ttgttgtaag gaatatctac attgattctg68701aaatatatta ggaggttggt cagtttttgt gtgaagagaa acatttagcc aggtctcaaa68761gttttcagag aaggagaaga agatgctatt gtgaggtttg tctggtggag gtgatgagac68821ctcagaaagc acatgtaatt gacaacataa aacaaaacaa aacaagaatg gagatagcat68881gaatagagtc tcattaataa ataacaaaaa acaggttcct tgagtatcta agaaaggcaa68941aattccatgg ccYctaataa atagtgaaaa tgatggaaga gaattcccac gccatgtcag69001ctcaaaacaa gtatattttt tgcccaagcc atgctcaagc tcttgctctt tttctatgcc69061tcctgtgctc atccccactc ctattgtcta ggatcccgca cactgggtta ttgatgtagc69121tagtcatgac acttggctga tggagttcat ttcaataccc tagtagctaa tgtcaataga69181actttcattg attttccagt gtcctttaat tcgttaggta ttgacctttt atttaaatcc69241cacatgacca ttccaaacat tttccacact tttcaagcct caatttctag tcccttcatt69301ttttacaccc tcgtcatgtt cagttgttaa actctatggt ttactgcaaa agctgtgaga69361atctagcgta agtcccttgt gttcttgata ttcaacctca aaatccttcc atgattctct69421catctttagt gacatcaaag gcattagtta tggatactgt tgacacattt aatacccatg69481tgagcctaaa agagttttga atcctctctg agtcacaatg tccacatcag tggaatgaag69541ctattgtgaa gatgaaccaa gaaaatgaat tcaagaatgt gttgcaggaa aaacaaatag69601atcttgttgt atttgttgac tcggatagat tggtaaaact tcctcaggtt ctgtgtttta69661aaaatgtaac agatccaaca catatttgga aggtagtctg ataggatttg ctgtggggaa69721gtgagagaaa gaccaaagcc gagaataatg gtttccagct tcatccatgt ccctaaggag69781atatacctaa tgtaaatgtc gagttaatgg ttgaagcaca ccaacatggc acatgtatac69841atatgtaaca aacctgcaca ttgtgcacat gtaccctaga acttaaagta taataaaaat69901atataaaaaa aatttaaaaa agaccaaagc caacaatctc ttctaaactc atcccttttt69961aattttgtct tttcagccac agcagcagaa aacaaaaaca aaaacaaaaa aaaacagcct70021ttatttccat tttccccagc tccactcact atcttgttcc tagccacaat tatctcttct70081ctggattgta gcYgtagagg tccaattact ctccctttcc actcttgact gccttcaata70141tattttaaca cagcagccag agtgatccag tcattttcct gctagaagac ttttgatggg70201tttccatccc actcagagta aaaactgtcc ttaaaattgt ctacataatc tgcccaatca70261attccctttg tgatctcttt atctctccct ctgtcaccat gctccaagct tatggtaccc70321cttgtacttc cttatactca ttgaacttgg ccttttcaat ttctgtctct cctatctgcc70381taaaatgata tttctctgtc cacctcattt ttttttcagc atttgcttaa agcttattag70441agaggactgc cattgccacc ctcttcaaaa gaacaacttc catcctttgt actacctatc70501tctcttattc tgttttattg ttttttataa cacttacaat tattttatta tgtactgact70561tgttcatttg tcttcctctg gtaaaatgta agctgaagtt ggtctgagat ttcatatatt70621tggtttacta ctgaagcctc aatatctaga aaatatttgt acataaaaga atgaatggtg70681gccacatggc atacattagg taataacact cccctaatta ataaccattc aatgggatct70741cattgctctt taataaaatc aattaaccta ctatagccta ctaaatttgg actttatata70801aaatgttttt atctttgttg aaagactaca ctttgagctt ttgttcctat tattttaaat70861attttgtcca ttaattaaac agcttgttat attcagctac tctcacttta cttcaagtta70921attgagaatg gtaccattta ttggcacaga agaaatgaat gaaggaaata tttggccagg70981agttgcagaa tgcggaatca aaactactat tttagaaatc agtaataata cccagatgct71041attctaaagc tttacaggta ttgactcctt acatgctctt actaatttga tgaaatagat71101agttaatatg cccattatgt agatttaaga catcaaggct tagagaattt aaataccttg71161ctcaaggtca catagccaat aactggaaga accaggatat tagcttaaat tgtttgattc71221cattctctta acaactatgg atatacctct ttggagctat ccaaatggaa aatgaaataa71281gtaatctgat atatgagtct ggagttcKgg taaggatatg gaatggacac atgcatttga71341ggccagtctg catatagatg aagtttaaat tgcccctcta cctttcttta tccctacttc71401tcttttattt tcagtctctt tcaaattctt tgctccttcc ccatttctta aaaaaggtat71461tctctatctt gaaaataacc tgctcatgta ttctaagcta aattaattag gtgtctttgg71521ttgcaaatga caatccaatt gaagtgaaaa gataatttaa ttctcacaaa actggcctat71581tcagggatga gatccaggct cctttcatca ggctttggta tcgcttgctc catctctcag71641ctgtgatttt tttgtgtgtg tgttgcccca gttctcaggc aggctctcct ctcttggcag71701taaagtgact tttagtagct cttaggctta gatttcatcc tcttatctat cccaacataa71761acatagattc tcttttacct gcagttccaa tacagagcct cagctttaac attcactggc71821tctgactatg aagtattgtg ttcaagagga ggcagtgttc tcaatgccag gcctacacca71881cttgcccagg tggagcactg agagtagggg tagctacacg caaaacacct agagcaagcc71941tcggggagta gtgaatccca aggaaaagta ggatgctgtt atcagaggaa ggggaagtag72001ataccaaaca ggaaaaacaa aagatatcct tcaggggctt aaaaacaata gaataagtta72061caggaaacta tcaatagtta catgtacaca aaaatttaaa tcgacagtaa tacaaaatca72121taatgaacta aattaaacta caaacaaaat gctagaaaat atttgtaaaa gtgtaatggt72181gacttgtttg tgtcaccgct tcactgctac atgaagtaaa aatcaacaag aaaatactaa72241gaccccactg gatagatata aaagatatga acttagagtt tcaaaaggag aaactagtag72301gcagtataaa tccgaaagca aatatattgc aatggagaag ggcagttaat cattttttag72361aaagttaagt ttatgaaata tgattgatat atattttatt ttacaaaata atgtaaatgt72421gttatatatg cttggaatta ttttatatgt tgtatttcat aataaagtag aacatcacca72481gaatttgatg acatacttgt catcaataat agatttgaca acactgcaat taacacaaaa72541cccacaagga atttaaaagc atagcttgaa actgaccaaa taacaactat actagcactg72601atatagagct tacttattcc tgacacagtc tcacatacta tgtatttatt acctctcagt72661actcacaatg ataagtacta ctattatctc aatgttgtag atgatgaaac agagagaggt72721gaagtaactt gcccatagtc acatagccaa gttgtagaga attaattatt caaattcagg72781aagtttggct ccagcatcca agtgcttaac tcctttacca gtttccagag aaaaacagtt72841ttgtctgcaa agcatttaaa taaacccagt tacatgtcag tgagaaaaac aatactcaaa72901cagttcagag ctgttttttt ttaaacctgc atatttgaag aaggttcaga taggagttca72961gacagagtat gagtagaaga caaaacataa gattacatag agaaagatWt ggggtgagat73021gtaaaagatt tgcatttcta aacttctcga aattcacact tctttctcaa acacctgtgt73081cttctttcca taaaaaatta aaacttttag aaaggactgc aatatactgt acagtctata73141tctcacttcc ctcttgcatt taatcacact ccatttagat gacattcagc tttaatctgc73201ctagactgcc tgtactcact tcatttctca accctagcta aacttgcact ttgtcccata73261aggctttcaa actactccca tctcttagta atctcgtcct ctgagaacac ctattccact73321tcttttcaaa ttacctttgt gtaatgttac acatctatct atatatatct acatctatat73381ctataaatgg gcatatatac aatctcagga agagagaacg agagagatgg agggagagag73441agaccttctt tttgcatagt ccctgttttg gaaatcagaa gactaaggtt atgtttactt73501tgtatgccaa gcacacagca gaatgcccta aattcatcca tttatctgca catgtttttg73561aatgcatgtt gtattctggg cactgtgcct ggcatcatag atacaaagga gtggaagata73621cttttcctcg gccttcaaag atctctaagt gcacacgaaa aacaaatgtg tagataaata73681attaaaacac agtgtgaaaa atgccatagg gtaatacata cagggtgcca tggcaaccca73741ggggccgaat ggcagcttct gcctggggag ttgaaaagat ttcacagaag aggagaaatt73801taagctaggt cttcagatga gtaggagtat aagaggcaac aatagggata attataaaag73861catgtttgcc ttgataaata gtttgcactt tatcatttag ccagtacaaa ttataaaaga73921gttttacaaa agagaaaaat gtgatttaac ttacgtttaa gaaagatagc tgaggtaggc73981ctgagaatgc attggagtga gRaagagaaa aaaacaaatg gctttttcaa caatctaggg74041aggaataatg gaatgtctac attaaaacaa cagtaacagg agactaacaa aaagaatgag74101tctgaggaaa gttaatattc tttattttat tttattatta ttatacttta agttttaggg74161tacatgtgca caatgtgcaa gtttgttaca tatgtataca tgtgccatgt tggtgtgctg74221cacccattaa cttgtcattt agcattaggt atatctccta atgctatccc tccccccatc74281ccccacccca caaYagtccc cggagtgtga tgttcccctt cccgtgtcca tgtgttctca74341ttgttcaatt cccacctatg agtgagaata tgcggtgttt ggttttttgt ccttgtgata74401gtttgctgag aatgatggtt tccactttca ttcatgtccc tacaaaggac atgaattcat74461cattttttat ggctgcatag tattccatgg tgtatatgtg ccacattttc ttaatccagt74521ctatcgttgt tggacatttg ggttggttcc aagtctttgc tattgtgaag agtgcagcta74581taaacatatg tgtgcatgtg tctttatagc agcatgattt acaatccttt gggtatatac74641ccagtaatgt gatggctggg tcaaatggta tttctagttc tagatccctg aggaatcgcc74701acactgactt ccacattcta tggcataata atagaaattg ataacttgga ggagaaaaga74761aggaagggtt gagacttggt gagaaattta gcagaggaaa atgagcagat ggacactcca74821caacaaaaat aggggatgca gaaggaaaag cagattggaa aagggcaaca gggacacaSa74881atttggctat aggcattttg attttgtggt acctgaggaa cattctcatg gaattgtcta74941ggaacaatta gtcagtgagc atctggaacc caagtgaata atgttgagaa tttctaaaag75001tttaggaaac ataggtattt ccatcacttc cattataaaa acttcattgg gaatgttgga75061ttaataggaa gatcatgcac agaatgatta tttaaggtcc taaattgttc cacctgagca75121tgggtaagga gaacaggtgt taattatttt tgctgcgagg ggaaataatt taaaaactag75181agggaggaga gggttaactt tgggaagaga gttcagagaa cctgagaatg tgatgagttg75241tccccttttc cacccacact ggagaggggc atgccagggg cagttgggaa ggatcaggca75301ttcttcccat aaagtcgagc ctatctctct atgccagcag aacatgctgc agggaggcac75361aattcccacc attctgaccc accatttcct aggtagtcaa acttagggtg gcaagaacac75421ctaagattcc cacagtctag agaaggagga agagctggca aggacaaaga ccagaggaaa75481tggcctcctt gtgcagggag agcccaccac ccactgggat caggagaagg tcctgttatg75541aggagcaacg cttgtgaatg aagaagggtt ctcagctggg tgcctgaaag ccatcaaaaa75601tgttccatga tcacacaaaa gagtcttaca tattttcatt actgcaaacc agccttgaaa75661atatatgtat gggccaagaa aactttgccc accgaagaag aacctccctg ctacaacaca75721cctgccagtg actgcccagt gataaatgct tgcaggcctt gtgaaatgag gagatagctt75781tgcaaagggg accagagtaa aatacgtaaa aagaagggaa gcccttatag agactttaaa75841ttggacagtg gctaagactt tcattcttac atgagattaa acaagtaata atagacagat75901tgagtttccc agagtatgtc agctgtacac aggcaggaag ttaaaaaaaa tacatgtggt75961cataagaata catgtttgca cgtctgaatg gtaagtgttc aaaatccact ggatatgcat76021ataggatgaa actaaaatat agatatggga gatcatacaa cctgtttgta tataagtaca76081agaggaaaac atggccaaaa atatttgttg ttgataagga aggattttaa cactaatgaa76141ggaaaaggat aacgagagat ctgtgaaagg aaataaatta tgtagatgca aatgacttag76201tgaatggctg taggagcaat tttctaaatt tgcaggtgat atttaattgg cagacattgc76261aaacagcaag gagcaattca atcagataaa gaacttgaat cattaagtac ttggcctaat76321agatggcaag cgcagataag tggtgaataa taagtcttga atcaaaacta aagaacagag76381agtgaacatt tgccaaaggg aatgatacca tccaggaatg gctcttagat ttaaggagaa76441cttatagaca aggacaaaca aaacttcagt aaaatattac aaataaaaag atttggtggg76501ttacagctta tccagctgaa gctgtgatga gaaaatctga caacttaagg atagataaat76561cctgaaatcc acggttggct attgaaattc catttgttac ctagaatttc atctatccct76621gatcatggtt tggagataaa attaatgagt aagataacat ccaagcatat aagaggttac76681agatttgggt gaggatacta taaataactt ttaaagacat ttcggatatg aaattctcta76741tgttctatgg gcataattgt gaggtattgt gtttagattg cttggtcatt tttatttaac76801atgccagttc tagtctacgt tagtctggaa attataaaca tagagaaata tgctacaagt76861aaaagagaat aataaaaatt tattatagcc tagaaaggta gttgatgcaa tatataatat76921atttcctctt tctctKtttt tgcaatggtg aatactttac taaatgaaaa ggttaatttt76981aatattaaag agaaatggaa acatccttta gtacaacatt aaaaccacaa atggaacctt77041taaatattca ctcactctag caatcaatgt tccaacctca tttaaaggat tttttttaac77101ttgacataca aatattcaga atgaatattt ggaagcagag ccacgagcca taccttgaaa77161gataactgcg gacttactct tgcctgccat ttggRtactt cagatttcag ttgttctaag77221tctcaatgat cctgagtttt ctttttgtaa tttggtaatt ttgtaatggc aggctttaaa77281ataagtaaag gttttcttaa ctaagaacaa aaaaaaatcc ggagacctaa caaggctcag77341ctgtgtccag gtaggagatg actgcagttt ggcttcagag gctccctcta gcagtgtgag77401gacatctgag tgtctctcct actcatttta tatttcattt gatactgcac agaatcacta77461ggagaacagc cagaattgat ttacttctca tagagacaaa ctgtttctgg gagctagtta77521tcttcttatt aacaaagagc ttacattccc ctcccctcca gagctcctaa aacatctata77581taatagctac attaagtgaa ttctacaatg attgaaaatt ttactataat gaagataaaa77641attcactcaa ttctagttct tttatccttg atttgcattt gaYtgaaatg tgtatttgca77701gtttgggcat ttcagtcagc gattgctcct gtattctttg cccataagca gccttcagat77761ggcctcttag aaaattgaag aagtctctac atgactggaa aactctttct gatggtctgt77821ttcttcaaag atatagcatt acctcttggg aattatagaa acaatatata ttgttaagcc77881tcttctaatg ctactgtaat ttataactgg taactttttc ccccacttag cattcaataa77941gcatttattg gggcctaatg tgtaggtgga attttggaga atacataaag tatagaacac78001agagttcttg ttcttcaaga gctaagcagc tctatagaga agagagagac agaacgacag78061agacagagac agagagagag agagaagaga tcaacacata tccaccactt gctttactat78121ctatacttca acttttggtg gactcatccc atcttatgga ttcaattatc atctataagt78181agaccacttc cccaattgtt tctttaaccc agacctctca cctgaactac aggcttttat78241tcctcacaat gccttcagca ttttccattt ctaatgggta ccYcaaacat taagtgttca78301aaactgaatt tctgatttca cccctttccc Ycatccttgt ctgttgtagt gtatggcaac78361tccaattttc aagttactca gtgcaaaacc tttgagttgt ccttgaattc tcttctctct78421gtcacgcctt atatacaatg catcagcaaa tttgtctggc tgtaaatctg aaatatacca78481taaatataaa tacgatcact tctcaccact cgaaagccac tatttttctc tctttaggac78541tatttcaatg gccctttaac tgctcaccaa gctactgctc tttttcctat ttctgttaaa78601aaatctattt ttaacagagc agccaaagtg attgttttaa aatgtcagat cgtattacac78661tctccctata accctccaat agttttcctt caactctaat ttacataatt ccctataatg78721ccttatatgt tcaattatat acatatacac ttaccaccat ctctgtgaaa tctctttctc78781ctacttccct agtatgagta ttgcttaggt ataaatcaga actcagaaaa ataagagtaa78841gaattaaaaa ggacatatgt gctgaaaaaa atagagcaat gaataaatac tggggaagta78901attagaagga agagattata cagaaaccat aaggcaaaaa gttaatcaaa tttatcaagc78961atattatagg ggacatggcc aactccacaa tttgttcacc tataatctca ggcaagctat79021ttaccttgtc tgagtcttag atttggcctc agcgaaagga aagtggtgat acatcatgag79081cagggttgca gcacagctgg cataaatgga ggtttatccc acacatgtgg gctgaaaata79141ttagaatcca agctaccaag gtcagagtgc ctggctaaga gcttcatatg gaaaaaaaac79201ctttaagtca atgacaaaat gggagagact tttttttttc aggcagtata tagccaagaa79261tctattcctt gaatgctgga attgaaggtt atataaaagc acttattact accaaattgc79321aaagaacaag cagagcaagt aagttgagag agagagagag aSatctttct 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ttaaattact81061gcatttcatt gggaatccaa gttagaaaat tccttttccc acatttttaa tacctaaaac81121ttgggaaatg aataacatta taagtacttg aaaataatat tcactgattt atcatgtgta81181agccctgtcg aaatatttat tttctactga gcttggaaga tattttaaaa tgattccatt81241aaagaaattt ttaaaatttt tgaaatatct atttacttaa gatgttgaag aaaacataag81301catctacctt taccttccat tttttagatc tcatatgata tgacaaataa atagaaaatt81361agaggaaatt ttacaacagt actctaaatt aagtaagggt accctccatg aaccaggaat81421tggcagattt caaaaaagca cactcctaag aaatttctgt ttttcacgtg accctgacaa81481aatccattaa ttgtcctaat ttggaagggt acaaactgca gaaaagagca gggtattagc81541tcagcaggaa gcataatatt tcattgccaa gttgctgttg tgactcagta gcagcacttc81601tgttatcttc tgcatggctc ctcactcttc agcgagcaaa ttaggactca ttcacatggt81661gatccagggt tcctggcaca gcaagataga tggcaagcca ttgtgccagc cctccaatgc81721tctgtttgta tcacattgct tttctcccat tgatcaaagc aagttcctgg ctaatcccaa81781agttaaagga tagggaaata gactgcacca attgttggaa gagctgaaca gtacattgca81841aaggggcagg aataccagaa taggaagaac tttgtggcta tcttatgtaa 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aactcaataa82741acaaaatatg aagccattaa agcttgagtt aaaatgcatt aaaatctgta ttttagaatt82801cataaatcaa tagggttaat tgaagggaaa aaacagttct ttgaaaagat ataaaacaaa82861aacaagcctt gggcatgtct ggttttggaa aatgaaatgc ataaataaaa gtatcaaaaa82921catgtgtaca ccacaattaa gaaaaatttt cacaagcatg atggaacagt aagtacaact82981ttatcgtaat tatttgaaag aaacgtatgg catgaattat tatcaaggaa aacatcccat83041cattaaaatt gacccaagaa gaaatagaag acaattaaat atatgtccaa tatgacaaaa83101aatgttattt gtttacaaac aaattaataa tgttatctcc tgcctgtttt cttaatttca83161ggaaagagta ggccaaatga ttaagacatt tcataaaagt taYccaatta attctgaaga83221gctagagtaa ttcccaaaag aatggctgaa aatgaaatca catacaaaaa aagaaaaaac83281attcaatatc actttagtag tggtaataaa aatacttatt aagtgataat tgaattcttt83341tacaaaattc ttttggatat gaatatccaa aaatcttaaa tgtcctttca tatttaatcc83401gtcagcatat tagaacatag taaagtatta ccaaacaggg tttattacag aatgagcttc83461attcaaccaa aagataacag gagaatcttt ggcaaaatat ctaatagtaa gcaaagttgg83521agacatggat tagataataa tatgaaatca tcatgtgttc taaaaatgaa agaatggtat83581taaaaaatca aaggaaaagg ggaaagtagg ggaaaatagg atatcgtaat gcactttagg83641gaataagtgg aagtaacaga ttttatttaa aattttcaaa acgttaactg gaaaaaaagg83701agtaaaagca taataaaatt tttaaatatt gaggttaaaa actataataa aagtgcaaat83761ctttctagat agtaaaagaa aaacctacca aagaaaacat gctacataga aaaacacagt83821aaatataaca aaatctacac aataataaat aacataaaga atagattaaa taagatacat83881ttttgggata tggatcaaac actacaccct cataatatgc cattttctca agcatacatg83941gaacattgac aaaagtcaat catatattga ttggcctcaa agaaaacact attaagttcc84001atttaagtac tttattacaa atagtgttcc ctcatcaaaa tacaataaaa ctagaaattt84061agaagaacag taagagaagg cttttcacct gaaattaaga aatcatcatg ttaaacaact84121gtagaaaaga gaaaaagaaa caaaaattat ctttaaaatt agtggtaata aaaatactat84181atatcagaat ctgtaaagga tacttaaagg cgtaattagt agtcttggcc ctccccttcc84241cttcccttcc cttcccttcc cttcccttcc cttcccttcc cttcccttcc cttcccttcc84301cttccccttc ccttcccctt cccttcccct tcccttccct tccccttccc ttcccttccc84361ttccccttcc cttccccttc cccttccctt tcccttcctt cttttcttct 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tttttaaatt88621ttgcttcagt gcagcacctc taatataagt aaggactacc acatactcat tatccattac88681agtgttctgc tgtatcattg attctgaagg atggagtgaa gcacctcttt aggaagacta88741tacaaaactc agagatggga aagagagaga gagagagaga gagagagaga gagagagaga88801gagagtgtgt gtatttgtta gaaaaagttc attatatgat tctgatatgc ctcccacagg88861gaggctagaa atttctcctt gaaaatagaa tagccaaatg ttgaaaatag accagaattt88921aggaatttgt ttatagatat atgacaagta attgttaaat ttaataaata gtgtagcaca88981tacaaataat cagctccctt ttcctaaata aaaaacttta gctattttta ttctatttta89041aaaattcact tcgtgatatt taaaggtatc cattattaaa atcagtaacc attccaattt89101ataatcattt aaaagtaaaa catataatta tttattagaa aaatatttgt gaacatttta89161taaatattat caacatgttg tcagtaaatt cctcctcagg tggaattttc tgactttggt89221tgagtcatta aatgttttgg gtcactagtg atcaattagt aaattactga tccatagtac89281tttaatggcc tgaaaaagta aatgcatctt ctgagcacct aattgaatct tagttattta89341ttcatcatta aaatcaagat aaatgagtca gctcacaata atgaaactga acagttacat89401tcatttcaca aatagattaa actaaagctc agaaaagacg ggacaaggga gttaaacatc89461caggttagat tttccatctg aaaagaccca attcccaata tcttgctata aaaattaaat89521acatatatga gtttgaaagc aatatttttc tgcaagttca ttttcatata gcgttattaa89581gtttaatacc attcagttaa taattgtaga tccatgRtac gtatactaat atggtcttgt89641tataatgtaa atagtacagt ttaaacagca aaatttcaca ctgttttaat ataaaaaatt89701tcctagaacc aattaccctg agtgcctact atatggttca tttggaaaat gaatgatagc89761tgcaatatgg taaaatgatt atgagcacag ccttcggaat aagtaaaaca tagctttaat89821atctaacttc tgtacttact aactgagatc tgaacaagtt acttaaactt ctaaggttta89881gtttctccac ttacgaaatg gagaggaaaa cacataattc atagttcatt gtaaggacta89941agtaaaaaaa aatacttaaa tacttagcac agggcctagc aacaaagata tatgaactcg90001gtacacacag acatacaaac acgtacccac actgcttaac tttagctaga atatttttaa90061aagcattatt agtttgagac tagattcatc caagttggtt tagcattcta ctagggatgt90121tacttttcat atctttcttt gtttttgttc ccaaaagcta taaacacaag ttttatcttc90181tttcctgaaa caattaaaaa gaaaatacaa gaaaatgttc aaaaaataat ttactagtgt90241ttttgtttgt ctggaagggt catcctgcag ctttaatcac agctgaagat cattatttca90301aaaaagacac atcttttaga tatttaaata tgtattatca tattatgcag tttaaatgtg90361aagtcatcta ccctctggtt tactgagatt ctgttacatt ttaaataaat agtaaatgct90421gtagttaaga gtgctatcac tgagaatcta agaagacaca ttagaaaggg attattactc90481caagaagaat tctctttcct taatcattac tttttcatta aaatatttct gaagtttata90541caatacaatc atagtagtga ccttaggcat atgacacctt agtgctataa aaactctaac90601aaatctgttt agagcccaat aatataaatt tctgtgaaga gaaatataaa ccaatggtaa90661aatgccatgt tgaagtttct aaatagccca cctagtaatt tacatgttaa gaacatattg90721aatatcttgg gaacatgttc ctagaaaaga ttctccatta taagcttttc ctttactgtt90781aatgattgct ttgataaaat gacccacgaa aaaagacaat tttctccctg tgttatctgt90841gtctgaaata ttcttcactg attttacata tgctgataat atgaacaagg taatttgtct90901gactctggtg gggcaagatt ttcagtaaga aatgcaaaat tcacacatag ctcttctgta90961agaagtctWt gcagtgtttc agtttatata aaaagattta tattgcctga ggcatctatt91021tttttttcct cgaggcaagc tgaagtggca caaatgaaat tgtttttcac actgttaatg91081tattcctttc tctttcaatt tctcagagag ccgacatagg gatttctgct ttaaccatca91141ctccagatcg tgaaaatgtg gtggacttta cgacacgtta catggactac tcagtggggg91201tactacttcg aagggctgaa aagacagtgg atatgtttgc ctgtcttgca ccatttgatc91261tctctctatg ggcttgcatt gctggcacag tccttctggt gggtctactg gtctacctct91321tgaactggct taatccccca cgattacaaa tgggatcaat gacgtctact actctctaca91381actccatgtg gtttgtgtat ggatcttttg tacaacaagg taaggagcaa aagtacattc91441tagtatttaa aaaaaataga atgtgatgtt tccaaagcca tgtattcagt taataaggtt91501ctgtatctga catcaataag tgttctaaag ggtactcaca gaaatgctca gaaaagaaca91561tttgctactt cctcctagtg gatctcagac acaccaagtt tccagcaata atggttcatt91621gtcttttgat gtaagtttaa tttcatcaac aaaggcaaat gtgaatgtca aaggtaaagc91681tcacagaaaa catcaagatc agattttcct ctccaaactc tgactttctg agaaatagcc91741ttataaggat gaaattactt attaccagag aaggtactat ttaattattt acatatgtaa91801gaaatgttag gacttgttct ttgttcagag acattatttc atgcattaaa aatattgtca91861ttgaaaagac tttggttaat ttgagactga tgagaaattt tgtgttttat cttttacttt91921gatatgtaat ctttactggt gatttaactt acaatttcac tattttctaa agaatgtcat91981tgctctgtta tttaatatcc aatctgccca actctttaaa cttgtccaat taattatttg92041gctctcactg tttcaaaata gaataatatt tattgcattc cttacttgag actattgcct92101catagagaat gaaatagtaa gaaaattgat agtctcttgc aagctctaca catatattga92161agaggaggat gtttgctaca atggagacat tatacttttg tgctaatatt tacaactctc92221aataacatct ttctttttat tcctattttc tcttggacct tccatttaac ttcatttttc92281tattctaatt taatcaaaga ttagtctaga accttcatct gacttgctaa cttctaatct92341agcccttaaa ccttttgtaa gcatgctttt ccctccaccc ttccatatcc agggctctaa92401gcttacctgt tactgtatat ttttcacaga cacttttagt tctttcatta ataattaatt92461cagtaaatat ttaatccaca ctatctaagt agaactttcc taagcaatta gtgtatgatg92521gtgagcaaga aggtctttgc catcattgcg ccacaacaga agtctaatga gacacaaaca92581tgtaaacaca ggattacaat tgtgggtaga aagttctgtg gtaggataag catagactgt92641taggagatca taggtgtaga agcacttaat atatgttaat gtcgcagaga aggcttttta92701aagtaacact ttatacagag agacagagtt aactatggaa agtgcttctt gaggaagatg92761aatggagaaa aggagacata aacggttagg atggaatttc agaccaagaa gtgagagaga92821aattaagata gtccaagcag agaggatcta gtaaagatga ggctgaagct acatttgtta92881ttataaggag tttgaactga tccttgaaat gatcagatat ttaaagataa taaatgggaa92941aatacagatt caaattttac tctagaaata ttctggttat aatgtggaga atagattgaa93001aaaaggcaat gtgaaaagtc agacaaatta gaagactatt acaataactg agcaaagagt93061tgatgtggct tgctcaaagg taaggtagct ttgggagtca agaggagagt attgatgaaa93121tggaatcaac aggctttgat tacctatagc gtggtgtggg ggtcagtact gaagaaaaaa93181ggagataaag ttttatccta ggtttttgaa tagaaaatta tgtatattgg atgtggatct93241catttactga aaaaataaaa cagaaaaaac agatatgaca ggagagatga tacattcatt93301ctgctgcaca ttgagtttga gctatccgtg aaacatccaa aagagtatta ctaatgtgtg93361cttagtggtt tgatatattt gtcagatgca cagaagagac atctggactt aatatatatt93421taggagatat tggaatgtag gaaattttga agacatggga gttaatgaga tcacacagag93481tagttgctct taattgcaaa ctcctgattg aggaccactg gcccatacaa agcctaggac93541agagctctaa ggaaaggaat ggatagagga gcactcagtg gtgcctgata aggagtgact93601ataaatgcac aagtgaaaat cagagcagct agtagtatac gtttggttga ctgtgttaaa93661cctttcaaag aatcaaatga aattaaggct tgaaaggttt ttgttggatt taacaataaa93721tttattattg aagcaaaaaa ggcttgtctt tgccctatga tgtctgaggt ttcagctaga93781caattcagag gccagaggct aaaatcatcc aaaggcttgt tcatttcact cacatgtctg93841gtggttgatg cggtctgtgg gctagtggcc tcagcttttt ctccatttgg gcctctccat93901gaggtcactt tgcatgggat agtttgactt tctcacagca tggtagttgc tttctccaca93961gagaacatcc caattaaaga attttatgtt ccaggttggg agtcataaac ttgtgtgatg94021gtgtgaattc ctcttgcaga gaacatcctg gatgtaccca cctcatgggt ttttatgaga94081atttattaat gaatggttaa aattgtgaag ttcttagata taacttatat aagtgtcaca94141taagtgttta ctaaataaat aaaacaatga attagactca gcggcagata attgacatat94201gtaaaaaaag ggataacaag acaaatgatt gtagatcatt ttgatgtaSa tattgattga94261aatagtagat catggggtat atggagaact agaaagagaa ggaccaagaa tgcgaatgta94321aagaagagta agggtagaaa ttgatagagt aggcctggca tggtggcaca tgccagcact94381ttgggaggcc gaggcaggcg gatcacctga ggtcaggagt tcgagaccag cccggccaac94441atggtgaaac accatctctg ctaaaaatac aaaaaaatgc caggcatggt ggtgggcgcc94501tgtaatccca gctactcagg aggctgaggc tggagaattg cttgaaccca ggagcgggag94561gttgcagtga gccgagattg tgccattgca ctccagccgg gatgacaaga gtgaaactcc94621atctcaaaaa aaaaaaaaaa aaaaaaaaaa aagatagagt agttaggaga gagtagtaga94681ggtctcaata agattacaga aaaagagtga aaacataatt ataaatgagt ttggagtctg94741tatttataaa ataggacatc taagcctaat tttttttgaa atgtaataga ggagaacatg94801ttgtaggtat gtggatacaa attccagatg ttaagatttg gtgaaggact tcaaagctga94861tcaaggaact gagagataaa gggttaggtg agccagctgt aatgatggct tggattagac94921tggagaaaaa gaaattgagc catgtgtcaa agttgtgaat aaataaggaa ggatgacaag94981gatgttgata gatatgagca ttgaccagaa ataggaggtg acatacctag atataattaa95041cctctgtttt catcttactt cttccaattt attcagtttt tcagtgtatg atttcaacaa95101ctgccaatat gctgatgact cccagatcta catcatctat tcttgaactt cagatttgta95161tattcaactg ttacctaggc aactctctga ctataccaga ggcaccataa atttgaacat95221gccaaaaatg taattcattt tagaatttga accttcttag cctctcacat tctctattcc95281agctgatcca ccaccaacca ttcagactca tgttagaaac tctgaaaata gttttcattt95341cttcctcttt ctcatcttgt atatccaacc ataatcaagt cctgtcaatt ttacctacta95401aatatttcta gaagtggaaa tctcttctta tctagaaaga ttagcctaga ttgtcaccta95461gattgaggct acctcatttt tcacctgaac tataggagtc tcataagtct ttcttcttcc95521agtgttgtct cctgcaaata tacgattcac atacttgcat atatacccaa gttatccatg95581ccatggaaag ataaacacat aattcccatt cttcagttat tttcttggct tcccaatgcc95641cacagtttag aagtctgagt tcttcagagc ataaacaata ttccatcacc tggctcctgt95701ccaacactca gttctcatct cttaccattc gtgcctcaca tttaattgcc cagttactcc95761aaacttacgg tttgaccata agacaagact ctttcctaac tcttcacctt Kgtatctgct95821ctttccaatt ccttgagtgc ctttgttacc aacctgatta gactctactc ccactctctg95881tctttataca gcaagttcct attcatcctc taattttttg cttttatttc tctactttca95941agaagtcttt cctgggattg agaaccatct tctatactcc tcaacatgta tttgtcatag96001tacttaccaa ccatagtgta attccttttt ttaaacatgt ctccacctga gtcctttgaa96061tataagatag tgtactattt aatctgtgta gtctctttgc ttatagttaa gtgccttgta96121catgttaggc atttaataaa ttcatattga taaatttaat gaatggatgc taaatactta96181actaaataaa gcatggaggt tagctgcaat attttgttta ttagattata gtctcaaata96241aaacactaaa attatccaca aatgacttaa aactcactaa accaaaaaga aatttatctg96301taatgtcccc actgagttgt tgtaagaaac taagaggagt ttataagtaa ggcatcctct96361tggttgaagc ctcatttgtg aagacgttga catacttatg aattggcttt ctgaattctt96421cctccaagtg accaaatttc aataagtttt ggagcacacc caggaaaaaa gataaataga96481attacccata tggttagcat gcttttctag ttctataaac atgcaacaga taacaaaagt96541tataaatatg ttaaatacct ttctatccca ctgctccctt aaatgagttg cacagcctgc96601aggttgattg tacatttata caaatttata atgacagata atgctgaatc gcatatgatt96661agctacttca tctttgaaaa gctgctattM ttccacttgc taacaatgaa aaggtgaatt96721cattaaaaga Yactgagagc atctttatgc tctgattaaa aataaatgaa gaaaaggctt96781ataaacccta tgaaaaagag aataaatcaa tgacagtgtc catgtatagg caattgactt96841ggaactggtg atatttccaa taaaaataca gtcttttaag aggaagtaca gctgttattt96901cagaattgca gtcttcattg agccactata ccagattgaa tagggataaa gaggcatttc96961atgtgttatc agacagattt ctaaaaaaag agttcacgga cagccaaaag cagaaaaatg97021ttaaatatat gtgagttgtt tactaatcct gacattttaa aaaatctgta acttcaaagc97081attctggaaa aatagctcag ggaatccaac tgtgcaaaag cagtatggtc cattatagag97141ataaactcag tacatctgtt tggctggaac attaagagct tgtgaattag gttgtaaaat97201gcacgaatga gagaccaatt ttatacaact tttgttgtca ttttatgtcc tccgttatct97261ccatgtgtac atacatctcc tttcaattaa tattcttaag tgaaactgga tttgattttt97321agaagtctct tatgtttagt ttattggcag tgactctatc atctggtctc cagaggactt97381caatgacttt gcaaatgtag ttgtatgtaa tttKctttct gtttacatgc aaagggaaat97441ttcagaatta tcttcagatg tttgtgtctg attatgggaa atagaaatat ttatagtcat97501gtaaaatatt tgaagcaacc acatatatgt ttatttagca gcaagcattt attaagcacc97561aacaatgtgc caggaacatg agtagcaaaa ggaaaataag gaataactct taactagggt97621ttaataaata tttcacgagt atactatgtg


Following is a genomic nucleotide sequence of a PDE4D region (SEQ D NO: 4).

>5:58309301-584080501ctctaaatat tttccattga tgaatttcta attgtttttg gcctaagtag tctgaaaaca61atacacagat ttagggttgc aactaaaaaa acgggaggat ttctaagtga atgcttttga121atcctttgtt ctcattatac atcagaatgt ctgtgtacag cagttaaggc ataaaggaaa181gtaaaaatgc agttgaatct caatactgta ttttgctttt cagaactgca attcttcaat241ttacattaSg catttaagat tgttcaggaa gcaaactaaa ataataaaac aaaatgtcct301taaatgtaat ctcctttact tctacatcac gccagtgtgc tactgggtat attatatatc361ctcccaatat atatttaagg aggtggtatg ggtccaatag taagaaaatt ttcttatttt421ttcctgacaa tattctgcta aaaatcattt gaatatgctg cactgtgatg cattacaagt481ttggtagata tcagtattca aagttattta aacaaatact ccattgatgg tataaaaata541aaWccttcaa aatgcataag accaaatata tctatatttg ctatttttac atgtttttaa601aggtacagta ttaaacataa agctgtccag gaaaaatttt cctcaaaaag aaacgtacta661aaattctata tgtagattct tggcaatatt gttcataatc atagtacaaa tggttcataa721tcacagtaca aatgtgaagc ccttcaaaaa taacatcagt tgtgagctgg ctaaaagcta781ggagctgaat tctggcggat aatgagggct tcttatattt actctctata cttttctgca841tttctgaaga tttttagcca agaaatggct aacaaaattc aaataatgga agtctatata901ttttaaaaac atttttaaaa atctgaatca tccacagatt taaagggagg taaggaatca961tgactacttg gaYaaccaag actgaaataa gttttctaat ttttttagaa ttcaagtaaa1021tctctaaaac aaaggggaac ttgtccttca aaaagaaaga aacaaagcaa acgacRaaca1081ctccaatctg aaaaatcctc agagtaacag aaaatgaatc ttttaaaatg tgttgtgatt1141ggctcccagg ttcaagcgag tggctcaaat accaaaaatc tgtgaagtga tgtttcattt1201aggactgaat aaggtttttc tacctccttc tattgtggag acaggatcac aatgctaatg1261ttaccacagg gcatgSaaaa agcctgccaa gcatggacac aatcttattg aattgtttat1321taattcattt cttgagattc acaaaacagt gtaataaaaa ctttgttcag ttttgcaagt1381ataatagaca atcaagtttt cactttagta tcacttacat agttaagtaa tgtcaatttt1441taatgtcacc tagggcttta tagctaaagg tgaaaaaaac gtattcctcg tcaggttaaa1501gtagtataga tttttagaaa cagccacaaa ttaattttat aaactttatg tgcaacatac1561taactggaat ccataaatca gtataagtaa tttggcccRa taatttattt gcaatgaatg1621tatttaatta ccatatattt ttcaagcaca attcaaacat ataccacatg acaaacagaa1681gaactactgc gtatctaaaa aagctatttt aacactcaaa ctacaactga tgaaagttat1741acaatcttat cttgaccact attaacacgt atttcttcct agttcatgtg taaggaaaga1801atacataact gatagtttga acaaattaca gtagagtcta agctttctaa ataattttgt1861aatcagagta aggagttttc aaaagctaag taagtcttac ctttatgtag ccccaagaca1921ctgacagtaa atagtttgct tcaggcattt ttgattgatt atatgtatat atatatatat1981gtatatatat agtaagctct aaaatgtatt tagcttcaaa atctcgacac tttaacaacc2041tccacaagcc acgcagagta tgagttttta aagatttttg gtaattaagt atacataaga2101aagcctcgca ttaaatccca tccagccgtc ttcccatcga atacatgcca tttgtaagac2161tccagaatgg cacaaaattc agcaactatt ctgaataaag aaaatccacg tgataaagga2221atatctaaag atctaagggt ctgcatcttt ctctcccgag ctccagggct taatgaataa2281tgtatgtcaa gatgcttagt tgcaagaaag gctagtcctg tcaaaagcta ccaaataagg2341aactgcaggg aagccgggaa gagtgacaag aagcccctcc cataaaaccc caactctgca2401ccaattgcat tccagctctt agcctataag gcgagggggt gtggcctcgg tgcaggctgc2461tttgggattg gttggcaagg gccagcctct ggggaggctt tctcctcacc cgacaaacgc2521cattgaataa tggtatccct gcagctctga ggccaccctg agaaaagatg aacggggctt2581ccctcttgca gtgatgaata atgaccataa aactcctcaa aattcgtagt tcattcttaa2641gaattgccca tccttttgga gggcattttc tatgaatttt aatgtcctct ggcttccctt2701ccttccaaat aaaaactgct ccaaaaatgg caatcgagca ttttaattgc ttccYtctct2761caaatccaaa acaagtggct ccctggtgat gtagaaatga ctgtagttct cccctcatcc2821aacataaaag catagggatt aaacaatacg actaatgtcc agaattcaca gatggcacag2881atggcaatga cacattccct cacctgtgtg Scatggctgc tctcagctcc ttttgtttct2941attgttatgt atgacagagt tctaaaacct tcaaaatcta ggggtgggac cacttgcaat3001tctgggggga gggaaatgtg aaagctaggg cactgtgtat gcataaggaa tgcagtgttt3061tgtatataga actcaggatc tgtattttga tcagaagaga atattttatt tatttattta3121gagacagagt ctcgctgtcg cccaggctag agtgcagtag tgcgatcttg gctcactgtc3181acctctgcct cccgggttca agcgattctc ctgcctcagc ctcccgagaa gctgggatta3241caggcgccca ccaccacgcc tggctaattt ttgtattttt agcagagacg ggatttcacc3301atgttggcca ggctggtctc aaactcctga cctcagggga tctgcccacc tcagcctccc3361aaagtgctgg gattacaggt gtgagccaac gtgcccagcc agaacagaac attttaataa3421ctgtacacaa agttaagaaa ggaatgagtg gctcttagga atccagaatt gagctcaaga3481gtaatcagac attttacgag gagggttaaa tgagaaatca aagttctttc tagaaaaaca3541gcattttcta tttggtttgg tgtagtatta ccctgtaact ttaatactaa agaggtcttg3601tgggtgagaa acaaggaaaa actaggtttt agttgatttt agcatataat tctgtgcatt3661ttacctcctc tccatctcaa agcctgtgct tactactctg tgctttaact tgctggtatg3721gctactctgc agtcttcctg acatttaact atttccacat gtggcatgtc tgtcttagag3781agcatgctct ctgataagca ctcctgtaac actgtgtctc tctgagtttc tattggcctt3841tagctgctac agtcctctgc ttttgttaac atctgttgta ttcatttcca tcactcttac3901tcctctacaa aaggaagaaa ttaaagctcc aacattccac taaagctacc cccagaggaa3961tactaaggtc ctccttttct ctggtctccc tacttctctg aagtgttcca catgtttgat4021cattcctact actctccctc aactcccagg atcctgaact tctttaattt tccctaggcc4081cacaatcttc aatgaccact tctaacttga acttcagtgc catatttctg aatacaagat4141tctcctctcg aatgccctgc tagtcacgac aaactttttc aaaactgtga gacatttttc4201tatttaaagt agttcttagt ataattactt ccatttcagt cagtgagcct atatttcttc4261cagtatctca gatggaatct atgactcttt cctaccattc aacaggtgtt tcatgtgcgt4321cagacactgt caggtgttta atataaacca tctagctgaa tccttgagta acccggcatg4381ttcccctata cggcatcacc ttccctcctt cattcaactt tgttagcaag ccctatcttt4441tatccagagc tgtttctttc agtttRttcc ttaccattac ccctcccgta atctgaatcc4501aaatatttaa aagactgaga gaaatagaaa gtaactttaa tatcaccccc tctaactccc4561tcatttccac ataaagttga gacctagaga gaaaaaatga ttttcccagg ttcactctgg4621tactgagaac aagaattgca agtttaaatc ttttgtgcac aatcactgac aaataatctt4681tttagtgtgt cagcttcctc atctgtaaag tggattactg tggcagctag tctccaaaga4741tactcttaat gagccacact gtcctacact gaatctgagt tggcttgtgt aaccaacaag4801tgatggtgca tgactgctga ggctaagtca taagaaatct tgcagctctc atcctgcttt4861ctttgaatgt gctattggga cccctaagcc attaggttga aaaaaaaaaa ggtctgacta4921ctctgagagg ctatgctaca agaagtccat gttaacttca cagacagtga agagagaaag4981cgcaagagag cacttgcaca agaaagagca cacatgcctg gccagtcttc agcaatgcca5041gccaccccag cccagagcca gacctgaggg gcaagaagcc atcctagcca tccagccagt5101tcagctttca gatagctacc cactgggctg caaccatatg aggaatgcca agcaagaatg5161tctagccaag 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aaatgaatac6901aggggtgtta tgttagaaaa attttccttt ttcctgatat gatgaatgat tctttgaaag6961gtttcaaatg taacaaagtg ccaYcttcac aatatacact attgctgcat tactagaaaa7021tttggtgtgg attaaaacca tgtaaaaata tttaatactt atacgtaaaa agtagttggg7081ttctaggctc agagaattat aaatgcattt tgttttttca cctatgtgaa tagctgctgg7141gactttttgg aagttgtgtg ggacacacag caaacctccc tggtgaaagg ctgtcccatg7201tatcccagga catctagcct ccctggcctc tgcYcaccaa gcaccaggag tactccccag7261tcactgtccc ctgaaatttc ctgaatgttc cccagtgtta agaatcactg ttctattttt7321ttcaactgtc ttcaactttg actcctcatc cagggtggag gatctttgag gccagaaaag7381tatcttatta tgtccctgta tttctcaagg tagtgtacta ttgccacaaa aagattgttg7441gctgatgcag atgcaaaaca tcaatatttt tatactgatt ataggtgaca ggaaaggaca7501agggttttca ccctcagcaa aatcatcaaa aacatttaaa acagattaca tatagtagat7561aatactcctt gtcttaaaac attatgcaga aacacacata cagtttccct tccctctaaa7621atctgcagcc tcttctccct gctgaatgtg agtgatggtc ccttcattca acagacttct7681atttggcaac tattatgtgc caggcattct aataggtgct ggatgtgaaa ggatttaact7741tattcaaata 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tgctctcaaa tgcccaaatg8641attttatata catatatgca agtgtgtttg ttgaaataga aaaaatagtt tcttggcctg8701gtgaagtgcc tcatgcctgt aatcccaaca ttttgggagg ccaatgcggg aggattgctt8761gaggccagga ggtcgagacc agcctgggca acatagagaa accaccgtct ctacaaaaaa8821tttaaaaatt agccaggtgt ggtggcatgt gcttgtagtt ccagatacta ctgaggtggg8881aggtgggagg tgctgaggtg ggaggatggc ttgaggccag gagtttaagg ctgcagtgag8941ctatgattgc accactgtac tccagcctgg atgacagagc aagaccttgt ctcaaaaaag9001aaaaaaaaaa ttcccataat gttcagttag ttctcttttt cagacttttc ctagaaatac9061ccctcagaat ttctagaggc cacttccctg ctattccttg ttttctcagt ccttaccaga9121tacccaagca attaacaatc tttttgaact atttcagtac atttcaggat atttgaaatt9181ctgctgatgg agctgaactg ctgatacatt aacacatgct gtcattattg actttgtaac9241agaggtcaag agagaaaaga tgcatttttg aatagggaaa aacaaaacta aattatgggg9301aaactaaggc tcagagaggt caagttgtct tgctcaaggt cacaaagcca gtagtaagta9361acagggccag gatttgaacc cagactgtct ggtttcagag tactctaaat tgccaaaaaa9421agaaaactat ttcaggcatt attttatatt tagcctagag cctacataat agatccgtta9481atataatcaa ttctaagctg tatattatat tactgtgttt gaaatattta agaaatattg9541tttaaaataa gtgtattagc tcttRgacct ctccaacata aggagttttc caggcagtag9601cactgtttgc agtaggactt acattattgg aaaatatttt atcctataat caatctacat9661ttattttaca cctttcacct taaaattaaa agtcgtggta gttattaatc aagaagcaaa9721tctatataac gtggtctctc atatatccag tactgttcag cttgaacaaa tgcaaatcta9781atttttaaat gtcccttgaa gaattctgag gcaaagttaa acttcaagta ttaaacagaa9841tagccacaga aaactagtgt ttctcagcct ccctttgctt tcaaatgcct taaaaatatt9901ttagaggcag acaataatct agaattgatt cataaccaat attttacata acagaatgtt9961acatgtattt tcatattata aaaactatac tttctttgat taatgctagt attctgaaaa10021catcgttagt gccagtaaat ccactaaatc tgtttgtatt tactgccctc tagtgataat10081ggctctacat ttgattaaga aaaaactatt cctttcagta aatgaaaaca tctcttgtaa10141gttttatgga gatttgagat taagaggaac tccaggctgc ttttttaaaa ccaaataatc10201atctgaacaa gctgagaatc gttctctaaa tgatcttatt ttaatttttt tttaacaaaa10261aagtctcatt taaaatagta aacacctgca acatgtatgg agaaaggaaa ccatttttgc10321taagaggctc 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gcttcagacg13741atgggtaata aacttttccg agStaaagga ggatgttcaa acccatcgca aagaagctaa13801aaaccttgaa aaaagattag acaaatggct aactagaata accagcatag agaagacctt13861aaatgacctg atggagctga aaaccatggc atgagaacta catgatgcat tcacaagttt13921cagtagccaa ttccatcaac tggaagaaag ggtatcagtg attgaagatg aaatgaatga13981aatgaatgaa atgaagcaag aagagaagtt tagagaaaaa agagtaaaaa taaatgaaca14041aagcctccaa gaaatatggg actatgtgaa aagaccaaat ctacatctga ttggtgtacc14101tgaaagtgat gggagaatgg aaccaagttg gaaaacactc tgcaggatat tatccaggag14161aaattcccca acctagcaag gcaggccaac attcaaattc cagaaataca gagaatgcca14221cgaagatact cctcaagaag agcaactcca agacacataa ttgtcagatt caccaaagtt14281gaaatgaagg aaaaaatgtt aagggcagcc agagagaaag gtcgggttac ccacaaaggg14341aagcccatca gacttacagc tgatctctca gcagaaactc tataagccag aagagagtgg14401gggccaatat tcaacattot taaaggaaag aattttcaac tcagaatttc atacccagcc14461aaactaagct tcacaggtga aggagaaata aaatccttta cagacaagca aatgctgaga14521ttttgtcacc accaggcctg ccttacaaga gctcctgaag gaagcactaa 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caaaaaaaag16261agaattttag accaacatcc atgatgaaca tcgatgcaaa aatccttaat aaaatactgg16321caaaccaaat ccagcagcac atcaaaaagc ttgtccaccc taatcaagtg ggcttcatcc16381ctgggatgca aggctgcttc aacatatgca aatcaataaa cgtaatccat catataaaca16441gaaccaaaga caaaaaccac atgattatct caatagatgc agaaaaggcc tttgacaaaa16501ttcaacagga cttcatgcta aaaactctca ataaattcgg tattgatggg atgtatctca16561aaatagtaag agctatttat gacaaaccca cagccaatat catactgaat gggcaaaaac16621tggaagcatt ccctttgaac actggcacaa gacagggatg ccttctctca ccgctcctat16681tcaacatagt gttgaaagtt ctggccaggg caatcaggca ggagaaagaa acaaagggta16741ttcaattagg aaaagaggaa gtcaaattgt ccctgtttgc agatgacatg attatatatt16801tagaaaaccc catcatctca gcccaaaatc tccttaagct gataaacaac ttcagcaaag16861tctcaagata caaaaccaat gtgcaaaaat cacaagcatt cctatacacc aataacagac16921aaacagccaa atcatgagtg aacacccatt cacaattact tcaaagagaa taaaatacca16981aggaatccaa cttacaaggg atgtgaagga ccttttcagg gagaattaca aaccactgct17041caacaaaata aaagaggaca caaagcttat agataggaag aatcaatatc atgaaaatgg17101ccatactgcc caaggtaatt tatagattca atgccatccc catcaatcta ccaatgactt17161tcttcacaga attggaaaaa ctactttaaa gttcatatgg aaccaaaaaa gagcccgcat17221tgccaagaca atcctaagca aaaagaacaa agctggaggc atcatgctac ctgacttcaa17281actatactac aaggctacag taaccaaaat agcatggtac tggtacaaga acagagatat17341aggccaatgg aacagaatag agccctcaga aataatacca catgtctaca accatctgat17401ctttgacaaa cctgacaaaa acaagaaatg gggaaaggat tccctattta ataaatggtg17461ctgggaaaac tggctagcca tatgtagaaa gctgaaactg gatcccttcc ttacacttta17521tacaaaaatt aattcaagac ggattaaaga cttacatgtt agtcctaaaa ccataaaaac17581cctagaagaa aacctaagca ataccattca ggacataggc atgggcaagg acttcatgtc17641tgaaacacca aaagcaatgg caacaagagc caaaattgac aaatgggatc taattaaact17701aaagagcttc tgcacagcaa aagaaactac catcagagtg aacaggcaac ctacagaatg17761ggagaaaatt tttgctatct atccatctga caaagggcta atatccagaa tctacaaaga17821acttaaacaa atttacaaga aaaaatcaaa caaccccatc aaaaagtggg tgaagtatat17881gaacagacac ttctcaaaag aagacattta tgcagccaac agacacgtga aaaaatgctc17941atcatgactg gccatcagag aaatgcaaat caaaaccaca atgagatacc atctcacacc18001agttagaatg gcaatcatta aaaagtcagg aaacaacagg tgctggagag gatgtgaaga18061aataggaaca cttttacact gttggtggga ctgtaaagta gttcaaccat tgtggaagac18121agtgtggcaa ttcctcaaag gtctagaact agaaatacca tttgacccag ccatcccatt18181actggatata tatccaaagg attataaatc atgctgctat aaagacacat tcacatgtat18241gtttactgca gcactattca ggatagcaaa gacttggaac caacccaaat gtccaccaat18301gatagactgg attaagaaaa tgtggcacat acacaccatg gaatactatg cagccataaa18361aaaggatgag ttcatcatgt cctttgtagg gacatggatg aaactggaag ccatcattct18421gagcaaactg ttgcaaggac agaaaaccaa acaccgcatg ttctcactca taggtgggaa18481ttgaacaatg agaacacttg gacacaggat gggggaacat cacacactgg ggcctgttgt18541ggggtgaggg gagtgggagg gatagcatta ggagatatac ctaatgtaaa tgacgagtta18601atgggtgcag cacaccaaca tggcacatgt atacatatgt aacaaacctg cacattgtgc18661acatgtaccc tagaacttaa agtgtaataa aaaaatWaaa aaagtagata gtcccaaccg18721ctgtattctt tttgaatcct tttgccactg tttcatatca cagttttttt ttttttctga18781gccctagatt atcagtctgt tctttttttt tttttttttt tttaatgtag tccataggaa18841tctgctgcct cacRgtcagt atcgtgcccc ttaccccaat tctaatatga caggtttttg18901tctaagacag catttcctag aatgtgttgt aatgtacagc agcttcatgt gataattctc18961aaagactccc actgtcaaat gttagcatat tcaaggctct gccaggacct gtaatacata19021ttctttcttt attctgttta acttagcatt tctgaaacct atcttactac tgaactcttg19081acatttatta acaaacaaat acaaacRaaa ataccagggt tccaagtaaa attettatat19141aaagcaaagg gctttaaaca tcagagtttt ttagaatggt tattcactca tgcactcaac19201aaacacttat tacatagtat gtgccagcat aggggataca gtaataaaca aaacagacaa19261gttccctgtt catgtaaacc ttggacttat ggggcaaaaa gacaataaaY aagcagacaa19321aaaaaaatta caaacactct caatgaagga aaagagggta acatcgtaca ttgatggggg19381actataaaat taagtagtaa ggaaaagctg cacttgagaa ggtggtattt gggaagagac19441tcgaatgcct agaataagcc aaccagattt ggggcacagc actctcaaca aaggctgagt19501aacacagcca gtctgaggga ggacaggtct acggaatgag agccgaggca agtaaaggca19561acatcacgtg ggtcctgagg gtatgagcct tccagagggt gtgaggatac cattagaagg19621ttctgagcag ggaatgatag gatgtgattt acattttgta aagctgtctc tgtagaggat19681agtttgtaaa agtgcttgag gcaaaactga caagacttga agacttgcac aacagaactg19741aagaaatgag aagaatcaac tcctagactt ctgggatgat caatgtctag gatggacatt19801ggtgccattt gcaagatgga gaagaccggg ggaggtacgg atttaaagga gggtatgtaa19861ggagaaagaa gaatcctatg agacaagacc agaacatgta aatacatgaa gttttggatt19921tcttactctt caaagacatt ttacctcctg tccccgaagt tcttcacaga gttcaggata19981agaaaagctg ccagacagtt gagttttgaa taagtagtaa ctttcaaaca cttgaaagac20041attatattag aatagactac atccatcaaa ataNttaaaa atgtttttag aatagtccaa20101taatttggaa tatgaaagcc taagaaactt ccttatccaa ggccRcataa tataaccaaa20161attagaattt agtactccta gttggcaata tttttatgaa attactgttt tactaagaca20221ttttagaaat gaagacttta ctgaaggcaa taataagtgc aattaaaagt ggtacaataa20281Kaagacttct ttttcatttg caacaggtta gtagtgtatg agaattatga gatgtaaaat20341agtgtagagc ataggcttct ctagttggct tcatgtgagt tcgaatcttg gccctgcctc20401tcttaccagc aatgaaatat gcagcatttt acttaaggat actgggttgt atggagagaa20461tcagagttaa ggttggtgat ccagcagtgt catgtgtcag gagctaataa attgtattgt20521gaccagaaac actgaaactt gttataagga aagcaatcta attaaaacag ctgcattaaa20581atttctacaa tatcttccta acagcttatg ctatcaacag tttgtaaact atcagaatca20641cggatactgg ctgagaatgc ttttggagat ttcaaattgg cataattttc tcagaatgca20701ctgatctgac aaatgtacag acaggcagac aggaatacta ccactcttca tgaataactg20761tctgcctctc ctggatttct tccatgttgt gtaagtctat tacactttgg gtgaatgtag20821ctttagtaca ttgagttaat atcattcttg caaagaagct ctttataaat tccttaaact20881taatttgact ctggacacaa acaaatgaga acaaaataca gctcaaggat taagatcctt20941aaccaaatat gtaaaaaaca cgaaaagcct tacaaacagt gatcaacagt taaacatgcg21001ctatcacctt cccctaacag ctagggaagc atgtatatga atggaaeata tgaacttcca21061tttggtgtac taagaaaaca catcacgcag atggctttta tagcttccca aataaggttc21121taataattca caaaagtgtt gttccctaaa acccataata aacaataata aaacctaatg21181tttattgagg gtctactatg tgtcaaggag agtcctatgt actctcctgg aattacttca21241tttatttcta ataataacct ttaatgagca ctgtcactco cgtttcacag atgagcctta21301aggtcttagc tatcaacttt gcagacaaca cccaagtaaa atcctgcccc ctcttttttt21361tttttttttt aaccagaaat ccagtcctga caactgaaag cttatagggc atttccgctt21421agatacatag ccttacctaa attatatgtc taaaaactta actgtcatat tgtccagccc21481tcccccaata cccaactggc ttctcttcat gattttccaa ctataattct gtccattatt21541caggtttaga atttcatgct ttcttctggc tgtggtcctg ccaagtctta tgtatgctgt21601cacccttctc tgtgcaatct ttctcctact cattcctctc ttttcatcac tatcctattt21661caggccctta tcactcttac acctaattcc ctaacggttt cttcttgctt tcagtacaat21721ttccccttga tataatctat cctgcacact accaccagat ataaccttct aaagtcacct21781tattttagtt tcttcataat attttcctta tagtcaaatg taagggttct tcatgaatta21841taggacaatg tgcaaatggc ttgacctggc atttaagaca gtctgcagta tggcctcaat21901ctacatttct cacacctgcc actggtccta taatcacatc ctctgttcca gagaggctca21961ctcctccaga atgcccacta ccctcctctc cagcaaacat acaataaagc gaatccacat22021gaatacccca tcctaccctg ccttatccag cccctggaat accacctctt ccctattaga22081tgcctatata aatcctcagt attcaagatc cagcttaagg agcacttttt ctgggaccaa22141tcattctggt cctctgtatt gaatactcga actcctctac aggacaggaa cataatgtat22201tattacccta tcattcatta acacacaaca ggcttacatt atatggctgg ttgtattttc22261agaggtatgt ctatatgttt cgctatctat ctatctatct atctatctat ctatctatct22321atctatgtgt ttgaatacag atacataaaa atctcatttc acctataaga acctctggag22381cagatacatg tcatacaata attgggctaa aacaaaaatc cctcagtgaa aacctaaaga22441ctgggttgtg gttgtttgca gccaaaacgt acaaaatgaa aacctcctaa cgatttattt22501tccacatgaa attagtacca gatctagaga aaaatggaca aggatcaaat acaaataata22561aagtcatcac caaactaaaa atttcattca aaagtgatga tgttggccgg gtgtggtgac22621tcacacctgt aatcccagca ctttggaaag ctgaggtggg cagatcactt gaggccagga22681gtttgagacc agcctggcca acatggtgaa accccatctc tactaaaaac acaaaaaaca22741gctgggcgtg gtcatgcacc tgttataccc actactcagg aggctgaggc aggagaatca22801cttgaatcca ggaggtggag gtggcagtga gccgagattg tgctactgca ctccagcttg22861ggcaacagag caagactccg tctcagaaaa ttaaaaaaaa aaaagtgatg atgtcagtaa22921agacccaaat cagggtcata tgtttaacac cagaaagttt gtatttgcta caagacagaa22981accttgacaa aataactttt ctgtgctttg ttacttcatc tgaatgaaga aggtaaacca23041gttgatctca caaatctctt tctaagggct tctggaattt tttttttttt ttaaacaata23101aaaggaaaga gacttcYctt aagcagaaca aagtccgact cctctgtaaa gtggctgaca23161gcaagtggaa aatggaagaa gaacaattac ctgcaaaatg actcattccc ttgtaacaac23221tacactacta gggaattcct tctcttaccg gctgtggcta gcgtcagact catgacaaag23281acctcatcct ggggctagaa ctaggtttag ggttttctca ttcattcctc tgtttctcag23341ctgcattttc atttttaatc tgtgcaatga ttacagaggc ctatgtttgg ttttcatttc23401tagtttcccc aggaagagac aactactatc ttgatattga ttaacacttg aaacttctgt23461taatcacaat ttcagtattt cagggaatca gagaaatcat ttggaagagc cttgaaggtc23521atccagggtg agagaaaagc aaagcacaag caacagacca atgtttagac acagtgaagt23581gaagRcctac aggagaccct ctcaacttca ataagagtct tttttatggc tgtcttcata23641ttctttcaaa gaaatcataa taaaggagtt agtgagagtg taaataaaaa ataggctatc23701atagagtgct gggtaactga gctaaaacta aagtaaacaa actcagtggg ccatcacata23761tgcaagctgg taaggtctca taaatcacca tgactgggta ttgggatttc aaaggcacac23821tctgtaagct ttctcccagc cctgttgatt caagctccaa ttgcactggg ttacttatat23881ggcagcatat aaagttgacc ttttaYgttt aaaaatagtt ccattcctca tccctcctaa23941ggataggcca cagtacctat catatgtccc caccacacta cataatttat gtaagttttc24001acttaatttt caacacaatc ctttgaggta gattatgtta gtcctSattt acagggaaaa24061cagaggctca gggaggccaa atttatttat ttatccaagg ttgcaactct actgtagggc24121agatttatat ccagaagagg aattgcaaag ctcctcagaa tttaggagat ttaaaatgga24181atcaagataa aggttcacat ttttcatctt ctattccatt ttactcttcc agcatctaat24241aataacctat gatatattag aacaaatcag cccatactta ttttgacagt ctcttttcac24301cccatttcag tttgtacctt gctgtctcag agcccatcaa ccacctttcc tcactcccag24361gcagccggtc cttcagggga tggcttggca gttggcccac catcctctgc taccagggca24421tgactcatgg aggcaacagg tgaagctgaY gccaactatt agtgctaaaa aagactcaag24481cctcatgaaa tataccatac ataaatcgct ctccagtcag ctctacccct ccctccattt24541ctacagctga ctgtctgttc ttccttaaac atttacatcc gccactgacc tgtctgggat24601ttctttttta cttcaaggYt ctcctaaagg ttcagtMcaa ccaggtttca ccaaatgaac24661cctgcggtgg aaaggggcag caacgggcat tggtcagttt gcctccagcc aaggaaagtc24721tgactcccct ccttctccca ctcttctctt tctctgcctc acactgccta atacgtcttt24781cctctttctc tctttctttc cttatatctt cattttccac cctattcaga agtgaaactt24841cccttgccac tttgccccca ctaagaaaac agacctccaa cacaacctct taaYaggcta24901attttaaaat catgaacctg cttacacctt ccgtgagttt atcctatatc ttctctatct24961gctgtctgct tcccactaag gttttatccc tccatcccac ctccaaatcc tttacagctc25021agattctcaS atctgcttta gtcacttggt ctcctcatcc cactgaccct attatccttc25081tgtgcacatg ttagagggca catgctcctc ctaggaacta gggccaggtc agttatgctc25141ccatcctgac atgacctaga gaacaaaaaa ggcaaaacga ggtactgtag gattcctctc25201taggaattat actttgctga aattgctctt gctattttgg aatctagtgc tcactaaata25261catttttaaa atattatttg gatatatttt gaaaatacaa ccagaggtcg ggcacagtgg25321cttacgcctg taatcccaac actttggcgg gccaaggtgg gcagattacg aggtcaggag25381ttcgagacca gcctggccaa catagtgaaa ccctgtctct actaaaaata caaaaaatta25441gccaggcgtg gtggcaggcg cctgtaatcc cagctgcttg ggaagctgag gcaggagaat25501tgcttgaacc tgggaggaga aggttgcagt gagcctagat cacgccattg cactccagtc25561caggcaacag tgcaagactc taactcaagg aaaaaaaaaa aagagagaga gagagaaaat25621acaaccagag aataaacact tgttcttcta tctctccatc ttccccacca atacaacatc25681cagaaaatag tcatctttac acttatttag aagcacatag atcttataaa aStttaactg25741agcattaggt tttcatcttt aaaaatattc tgaggctggg tgcactggct catgcacttt25801gggaggccaa ggcaggagga tcacttgagc ccaggagttt gagaccagcc tgggtaacat25861agtgagaccc tgtctctaca aaaaaaaaaa aaaaaagtta aattaaatta aaaaacagaa25921aagccggtct ggtggcacat gcctgtggct ccatccactc aggaggctga ggtgggagga25981tggcttgagc cagggagatc aaggctgcag taagccatga tggcgccact gcactccagc26041ctggttgaca aggtgagaac ttgtctccaa aaacaaaaca aaacaaaaaa cgttttgaca26101tgtagaatac tgtttctggg actaaattag agatttaagg tttgaggtat gagaaaatac26161ctggaatcat gccttacatt agaaggtaag gtaaatactg gtgtttccca atgagttgta26221gtcagattgt tcatatgtat caaacagaca atatactgaa atatttaaaa ataaggctaa26281atagcaacaa ataatttttc ccatgaattc tacttttttt tttttttttt ttgagatgga26341gtctcactca gtcgcccaga ctggagtgca gtggcgccat ctccattcac tgcaacctct26401acctcctggg ttcaagtgat tctcctgctc agcctcccga gtagctgaga taacagacat26461gcaccaccac acctggctaa tttttgtatt tttagtacag gccaggtttt gccatgttgg26521ccaggctggt ctcaaacttc tggcctcatg tgatcgacct cccaaagtgc tgggattaca26581ggtgtgagcc accatgccca gctgaattct actttttttt tttttttttt gagacagagt26641cttgctctgt cacccaggct ggagtgcagt ggcacgatct tggctcactg caacctctgc26701ctcctgggtt caagtgattc tcctgctcag cctcccgagt agctgagatt acagacatgc26761accatcacac ctggctaatt tttgtatttt taggagagac gggatttcac catgttggcc26821agctagtctc taactcctga ccgcgtgatc tgctctcctc tgcctcccaa agtgctggga26881ttacaggctt gaggcaccac gcccggctgc tgaaattcta cttttgaaag aacaaattcc26941ccttctgtag ggactgatga ttcagtctgt aatgatgcat tctcttcatc ttcttttttt27001gtcttttctt ctatatatcc tttaggcatt ctactgtatt aacactagat agaaaaatta27061agatttaggc ccaaacatta tcttctggca taaagtaaac taatcKtttc ctgatgtaca27121ataaataaac agacatattt ctagtagaag attccttatg atttatcaaa acccaattat27181cacttaccct tatggagatc ttagatctta gaaaccatac tgacaatata agattaagaa27241aacaacagaa aatcaaaata tataccaagg ataatgttaa taggtttcat ccttatcaca27301gcatactgtt gaaacttact tgaaatattt ttttaaaaaa gatacaagag gacaagtgtt27361tagtttttaa caagggaggg gactagtcaa caaaYattga ttacctaatt tatgaacagc27421tctggccaaa gtggtcaaaa aaaaaaaatt aggactttag ttttcctaaa cctatcttaa27481tttttaacag gattatagct ttgttcaatc tttacagtct ttagcctctt ttgtgaaatg27541ggtttccttg taaataataa aatgacacct atatatattt aaagcactca tgaaataatt27601ttatctcttt attaaaaact gtgataaccc ttccaatttt gaaatttatt gtcttcctaa27661attcttgcta caaagcctat cattaatatt gcagttcatt ttttccctaa agattgaaaa27721aaacactaac aaatataaag tctttatggt caaagaatgt actcctttta taaaacttgg27781agttgatgta aaggcacaga caacacaagt taccttaata ataaatgcac ttttctttgt27841aattttgggt aattcagtgt gatttgtaat tcttttaaaa gacacacaat cacttgtatt27901tttgcatggt tctttttttc ctaatttccc actatagtga aatatctgtt tttccttctc27961tattgggttt ggattggaat gatcaggtag aattaaatgt aaaataacaa aaggaaaata28021ctttatagat cttctcaaaa tactttgaag ggtataatct ctttaagatg gctttattca28081tatttaagcc aaaaacaaaa agcaaccaaa acactactgt ttatacaaaa agcagcttca28141aaatcagcca gttattttct gaaatggaga tggcagacat tagcctgcac ttactccaat28201atggcagccg catctttgcc tctttgctat ggacacatcc ccagcaggcc tgtacttect28261actctccaga cctgtttatg acaggccaag gtgtttccta ttatggtgcc tatggctgca28321cagtgcactg cttgtcagta ataaaagcca gaggctgtcc ctatagggat tacagtgcag26381cagaccagag atgctgatgg gaatgcaagc atgccctagg caaacattgc agaatactct28441ctgacaggca aaagccaaca aacacatcct ttcttcccag actagcaggg aaagtattca28501gttatgtcat tttcacttgg aacaaactaa taagaagaat gttattgcta aaataggtag28561agatgagaaa gagcagttta tgaccatgaa tatggcctct atggtttttg cctgtgcact28621acaaactttt aatttaaacg agatgagatt gatctagcat atactatgat aaaatttctg28681agacatgagt atctaaaagc agaactgaga ttaagtgaga aatgctcagg attcctgtca28741ctgaaagaaa aagaaaaaaa cctttcttga aaggcacaaa gtagaatgct cagactctcc28801atctaccaat acaaggtaaa aaacagcatt tgcattaacc aacatcatgc attcttgtac28861taatttatgt gactaactac aaaatgttat attgacactc actgtgtagg gtgtcaggat28921ggccaagtgg tctaaggcac cagacactca ctgggttggg ctaaaaacac Ygtagaagac28981ctcatcagaa caataaaaca gagacacaaa atattgtact aagagttaag agaattacaa29041ataaaagttc tgtggaaagt caaaggtatc caattaggaa agcctgaggt gggagacata29101ggacacccca gatataggat gggaagaaga tgggattaaa aaaaaaggct ttataaagga29161tgtaacattc cagataggcc ttaaaagatg gcttcgatct tttaaataaa actttttgtt29221ttagaacaga tctagattta cagaaaactt gtgtagacat tacagataat tcctatatac29281tctacactgt ttcccatttt taatgtctga ctttagtatg gcacatttgt cacaattatt29341gaaccaatac tgatacatta ttattaaaca aagtccacac ttcattcaga tttccttagt29401tttcacgtaa tttccttttt tctgttctgg atcccatcca ggataccaca taatatttag29461tcctcatgtc tcctgaggct cttcttggct gtaggtatct caggttttcc ttgtttttga29521taaccttgac agttttgagg agtactggtc aaatactggt caagtttcga gggtagaata29581tccctcaact gagatctgtc tggtatttgc ctcatgatta cactggggtt atatgttttc29641agtagggaaa ccacagatta aaagtgccat tttcatcaga tcatatcgag ggtacatgtt29701atcacttatc actgtcaatg ttgaccttga taacctggct gaagtagtga taggWttctc29761cactacagtt tctttttttt ccctttctac actgtactgt ttagaaggaa gtcaatatgc29821acagctcaca cttacggtgt agggggttat gttctccctc cttgagagta gagtatctat29881agaagttatt gggaattccg cacaggagga gatttgtcta ttttccccca cttaggtatt29941tatttaataa attgtatcaa tatgggttta tggatattta ttttaccctt tgggatataa30001tccaatacta tattattttc ttgctcaaat tgttctagct ttggccattg ggagctcttt30061cagtttgctc ttgcaactct tcagtatatt cccacgggtg tagggttcca tttgtttgag30121caggtcctta ctttttggca ctacaagatg ctccaggctc atcttacata tttccttcct30181gagtccctag aaatcagcta ttttttttca aagagtcttg gttcctttta ccagagaatg30241gtattagaaa ccaaaatgag ggtgctaagt gtgctcattg ctactggggt atggtagctt30301ctagaccctc tcggctgata gagcaaggaa atatttgtgt gtatactaga tggtaagatg30361ttgagaggta gaatggagag ttaccttctt aatatacttt tcttaatatt aaatattaat30421aagatattgt gtgcctgggt tactttcagt cttatgcaga ggaagaacgt atgtacattc30481atttatgaaa aacactggct agactattct tctgcactgc attatgcatt tctgctagaa30541aaagctcaga gattttcaga tattctgaca aaaatctcag gcttgcttga tgagctatac30601tgtaaaatta cagaaggaaa caaagggcaa actccttgaa ggatgaaaat aaaggaataa30661aacatataaa acaccaccaa aaaaagtgat taatggggga gaagagtaaa taaaacatta30721taatagtcct ctttggttag tatcaatatt attaggtcac tttatcaaaa ggatagaaat30781caggatggca gacacccttc tctaaccctc accccccaaa ataataaaat aaaaactaat30841gttattcctt cacatatgga aatgaatgag ttctactgag tatctagtat gattcctgac30901tcagtcgaga caattcccat cttttaattc attaaatcac cacagcaact atttaacaga30961tgagaaaact gaagcacaga aggcaacRtg gcccaattta cgtttggtaa aaggcagaga31021atgaatccaa ttcaggcagg ctgtctatag tagggtgctc taaatccacg gaccattctg31081cctaaggaat gaatatttta tgaattggaa tatttctgct gaacgaattt gccattttct31141cctctagtgg agaaatccaa ctgagggtaa agaaggaaaa atgttgattg tttaaaacaa31201taaattagtc tctaaattgt tcttgcagct gatttagact agtgtgtcca aaagtatgcc31261cagtgttagt aaatggtagg caaaatgctt taaggtggtg caagatgaat gttttctcat31321tttgttattc attaatttta gaaaaaatac agaaaaaata taacttgaac atcaaaccta31381tgatttcatg tataccatta cttaagatga ggcacttggg tgagtattta gatttaacaa31441taagttgctc ttagcatttc tatactttga caataaatta tccaaaaaag aaattaagaa31501aataatccca tttgcaatag catcaaaaaa atacttagga gcagccaggc gtggtggctc31561actcctgtaa tcccagcact ttgggaggcc gaggcgggca gatcatgagg tcaggagatc31621gagaccatcc tggctaacac agtgaaaccc catctctact taaaaataca aaaaaaaaaa31681aaggcaggtg tggtggcagg cgcctgtagt cccagctaat tgggaggctg aggcaggaga31741acggcgtgaa cctgggaggt ggagcttgca gtaagccgag atcgcgccac tgcactctag31801cctgggcaac agagcgagac tccatcMcaa aaaaaaaaaa aaNaaaaaac ttaggagcaa31861atctaaccaa caaggtgaaa gatctataca ctggaaacta caagacattg atttaaacaa31921ctgaagaaga cagaaataaa tgaaaagata tcccatgttc atgcactgaa agaattagta31981atgttaaaat gtccacacta tccaaagcca tctatagatt caatgcagtt cctctattga32041ttcaatgcaa ttcctttcaa aattccaatg tctttttttt tcacagaaat agagaaaaaa32101atcttaaaat ttatatgaac caaaaaaaga cctaatagcc aaagcaatct tgaacaaaaa32161gaacaaagct gcaggcatca tattccctca tttcaaaata tattataaag ctactgtaat32221caaaacagca tgttattgac ataaaaacaa acatcaacca atggaacagg atagaaagcc32281cagaagtaaa tccaagtatt tacagtcaat tgatttttga caaagggtcc aagaacacac32341aatggagaga ggacagtctc ttcaaatagt gttgggaaaa ctggatgtcc acctgcagaa32401gaaagaaact gtactcttat ctcacactcc atataaaaat caactcaaaa gagatataaa32461ggcttaaaca taagacctga aactgtaaag ctactagaag aaaatataag ggaaaatctc32521cacaacaatg gtctgggcaa tgatttcttg gataggactc caaaagcaca ggcaactaaa32581acaaaaatag acaaatagga ctacattaaa ctaaaaagta cctgcacaag caaccaaata32641atagagtgaa aagacaaccc atggatcagg agaaaatatc tgcaaaccat acatctgata32701agaggctaat attcaaaata tataaaaaat tcaaacaacc aaatagtaag aaaacaaatc32761gattaaaatt agRcaaagga tctgaaYaga cacactttcc tcaaaaaaga aatatgaatg32821gccaacagag atacaaaaaa aaaaaaaaaa aaaaaaaaca atgttcccca gccctgcaca32881gtggctcatg cctgtaatcc cagtgctttg ggaggctgag gcaggagatc acttgaggcc32941aggaattcta gacaagcctg ggcaaaatag caagaccctc tctatacgaa aaaataaaaa33001gccaggtatg gtggcacaca cctgtagtcc tggctacttg ggaggctgag gcaggatcat33061tgagcccgag aatttgaggt tacagtgaga catgatcaYg ccactgcact ccagcctgaa33121caaaagagca agaccctgtc tcaaaaacaa acgaaaactc aacaatatct ctaattctca33181gggaaatgca attaaaacca caatgagcta tcacctcatg cctgttagaa tgactatttt33241cctttttttt ctcttcaact tttaagttca ggggtacatg tgcaggatgt gcaggatgtg33301caggtttgtt acataggtaa acatgtgcca tgtttgcttc acgtatcatc ccatcaccta33361ggcactaagc ccagcatcca ctagccattc ttcctgatgc tctccctgca cccatcccac33421ccgccaacag accccagtat gtgttgctct ccaccatgta caatggctat gttcaaacag33481atgaatgata acaagtgttg gcaaggatgt ggagaaaagg gagcccttct acactgttgg33541tgggaatgta aattagaacc accattattg aaaatagtat gaaggttcct caaaaatcta33601aaaatagaac taccataaaa tccaacaatc ctacttctag gtatacaccc aaaggaactg33661aaattggtac atcaaaaaga tatttgcact cccatattca tttcagcttt atttacaaca33721gccaagatat ggaagcaatc taagtgttca tcaagtgtgc ataaagaaaa tgtgatatat33781atatatatat atatatatat atattatata tatatatata tatatataga ttatacaggc33841cgggcgcagt ggctcagatc tgtaatccca gcactttggg aggccgaggc 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atgacaaaat34741cccagcactg tgggaggccg aggagggagg atcacgaggt caagagatcg agaccatcct34801ggccaacatg gtgaaacccc atctctactc aaaatacaaa aattagctgg gcatggtggc34861atgcgcctgt agtccagcta ctcgggaggc tgaggcagga gaattgcttg aacttgggag34921gcggaggttg cagtgagctg agatcgtatc actgtactcc agcctggcga cagagcgaga34981ctctgtctca aaaatgacaa agtttgagca acattaattt ggactgtaaa ttcttaaaga35041atagaaaagt catgtttttc ttctaagaaa tattatgttt ttacattgca agaaatatgt35101gacacagagt ttttcttaat ctctcttttt tagtatattc tagacaggca agcacatgca35161atttattgag cacccagtgt gtgctaatgc accaaacgga gctttacata cattatagct35221aatggtctca ataacttttt cattttattt tcccctttca ttatcgccac ttataaatga35281aaaaactgag ctccagagcg gtaaggccta ttgcccaaaa tattagatag gaaacaacag35341agctggaatt tgaaaccaag tttgcctaat gaaaaacatt tatgttcttt tcactgtaca35401aagctgctgt aagtatcact ggtgcctact ccaggccagg gagtaaatat cattcatcct35461tatcacatac aaagtataac aaaacaaaaa caagaagctc tgaatactaa ataataataa35521taaatacttt ataaaagata aactattctc taagagtaaa agataataaa cctattgtca35581ttgtagttgg tcactgaact taactaattt cctaatggac gcagcagaat tgtttgttgt35641ttaagcaaat atcaaggcat accccccaat ccctgttaca gggaataaaa aaagtcttct35701tcaaatgcct ttcaaaacta atgtgaatat taaaataaag tgctactgat ctctctacat35761tctagaaaga tctcagacta acagtgtcaa ttaaactatt acaacaaata gccatgtaaa35821aactgctccc ctactagagc tacgctatca caaaattaac cccagcaatc tacagttcta35881gaaaaagagt tggtccctcc tgctgaaaaa gagaaaacca aaccctacat attttgtgaa35941tccactgaaa ataatgacat aaacagcact gcacatccat catgtattta tatcttaagt36001gatagctaca gtctatgtaa ctatcgcaga aatcttctta aactgaacaa aagcattatc36061tatcatcctt tctctctaga aaaataccag tttgtttaat ctacccataa cattagaaaa36121aatacttctt ttatcatggg caatccttat gtttcggaat ttttttcgaa aacgtagaca36181gttcataatg ctctcagaca gaagttacca ctactacccc aaatattaag tcaaaatgta36241actgaaaaaa agaaatttat ctagtaatga ttaatttatt gaataattaa aaattaggag36301tttttgataa ttaaatgttg ggaataatta aactttcact aaatactggc acaggaactg36361aacggatgac aacagagaca agttaagatt tgttttaatc ctaagtttta tgctaaggta36421acatcaaggg ctctactttt cagtgaaaga aaaatttcct ttaaaattgt ttccctcttc36481cattattact taaaagcaaa gaaagtattt tttctaacag tgattatagg attctcaatc36541tttcatatta actttaaggt actacatgta agctacataa atctttccca aatctacctt36601tattgagtag atgaaaaagc agatatcgaa ctcaaaacat ctaaatgttg attttctata36661attatagaag atattttctt ttgaaattta aagtttgtat ttaggcatat taacactttt36721ttaatctaag atttaatatg ttaatgtaga aaacaactga ggctgttttc tctctataaa36781actaacatgc cttttccaat taacttagtt tccttcttag caaaagttta acatttatat36841ctgttgagtt acaYtgtagt tgcataatgt ggaaatatct taagatttag ccacttctat36901gaagatccta tatttgttat aacacccctc ttgcccagaa gaaaatacat caacaaaaag36961tcctactata tgttctgcat tgactattac aaagcagtag ggggagcagc cagagaaagc37021tctgagacaa agcacccagc aaagcaattt aatttatagg caacagaaac atgctagaga37081ggtttgccaa aagccaaata cacaaaataa attccataaa gaagtcatga ccacatttgt37141aaagctggcc taagtatatt tggaatgaag tatagaaaaa tctgaagtct cttagaaagg37201gtctggattc taacttcaag acagactttc agcttgaaac acagtcattt ccagccatgc37261caaacctcaa actgccccca aaattagagc agaaacaaaa tacattttta tagtgatatg37321tcttgggaat aactcaaaat gatttcgttt tctcctttga acctcactga acttacaggg37381aaggcctggt gaaatgtgca ttattaggtc acaagaggat aacgttacag ggttccatag37441cataatcctt gaaagccctg aggcccaggc cgctgtcctg ctctcctctc tactgactcc37501catcctcaat atactttcca tgagagaaag gtaaccaaaa acatggtgaa actattctgc37561ttaaaaggtg ttttactgaa aaggcacatt gaccactaac ccttattaca tttcacatgt37621tctaaaaatt agtaaggtct gcattttcag ttttagagta aaacaggaaa agtacttagt37681tagctcttct gtctggcatt ctgtaactgg aatttaagaa aagcctaaac ttctaattag37741aacttcagaa tgttcatgtc tgtattatac cacaaaaact gtaaatataa tttaagcatt37801tttatgatac agaaatgtgc gctatagaca gttatctaag aattataaaa atccatcaaa37861cttgaagtgt ctggtataaa ttacaaccga atggtaaaaa gacattttag ccacgtaggc37921aaccaatgaa gtttgaccta aaacccaaat aatagcaata acaacagata cagtgcctac37981tattgtcaga tactatatta gctagctctt ttgtatatat tctttKgaac tcttacactg38041acttttcaag atagttatta tggtgcccat tgtatgctaa ggaaactgaa gctaaaaaaa38101attgaagtca tttctctaat gtaactccat tagcaagaaa caaaaccata attcaacttc38161caggtttgcc tgcctccaaa gctttgagac ctcactaaaa ttaccctcaa ttgtagcaat38221gaggttccaa aggaaatctg tacaaatctc aggcagatta atgtgcttat aagggtaaat38281gccatagatt taatcactca aattaaatgc catctggaat ctcttaccct acttggtaca38341agcatcctac atgtgttaca gccaacccta gccttggcca agaattcaat aattttYctg38401cttcaatgcc atcaacaagc aagaaacata tataatacca atacaggaaa tacagctagt38461tgctcctaga gcatcattta aaagctgcta attggctaag atgcctttta ttgagaagtc38521taagaaacag aaataatgtg ttaacccagt ttgttaaatg ggtttgagga atcagtttcc38581tccttcctaa tacctaaatc catctccata ataagtattc tctatcacca tttaaaaatc38641ctgatctctt actagtgttt ttattgtgct tttcaatctR ttagagtaaa ttttttaaaa38701cctcaagaga gaacacagaa aactgtcata atttttcaaa ggctaaagga gaataaactg38761aaaatatcag tttgaacacg tgtatgtaaa aagaatggat ggtaataaaa ctaacaactg38821aaaagcaatg tttctgactc attcattcat actcaagaaa tatcaaataa ctgagtggag38881atgatgcaag ctgtacacat ttccagttca gactgaaggt gtggcaacac tcacaggggc38941cttccgatca gctgctccaa ctcagtttac agcttttgtg gatgtggctt attcatgccc39001ttgttatgaa gaagaagggt aactttacaa cctttagcaa gagctttttt ttctttctgt39061gctaaccctt ttttgtctat aacagtcatg taagcttagc actgatttag aaataaataa39121gttaaagaag acacgaatgg cttggacatt aaaagtttaa gcaacagctt aagctgagct39181aagtttaatg ttaaaaatta gtgtgacagc aataattttt caattcagct ctgtcgtggg39241ctaggaaaaa atatcctaat ttttcagcca caagacataa acattgctag aatgactaca39301ttttgaaaaa attatcttct cactttacct agatttcatt ttaaccaaac agaccaacct39361ctcctattaa acctgtaaat taactcaaag tctaatctgg ggccttcata ataaagattt39421tttttttaaa tccctgtctt atctggtgcc tttaaaagaa aggaatcatt ttaggcaatt39481attatgacct aaaaaatttt taaatcttaa cgtatagatt aattccttga cagctgaagt39541catttacaat acattattaa atttcacatt cagttttaaa tccaaacata gatctcaaca39601ttaagaatat ggattttagg gaaagYaact agctgctcaa attcatttag ctgaaaaact39661actgtcgaat caccttgaaa aYatacacta atgcttgcac attgctaagK ggcttttgat39721tctgctcttc attttcttac acagMatcaa ccacacaata gaattaagaa ctcaggccca39781tggcaaagtg ctcccattta gcagttagga cactggacat attcagcata tgtctactgc39841tattgagaat caaattatga aaacaaacta tattttataa aactaagaat ttgttactca39901Ratgagaata aaggtgccta atgcYacagc agggggtaaa agtcccagta agagagcaat39961aattggtcat tctgatgagg agctgtgcca aatttagaaa tgaggcacaa atgacaaaaa40021aattgatcat cagtgtggac atgggtaggt cagtgtgcat atgggtaggt tagtatctgc40081tggccgtgtc tacagagccc cttttattta tttgaagcca acttttcact tgacaatgct40141acctacaaaa gcactgttaa tagataagac aatcaagtgg ctgttatgcc gtggcctttt40201tgtaaaaact gcatgagaac aggtgggata aaaaccatag aaaggtagaa aaaaaaaagc40261atcactcatt taaagatatg tgcacataga tgaactgtaa gataatataa ccttcttgac40321cttgtaaata ggtggccaaa aatacttaaa tatctKgacg aggcaactat tactaattgt40381ctcacaacat taYcagtcct tactggctga atccttcagc catctgcata cgacatgcac40441aggcaaatag ccactaaaaa catacacaat tccaattatc tccttgcata actaaagaca40501aaaagaacag gaaatccaaa aaatacagca aaactgaaaa cactatacct tgccttccgt40561gctattttaa ggctgtccca ggctgaaggt tacttctcag ccctcaaaac tccattaact40621gccaagacca gcaccttagc acatatggca cagatgccta gttgaagcct ccttgtacta40681aatgacctca aaaaactggg ctttctttcc aagattaatg gaaacaaaag taatgatcat40741aaggaacctt ctaactctgt taatgtttcc tgcggatatg tatggccaac tgaatatata40801aaggctcagt tcttgcgggg taccctgaca actagatgaa ttagggtgaa ggttccaagt40861tcgatgaact cttctgagtt tgagtgccct aggtggtgac attcaagtga tttcacagac40921atccaccaat tcttattttc aaccgggaat cccaagaaca cctttaaaca tgcaatgccc40981atggacccta ctgggtttct gctgcaaggg ctcagtgtta cttaggaacc ctgtgtcttg41041ggagatactt aaatttagca cgtcaaattg cttttggaaa atgtttatct ggcgtgacta41101ggggaggcaa agcaaggaaa caggaacctc cctctaagga gcagaatagc caacatgcag41161taagcctaaa aaacctctca atttatttcc cggggctatg ggtaccagtg gctcgccggc41221atgggaatcR gcagcctggg ggcaccagtg acagcagaac cggggcttac cttgttggag41281gccatctcac tgacggagtg cctggtctgt agggtctcta gctggtccag acaccagtcc41341agctcctcca gggtctcgct ggccagtttc tggtaggcct cctctgcgaa gagacaggga41401aagggggact cagttctcaa gcgcttcacg ggtccgctag cgagttcaaa gggggccatc41461ctgccatacc ccgccatgct cggatgcccg gtgccggcac atgagggctg ctccttcata41521ttgcccagcc cggcagtgca acgggggcgg aggctgtgct cgcggggcgg ccggcctcgg41581ggaggcacgg tctctccagc ttggcgtctc gggtcggcct ccagggaggg cgtgcaaaga41641gcggcgagcc aactttcaca cagcgacgcg agcggaaaaa ccactatgcg acttttcaac41701tgtgcggcgg gcccgagtcc cagtccagga gcYcggctct agcggatggc gagggggtgg41761cgagcgcgct tgggtgcccg ccccgcagag gagcgtctgg tccacagccg gatctcctcg41821gtccccaacc cggagccgcg gccccacgcc cgccccgcct gccgagcctt ctgcacKgca41881cttgaagtga atgaatcagc cgcggccggg tgcgcggcca ccacgtttcc tgttttcttt41941ctcaactcct cgggcggcag gcgcagcgcg gctccaacgc cgcagctttc cgggaacact42001ccccctcacg cccctctcgg ccctcggcgc tgcctggctc ctcctcaacc cccttacgaa42061aagattccga attgcaaaag cctgtccctg tccgtgccac ccgccgcgtc cttcccctcg42121agctctgccc cgggggcccc gccacctcgc agtgccatcc ccccggcgca gccgggcgcc42181actcgctttg aagtgcagac gaggaggcgc gggcgcgagc gtgtgtgtct gtggggctgc42241tgtgggactg tctgtgctag gagagcggcg gaaaacccgg cgtggagcgc ctgcagtccg42301ccgtccgggg tcgcgcccgc cgcggggctc aggagggacc ggcacgcagg cgcgcacggc42361cgcgcacctg tctcgctaga accccgcgcg ccccgccgag ccactgccct ccaggttgcc42421cagaccgctg gagcctctgc gactccacga ccggctgctt cctgcgaagt ttcacaaaca42481aggttattta ggaccctcaa ggtttctgag ggtttaagtt ttagggtttc tgggggttcg42541tttctaaagg cttaggattc acctacttca aggaggcagg gttgtgggaa ttaagaccgc42601attctttttc tacccagccc agtccctact aagtaccaga cttctaaatg ttggggcgga42661cagaaacaag caaacaaaat atacaatgtt gtggggtcgg aacgctttat aattcacaaa42721tttgacaata ggctgcattt tcatatgccg aattgcctaa gagttctctt aaaggaacag42781caatgtgaaa gaaccacatg gtaaggagaa tttacgcatg tcctgcatac taotcctttc42841ccctgtgaat tgcataagac ctagatgatc ttgggccaag gaagaaaatc tggaagggtg42901tttctaccca ccatgtgcag agtacactac aattttgaga aaacggaaag accatattca42961aaggcataca gaaaagcctg ttctgtttac aaaggctgac ccagggcacc agggacactg43021tccctaagca gatcagttgt gggagaactt ttctacatta gcatgcaata agcaaaccat43081tcatagtgag gagaagtcaa actcccaagg gtccatttga taaaactttg tcattgtcga43141gtggaaagaa gatactgaga aacttacact aagtggtggg atcccttgtc tttgtctttg43201aatctacagg tattggagaa gaaattctgc ccttgaaatt tagactccat aaattaacat43261ggcacaacaa ataaagttca tggactgaat ttaggctcct gggatttttg agatagcttt43321ttatgtgaac tttgtaaaag ttagagtaac ttttaaagta gttgttacat gtgccacgtg43381gcttattgtt atcaagaata cttgaactat ttactgttca ctttgagtac tctaggttaa43441aatttgcctc ttttttgttc tacttcctcc accccgcagt ctatgtaaat atatacttta43501gatggacaaa caactgccta aaccttgcca ggtgaattaa agtttcagat tgaaKctttt43561ttttccccct taacaagctt aaagatatta ataattttaa atggtaaata taaaatacct43621gctctgtata gcttccccaa ttctaagaat gtaaaaaata ttacatgctt gttataaaaa43681ttgaagcatt acacacaaat ataggaagtc cattgtaacc ccacacccta aagatcacaa43741acaatacttt cgcctatggc tctaacacaa tcattttcat tttactgaat aacttccata43801tgcaagtata gcatcaccta gttgccatgg tagtgcatct actatatggt ttggttttga43861tattttcctc tctctctcat tcccataata taggaatgta ggaaatttta agaggacatt43921gacttgtttt atgatcattt gagctgtcca tagttagcct atccagtgga ttaaagatgc43981ataaccattg tgtctgggat ttgttcagtg ccatcttttc aatcattggt tacaatgaag44041ctgggagtcc cctctgaggt tcggcKttct gtggctcctc tcccctgcac tccaactttc44101tcaaagcctg agcctcaagt gatttcccag tagYtaagta aactgccccc ttcctccatc44161ttcaccaagt tcccaaagct Kttcagactc aggcttcaaa tctaacagga tgtggctcca44221cacattatat ttcagttgtt attttttaat gtggaaaata attcaggaaa gttttggcta44281atgcttcaag acatcatgca ctttatacac aggatttgtt cttaagaagg tagtatagtg44341acaggaggaa caatttactt cagaatatcc attttatgtc caagccatgc accagccact44401tttgacagac aggatttgag tatgatgata aaatggggta agcatatatt ttaagttcta44461acatctgtat aaataagaaa aatgaaaaat cactggaaca catctacatg ctagtgagaa44521aataattact aacagagtaa agtttgctct gtgaaactgt tgctcaaata aagaattatt44581cttgatatta gcatagagct gagaatattg cttttttcca aattcctagg tgagtaggca44641atatagctag ccacgatttt tcaggatcat ttgtaaagct tcacttttag gaattttaac44701cccaagtgtt ctaagacatc aagtaactga ccttttcatc ccgccgaaca aacctcaaag44761tggagttgcc aactatccca caggaaattg agtcaccaca ccaagcaaca cacctaaatg44821tcgacagcta gcaggacaaa aacagtgagc cagtttaatt ttggctttta ccaagaacac448B1atactgcatt cattaataaa atacttcccc tcaacccctg ccagagtagt atacactgtg44941gctctcctta aaaatacatg aaaactcttt aactgcacca aatcttgcta agtcaaggaa45001ctaaacagag aaaaacaccc aMgcaaaaac tattggctaa actccctaaa ggctgggaga45061gggctatgga acagcaactg agaaataaat tgagccttga aggcccctgc tacaacagca45121tcagttttct tcaaggcacc tttgaactat gtaacacccg cattctgctg aggctcttct45181gtgaacaaac agtcctcaat tcttgdgggc cagcacttgg cttctgtcac agtgatatgc45241ttagaggttc ccctgacaca tggcctgaaa ctgtgccagg ggctccagga gaagatgctg45301aagaagcagc ttccttttga aaaaggaaaa aagtaatcac ctcagagcca cagcagttag45361ctagaggttg aggtcatttt ttgtgaaatg ttcagtccat tactcttacc cacaactcac45421agtgatgttg accattgagg taaaaggatc cactgtacgg gatgtgtaac tatgtggaca45481ttagtttctt tgccaacact tgaaggtctg ctaaaggact gtatcggctt gtcaeaattc45541ctagatagac ctattggtat acatgaagag aacaagtcca aaaaatacca cttattttgg45601acactatttg tatgccctta atttaaaaaa aaaatacaaa ttataacagc tgaggtcggg45661cacagtggct cacgcctgta atcccagcac tttgggaggc caaggcgggc agatcatgaa45721gtcaagagat caagaccatc ctggctaaca cagtgaaacc ttggctctac taaaaataca45781aaaeactagc cgtgcatggt ggcgggcgcc tgtagtccca gctactcggg aggctgaggc45841aggagaatgg cgtgaacccg gcaggcagag gttgcagtaa gctgagattg ggccactgca45901ctccaacctg gacaacagca gaagactccg actcaaaaaa acaaaaaaaa ttataacaac45961tgatccagat tttttttatt attacacttt aagttctagg gtacatgtgc acaatgtgca46021ggttagtttc atatgtatac atgtgccatg ttggtgtgct gcacccatta actcctcatt46081tacattaggt atatctccta atgctatccc tcccccttcc ccccacccca cagcaggccc46141cggtgtgtga tgttcccctt cctatgtcca tgtgttcgca ttgttcaatt cccacctatg46201agtgagaaca tgcggtattt ggttttttgt ccttgtgata gtttgctgag aatgatggtt46261tccaatttca tccatgttcc tacaaaggac atgaactcat cctttttcat ggctgcatag46321tattccatgg tgtatatgtg ccacattttc ttaatccagt ctatcattga tggacatttg46381ggttggttcc aagtctttgc tattgtgaat agtgccacaa taaacatacg tgtgcatgtg46441tctttatagc agcatgattt ataatccttt gggtatatac ccagtaatgg gatggctggg46501tcaaatggta tttctagttc tagacccttg aggaatcgcc acactgtctt ccacaatggt46561tgaactagtt tacagtccca ccaacagtgt aaaagtgttc ctatttcttc acatcctctc46621cagaacctgt tgtttcctga ctttttaatg attgccattc taactggtgt gagatggtat46681ctcattgtgg ttttgatttg catttctctg atggccagtc atgatgagca ctgatccaga46741ttttttaaaa ataaaagaac tacaacaaaa agctcctaag agcaaatact taaatctccc46801taaccagttc cagcttctct tctcttaatt cttacaaaat ttcccctttg ttctaMggaa46861ggaattgata ctgtctacag tagatagaac tggaaaaaat gatttctgtt tcaccgtgta46921ttgctttgag ctagtcattc ctttagtttg ctacagtaaa agatttgtgt aggttaggtc46981taacttttgc tgacttaatt ttttttcctc tatacatttt atctgatggg aaatacatga47041aggctttgga ttctctttca atgtgtacat gtaataggtt taagcagagt ttgctagtgg47101caagctgctc tcatctccaa gtgtatttct ggcatcaaat tattgttttg aagtatttta47161aaattgtata aaatatataa aactttattt agtacttcat aaagcttcca aaggaaagat47221gtgtgcaatt ttgtgacggt tttctttttc ttttatcttc tcactaacta caattgtttt47281tccgaatgtt gcctatgcct ctagtagaat ttttatatga aataaacatg aggttggctt47341tcattgactt ttagtcccac cagtaactca acatttattt agcactgact atgtgccatg47401cactttatta gaggctgcag aaacaagatg atgaaaagag tgtgtccctt acccagagtc47461cagcagagga ggtaatttca gcaaacaact gtagagtgca ctctcacaga aggaagcatg47521tgggctatgg gacagtaaaa gaggactatt taaatcagac agggacagag gtggagtggg47581aaaaggctga gtcctcaaga atgaaataaa agagagtggg aaggattttt aagagaaaag47641atgagcaagc acacagacct atgatgaaca agatgtctgt gtcggccagg cgtggtggct47701cacgcctgta atcccagcac tttgggaggc cgaggtgggt ggatcacctg aggtcgggag47761ttcaagacca gcctgatcca catggagaaa ccctgtctct actaaaaata caaaattagt47821cgggcttggt ggcacatgcc tatattccca gctacttggg aggctgaggc aggagaatcg47881cttgaacctg ggagatagag gttgcagtga gcagaggttg cgccattgca ctccagcctg47941ggcaacaaga gcataaaaac tctgtctcaa aaaaaaaaaa aaaaaaaaaa aagatgtgtg48001tgtcaaaaaa gaaataacca tgagtagggc cttgcttagg ggaacagatt ctggagaaat48061ctgagaaatc ctcagccact ggccatctca aagactggcc atgtcaggca tctgcaggta48121ggactatatc ttcaagagta ggagtcacag agtgactcag agtactgtgt gacatgggat48181ctgattttat tttatatgga aaattctagt gctatgcaat taatggaatt Kaagaaagta48241aagttgaagt cagtgcaacc attatctttg accatattaa gaataaaatt aaataactta48301tagaccattt gcttctctga cgattattct tatctaagac aatctctgta ttaaaatcct48361acgcagacat atgttcccac aatatgtcag gtatgaacag aaggactgcc caatgtgact48421tgaaagggag tggacttctt gctcttaaaa actacaacct tgtagtcact aacttattaa48481tcatactgta ataagatgga gaaaaaaaca atggaattca ccagaatttc tttcacgaga48541gtctgcctgc attaaaatgt tcgataaagc tatttatgac agaaggtgag actttgaaga48601gctttggttt gggtggaact aatctgtgcc tcatctacac aggaaagggg aggaatatgc48661cagttgctag agagggaata tgtatgtgtg tgcatgtgtg taagcgcatg agagagcgag48721agaatgtgtg tttgtgcaca tgcatgtgtg tgtgtgtaag agaaaggagt cagcttggtc48781tctgtgtgtg catgtatgta agggcatgaa agagtgagag agagagagag aatgtgtgtg48841tgtgtgtgtg tgtgtatgtg tgtgtaagag aaaggagtca gcttggtcta aagggtaact48901ccaatttgta catttttcct ttctcccaat catcaataag gttattgaag atgtgtgtgt48961gtgtgtgtgt gtgtgtgcat ataagagaaa ggagtcagct tggtctaaag ggtaactcca49021acccgtgcat tttccctttc tcccaatcgt caataaggtt actgaaggta caaaatcccg49081acttgttttg ttttgtttta ttcattgaag ggactgagct tgaaggccag attggcccaa49141gcagaaatgt ctctctgagc tgacataaga gaagagtcaa agaaagagga gaaagctttt49201ataagaataa ggaggccttt tgtccaaaaa attggagttt gagctaagtt taattaggca49261tctaggttgg gggcttcatg tgacatgtgt gcaactgtga gtgatattat tctttgaaag49321aaactggaag agtggagaaa gattccaatc tctattccac ttcatacaag caattccagg49381caattcagct actaatcttt ctagggcctt atttcaccta tagattggag ataataacaa49441gagccttgta agttatttta gttcaagtga gaggttgtga gttaaataat cttgcattga49501ttgcctaata gattcttttc ccttcctcct ccattgtatc ttcactttct cctggactca49561agtctctaac ttaaatgcaa acattctatt aattttagtg agcctatcaa ctaataccta49621ggtataacct cggggtccag aaacttaata gWtacctgga acagttttta gggtagttag49681aaagaaaaaa gaatttcaag gaatgaacag ggattcattc tgaagaagtt cacttagaga49741acacaggcca ttcaggaagc tacaaacagg tagggatata aagtttagat cagacagtgg49801acaaagataa agatggagaa ctagtcttgg aggacttgta tactattcta agacaatatt49861ttcttctaaa gaggccatta aaaatcttct aagtgaggaa gtcacatggt cagatttgct49921tttcaaaaag attactctgg gaatagtata aaggcagatc agaaaagtaa agaccagtta49981agaggttggt gaccagataa ggagaaaatc ctaagcagtc cctgaagggg aaggagaagc50041tgcagaaagt taggaggaaa aactctcagg agcaaagaaa aaggaaatgt caaaggaaaa50101tattgttatg gactgaatgt ttgtgtctct ccaatattca tatgctgaaa tctaatcccc50161ggtgtcacgg tatttggagg gaaagccctt cggaagtaat taggtcatga gaatggagcc50221ctcatgaatt agattcgtgc cattataaga agaggccaga ggttgctctc tttctaccat50281gtggatacat gctatgtggg cagtctgcaa ccctgaagat gccctcacca gaacctgact50341atgctgacac cctgatctca gacttccagc tcccagaact gtgagaaata aaWgtttgtt50401gtttaagcca tcagtttatg gtattttgtt atagcagctt gagctaagac aaatatcaag50461gctttgccat tgatattcag tacagaccgt atatacccac aggtttgcgc taagataatt50521ttcattccaa acacatattt cagcaacaca agactaaaga gggtgttaaa gaatgctact50581gaggaagctt ttgtctggga agttgtttga acaaagttac aggacaattt ttgcaaacag50641gtttaaaaaa agttacaatt atgtatgcta tttacgtatt cttgttgtaa ttttaggaat50701caattttatt tccctggggg gactgtagga gagcatctgt gtttccatca tatactatca50761atcttaggat ataacagtct tttgttcttc acctttgtca attactgcat acagtattcc50821ttagagaaaa caaggagttt gaacagatta tctttagcac ctacccagct ctaacattca50881tttattatct gatttctgaa attgtactat ctgggttagg tgttggtttt aaggttgttc50941attatagtta gcctggatgg ggtcagctat gtttgtagag ggaattccta aactgaccag51001ttacttgtca aggatcccat ccaataccat gatcctggaa ttctgtgagt ttagctcaac51061tgttcttcag gggtacatgt tttctatttg aaattgaggt atYctcagaa ataaagctat51121taataaatag aaagttctgg agtatattta cactcactct gcttatctcc actcctaccc51181ctaccatatt cccatccaat actttgccag ttgacttacc aatttcttct taatttctgt51241aactgtcacc ttcagtcaaa ttctcatctg tgtatttcta gattcatata atggtctact51301actggatctc cttggattca ctttttctca acacagtcct atttataaag tcagaataat51361cttccttaaa ccctggtttt attgtttcat tcttttaaga acctgctgca caactctctc51421ctacttattg tattaatgtc acacttctgt tcacataggc ctttttcggc tgcttttcaa51481tacctttccc ttttatttac atctaagact atcccatcca agactgccca tcttagccaa51541tctttccacc tggaaataat ttgctggctt ctgcctgtat gacttttcta atgtcatttt51601tatatttgtg tctaggcctt tctataactg tctagaaaat tcctgacatt tacaggcact51661cagcaaatat ttgtgagtga ataatcagta agtatgcttg ttttctatca gataagaata51721tttatttcca aaYgagattc aaacagtaat actggcctgg gtgtggcttc ctacatgtaa51781tcaccctcgt ctatctcttg ttctcagtct tttgctttca aactctttct ctttttttaa51841aagagtatta ggaactaaca ttgccaaaat ttggtaatgg tcaagcagat catggtgtct51901tactgaagtg aaatattaac attaaaataa aaatgacaag tattatggta tatcattcat51961atgtaatgat ccttacaaaa tagagtaaaa ttttaaaaga attcaccaat acaccagtat52021gatgtttggg agaaacagat gaatgcacaa aggtgcatct gatgcaaaca cccccagaaa52081aatgagcata agttcatatt atcaatattt ttcactctaa aagtgttcac tgacttccct52141gaagtcacca aggactccaa gttaagaata ctttcctgag tgaagaaaag aaagcaatta52201ttttaatcaa cactgcccca gaatctttta ttcggaatcg ctatctctgc tttcttcttc52261ttcttttttt taactttctc ataaatctct gtttagcatt tatatctctc tcactatgag52321atacctaagg gttaagaagt aatgccaaag agacatttgt ccagttgaag actgggatta52381agaaaaaaca cacagccggg catggtggct catgtctgta atcccagcct tttgggaacc52441caaggcaggt ggatcacctg aggtcaagag tttgagacca gcctggccaa catgatgaac52501cccatctcta ctaaagaaaa tacaaaacat tagccacgca tggtggcggg tgcctgtaat52561cccagctact tgggaggctg aggcaggaga atcacttgaa cccgggaggc ggaggttaca52621gtgagccgag attgtgccac tgcactccag cctgggcaat aagagcgaaa ctctgtccca52681aaaaaagaga aaaagaaaag aaaaaacaca caaaagattt cccgaaaaga ctaggccctt52741ttaaacaggc tatgaacaga gtctcagaaa ggtaatttct tatgtacaat ttttaatctc52801attacttgca ttacaagcaa cacatatgag tgataaacta ttttggccta ctggtaaacc52861tacatttgtt aactgtgtgt gcattataga gaacaaattt cagaactcaa gagtatatcg52921gttatatttg gcttatccag ttgtatatga actggctcca tacacgaata agataaatta52981gttttataat tttacaagaa tatctatgga gatttagatt tggctaagaa agttattata53041cacacagaag aatccacaac ctataagagc tcttcatggg aaatagtgtg atagatcaga53101aagagcatgg acttttgagt cactcagaac ttgaattcca gccttgccat tgttctagtt53161gtattatctg aaataagcca tttaaaagac ctgagcacat tgtatacatt gagaattaca53221gggttattat gagaaatgca taagaaatgt aaagtaccaa gggctgtatc tgacatatag53281aaggtattca atcaatagta ggtatactga accactttgc agagttgttt aaataagtta53341attttaaata aggtagttaa tatttgagag tttccttcct tttccacaga ttctcaatcc53401taaaacagtt actatttttc catcatcacc atcaaccctc aaatattaac cagttctgag53461ccaaatgtga gtgaacaacc tatgatttag aatagctttt agaccaggca cagtggctta53521cgcctgtaat cccagcactc tgggaggctg atgcgagcag atcacttgag gccaggagtt53581caagaccagc ctagacaaca tggcaaaacc gcatctctac taaaaataca aaaagtagcc53641aggtgtgtgt ggcacatgtc tgtagttcca gcttcttggg aggctgaggc aggagaatca53701attgaaccct ggaggtggag gagatggtgc cactgcactc cagcctgggc aacagagtga53761gactctgtct caaaaacaaa caaacaacaa aatagaatag cttttacaag accacaccaa53821atcatgaaaa gtcaactatg taggaagaat atgtatttgt cattggttaa tgacagagca53881tcacttacac tgaggttact gggaagatca tttcaaacat ttcccaaaga atgttccaat53941caatattgtc cttataagat tctccttact aatgacgttt tgtggtcaaa caagcttggg54001aaatattgta tatgtaggct ttttacagtg atttctaatg gacacgaacc taccaaaagc54061tagaaggtcc acagcaaaat gagatattta attttattaa caagcattat ctaaacctgt54121ttgattttag aatgcatttt tcacacaaca actatcacct cttgaagaat acctggaata54181ggttttccta tacctatacc tatatgtcag gtaactccaa aacattaaca aatacatgtg54241tttagtaggt tcccatatgg ttgaaatctc cactaacgac attttatttc tcttcctcct54301gactttgtat gctatcgaga aatggtcaga gagtaatctt cctccctccc tttcttcttt54361tctttctctc tttttccccc tgaaagagaa tagtcaaaaa atccatacat atttattgag54421cctctctgat gtgatagttg ctgtgaaata caagaacatg aaagattcag cagcctgggc54481ccaggaagga accataataa cctgctgaga aaatcagaca catgatcggc tgctgcctag54541agacagtgta aggtagcata taaatcattc agcctgggag tgctactgta gttcgagcag54601ggagagggag gtatggacta tagctcagtg tgctgggttt caggaagaag gtgaacttgg54661atgtaggtct tcaaggaaga ctgtggtttt aatggctgtg ggaggaggga gtccgctggc54721attgttttca ggYgtaggaa atgtctgcag cctgaataaa ggttgtatgt gtggacagta54781aatgggctgg gtggagtaga cacattccag ggaggagaag ggatatagag ttgaacactt54841aaatgtgtgg ccttgagcta gtggatattg tgggaattgg ataagtgcac tggtagccta54901agaggataga atggagaaga gagaaggatg gagactaagg agctattgtg gtagtccaga54961tgcagtggaa agcaaagagt tgtggaggta tccactttag tggtctacga tgacagttac55021aagcaataga aagagtatga cttgggaaca gtggttcaaa tgctggctct gcaacttagc55081aaccatgggg caaatttggg caaattaact tctctgtacc tcagttttct tttttgtaaa55141atagggctaa aaatacattc cctagaaggt ggcctccagg ccattttccc acactttatt55201tgaatgttaa aactaacttt aatctaaaaa tcatatattc atatctctat cttttttggc55261ggttcagttc aacttaaatg tgttatttgt taaaaacttg taattatcat ctattacatg55321taaaatataa gagctgcttt taatagtaat tcatctcctc cctatctttt tttaaaacat55381ggtcaaaatt aacaaaacaa tcttgtattt ttgatactag tagtggtatc actactacta55441gaggtacaag gactcttgta cctctctgaa aagtagcata attagcaaca gtattgatgg55501tatctgctat tttagattat ttaaactgta gtcactaagg taagcaaggg gaagaaggca55561tgtcatttat gtgtttttca tccttaagat tagcgtttgg aagcatatat tattccacag55621caatctggat aggtcttgcc atgccctgat cttgtaagcc caaattttat tttgaatact55681ccagctttgc acttaaatga cagctccttg ataaaagaaa aacaattgcc taacaatttt55741cttccaattg tctgaaaaca taatgggtgt acatacacac acacacacac acacacacac55801acacacacac acacacacaa tctctagggc atatttacta gatagtatta tgtaatgtgt55861agacattttt aattatgata attaagacaa aaatatgtgt agcaagtttt tgatttgaga55921caaatttgag atttactaaa attattatat gtgtgtcctt ctgaagactt catattttca55981ttatatatct tcattcttga agtataactc ttaaattgtt gaattaagtt ttatgaatta56041agttgttttg ttttttgttt ttttttgttg ttgttttttt tttttggcca ggcacggtcg56101ctcatgcctg taatcccagc actttgggaa gtcgaggtgg gcagatgact tgaggccagg56161aatttgagac cagcctggcc atcaaagcaa aaccccatct ctactaaatc taatcttgtg56221cctcaagcga ggcacaagac tcacttgaac ctgggaggca gaggttgcag tgagctcaga56281tcgtgccact gcactccagc ctcagggaca gagtgagatt ctgtctcaaa agaaaaaaat56341ttttttccat ttttaccaat accactattc tcaattcatc cactatttca ctaggaatta56401ctaattcagt ttacataatt tattcaatga ataaattatt caatgaagaa gcttctgggt56461atttaggtgc tacatgctaa tttcaattgg catattttgt ttttcaaatt tgttcttggt56521gacccaataa ttatacctgt ccaccttgaa agtgtctttc ttcatcacct tcaaggccac56581cgctaacaag acctttgaaa agaagtaaac agtagagaat ttcaacttct gtgatgacca56641ccgtcttctt ctgaatcccc agactccact catacaaggt tttggggaag tttaaatgaa56701atgaagcagt ggcttacaaa gtttattgac agtaaactac agtaaaattt atattttata56761ctataacctg gtagatttgt ttaaagtaag aggtgctcac ttttgaaggc atgtggatgc56821tggctttcag taatataaaa aaaatgtaca aaaaggtttt atacctatat ttatttttaa56881aaggtagagg agagcagtgg actcctattt aaagaaactc ttgtgtttta taaataatag56941tcatggcaaa atttgtttac agtctttaac aaaccatgca tttcagtata aattaaacca57001ataaaaagaa ttatatatat aaaataaaaa ggaaatgtat atataggaac agtatatacc57061atacacataa gagtaaatat atattcgagc caatacagag aattgaaaca taatttaaca57121tgaaataaca tttatcctta ctatgtatga ttcactctga tgttttctat ttWatttaat57181tttaaagtat taattgtgac cccttaaatt gattttgaaa tctaccaatt ggtttgaaaa57241cactgaggta agaaattacc ttgcttaata aatgttagtt ttgtttccct cttccctctt57301cctccctttt tataattaaa aaactctccc tctacttctc tacttcacgt gagagtagaa57361cacataaaaa gatttcagtt aactactgtg catatttttt gaagtaattt ctccataatg57421tgtgagtttt ctcagggtac tacaagttta ccaacagaac acataaagca gcggccactc57481actgaaatgc ctataggaga cagatagacc atatgaatga atgaatgaca tggttgctgg57541gcatcctggt tgcagtggct agaactgtgg agggtaggag cagaccacca tatatcctag57601gcatttcatt ggcaaatgaa caggagaagg acacctttcc gtttggccct cattttccta57661gatctttcct cccttcctct gtcaatccct cctacatagc ctatgttccc aaagcacccc57721ttgtattata ataataatta ttatgatatc tgtccttaat caagaactta tactggattt57781ttaatgcctt taggtcttcc ccaaacttca gttcatctat tcgaagtccc tataaaatct57841acctccttag acttgtctgc ccccattatt cccctgtggt tgacctcacc tccatctcta57901tcttttgtca gcaagtttcc tcagagttcc ctctctgcat acttgttcat gctgggttat57961ttgtttttgc cacttgatca tctagacctt tttccctctt tccctccttc tattcaattt58021ctgcctttca ctgctgtaca aaggaggggc agggaggccc tccagggtgg agggaatcag58081tcttgagata acegagagat tcagggtgat gagtcccaaa gttgaagaga atccacatac58141ttcttctgtt tttgttttac ctagcaagga gccttttcta tagacaaagt tRggaaacca58201gaggttatga cgtgattcat ctttgcctac ttaaacttta gcttgattca tcacttctca58261acaaatactt gttgaacccc accagtaata cgagaagctt ggtattctat gaggtgctca58321acttccaaag cttagttcag aagaattctg gcctcaaggc gtctaccatc tagaagcaaa58381caactaacaa atgaacaaat gcagtgattt caaaagaaat taaggtgtgc tgtggtagag58441gcatgcacag gtcagaaaag ttcagaggtt ccagacaggc ttcctgggga ggatatccat58501gccccScctc cacctggtag ttcatgatca gagtttgcaa gcttggctgg gatagaggga58561atagcgtgtg aaccacagaa ggagtggatc tggtggctca gacacggcaa gaaccagctc58621atggcactag gctgcaggca caccatgcac aaaacagtct tttctttccc cagttctcca58681aattctctaa agtggaagcc taggggtgag ggtaagaagg aggtaggaag ctacaaccac58741tggagcaaag gacgaaagaa ggggcttgag tgtctaaaag tgcagaaact caaccgactg58801gacgctgaga caatgtttaa aaaggagttt ttttgtttgt ttgttttctt gtgttttttt58861ttactttaag ttctgggata catgtgcaga acgtgcaggt ttattacata ggtatacatg58921tgctatggtg gtttactgca cccatcagcc caaactaggt tttaagaccc gcatgcattc58981ggtatttgta ctaatgttct tcctcccctt gctcccccaa cccccaccag gccccagtgt59041gtgatgttcc cctccctgtg tccatgtgtt ctcattgttc aactcccact tatgagtgag59101aacatgcagt gtttcgtttt ctgttcctgt gttagtttgc tgagaatgat ggcttccagc59161ttcattcacg tccctgcaaa ggacataaac tcattctttt ttatggctgc atagtactcc59221atggtgtata tgtgccacat taaaaatgac tttttaaagt ggcaactgtg ggaggcaaag59281gagaaaaaac aggagctgcc agataaggga gtgaagagaa cccagcactt tgagaattcc59341gttacatttt gcagcttgaa ttcttcactt tttgctccca ttatgtgcct ctttctcctc59401tccatgaact gggccctgtg gacccaggat cctgctgtct ttgcagggca aagaatggtt59461agaaatgaat tcattaaggt gagaaaccat tgctggcata attctccttc acggaaacct59521ggcacttaaa tttaacctgt ttggttagat ccagctctgc ctcccccatt tYtttctgca59581gaaacaaggc tggcagatcc ctgttcctct taatccttga atggaccaaa tgctgggtta59641tgctggggca gtgagggacc ttacaaacac tgaaatttaa gagaacagtt tttggagtaa59701ggcagtcctt gtttccaaat ctgagctttg ccactgaYtg actagcttgg caccttataa59761aagtgaatta acctagcttg ttttctaatt tataaaatgg agaaagcagt acctatatca59821cagtatgatt ctgaaaatta tttaaatagg actatgtatg taaagcagtg cctgaaaaat59881agcaagtggt cctaaagtca ctatgatgat gaattttata tgcaggcacc tagagcatgt59941taggattttt gggatctttc ccagctcaca ctgaagcttc actcttctcc aacagtctgt60001tatccaatgc tggataactg agatagtctt cccagcattt atcaatgtgg ttaggaacag60061taatcctgga aagcattctc aaattattta tctaattaaa caagcaaacc tttttagccc60121agacatccta aatctctgta gcttgtcttc gctgatttgg tcagaatagc tcagatggta60181ggaagggctt tctgggtaga aaaaaataaa ttagcagtct ggaaaacaaa agatctctgc60241ttaaaagagt ctctaaaaca gcctgatcag cctgtgtatt ttgccatatt atctagcatt60301agtaggggac tgggaaaaat ccagggctcc ttgtagagat agagactggc aaatattatg60361tttgatgcat gagaaccaaa tcagaagtta actctttaag ttattaaatc actaaacagt60421ctatcacaat tatgtgttta ttactagact gaatttctct ggggctggaa ccataatgaa60481ttcatttttt gatctctggt gctaaacact ggctgtcata tactaggtat ccaataaatg60541tttgttgaat ggaactgaaa aagcatgaaa cacttcccct gttaaggctt cttttctata60601atatttccat agtttctaat gcatctgaga atcattaact ggactgttag aggaatatga60661atatggttga gggagctaca aacttcatgc tctgagatgt cacatgatta gtgtaacttt60721tgttccaggg gagagaaatc cctaagagag tgactgttct ccatgcccac ccacccacag60781tgtcctatag agcctttcat tctccagatg cctataatga ctatcacatt gatttgttta60841catatctatt gccttgtctt ccttataggt acagagtcca tacatcctaa ttggcctgga60901acttccaagg tctatgcctg ttataccagt gtaattatga atagcattgc ctttcattct60961aaaaagtgtt ctggtttgaa tgctaaatca tctagacacc ctacttatga gagggttcac61021tgtacatcgt ttagtccccc aactcccctc cccttggaaa tctgggtact accctccacc61081gggggctttc cactatggag gcagctctct caatcacagc attcaggagg tgtaagtcca61141ctcccaacag aacagacacc tgtctacaaa gagactcttg gtggaagaaa aaaaaaaatc61201acttccgtaa gtttaagtct tccttttaaa cttgggtctc ttttgcacat cagaaacaaa61261gaatctctaa taattacatc cctaaatgta ctgaagtcta gaagacatgc ccatttgaaa61321actctaatct agtaattaaa gcttctcagg ttaaactgca ccttaataat gtagcttatt61381ttgtcaagat cagttaaggc cctgtaatgt gatttggaat aaatggacag acagaaatta61441aaatgtgctg gacaaggtaa tcagaaatct cacttcattt agtcaataac aatggcaatt61501cagcgggttc cttttactac tgggatgtaa ttgtgcttgg ctttaatttc ttgtaatgat61561ggaacaaatt aaattacttc atacttttag gaacatttgg ctacatcatg ttttggYgct61621tccataaacc ccactggaaa ttaaatcagc tctgtggttg ctcattctcc ctctttagtg61681ccatgtctgc cttctgtcag caaaatggta atattgtcta ccttaatcca ccagatgcag61741ttgagttaaa agaaattacc tctcccacct ctttcctttc aaatctccct atttgtagct61801atcaaatttt ggcatgcctg ctggaacaca gtcttgttag aacaagcacg gtaattctct61861cgtgagactt taggactctc tctacgacaa ggtcagaatg tacctgtgat tcaaatttag61921atgaggatat gagttggtaa gaacatgaag agcatcagac agttttcagg acacccacta61981cttttatttt gtgctatcag tttttccttt cccaaattgc aggtggagat gcaatcttta62041acgctggaaa tctcttgcta tatgccatta aaattaatta gtctagcaca ttttatcttt62101aggcccttac ctagggcagg taaaatattc tagcacaaaa taacacaact ttcctgaaca62161ccatggctac taagttcata tggtaaagat tatactatac attaccttgc aaatagagtg62221ttgcagactg atattaaata tttaaaatgt atgcaggatt attaataggc aacattgtgg62281cagagactgc taaatgtccc ctaatattga tgcttttctt catcacttgt tttcaaatac62341ctgttttcat gtaagcatgt gactgcccaa aatagagaaa attcacagcc tccttggttg62401ccaggtgttg ccatataact aagttttggt gaatgagttg gtagtagaag cgttatgtag62461atattatatg atgtgctaga aacttccctt aagagaaatt tgtcatctat ctttttatct62521gcctgtattt attgttttct ctttcctact ggctagaatg tgaagttgat ggctggagtc62581ggagcagcca tattggatgg tgagttgaat ttagcaacag aggctacacc tcacagtgca62641ataagatgga aagagcacgt gtccttgaag actgtactgg atagaggtgc catattaacc62701tcggactgcc aactttcaga ttttacatga aggagaaata tctgtcttcc ttaagccact62761tctattttaa atctctctat ttactgctga ataaaatctc aactaacgca aacaccaata62821acaaaaaatt cctattcact catgatatag gattatacct tagtcttttt tgtgtcatat62881atctgttcat tcaccatttt tgctttgatg ttcaataaac atctcaaatt taacatatct62941ataaaaattt tttaaatttt acgttcaggg gtatatgtgc aggttagtca tataggtaaa63001ttgcatgtca tggggtgctg gtgtacagat tatttcacac cgaggtaata agcatagtac63061ccctacagct tagtcttaag aagaagtatg ttcacatagg ccaggctgag acttggatgt63121tggatgactt tcttccagct tactctgatt tgaatatatt gtgtggtagt agatggctaa63181actgcttgct ccaaaactat ctgacaatgc tttttagaaa gtctgccaaa caaaactaca63241agaatcaccc tggagcttcc cttaggcttc agatatttgt cttccctgcc ctacttggaa63301atcattccag cctggaagtc attgtgagga accaaaaaat ggtctcccta ccatgaagaa63361taacactgct tccattgttg ggaggctctc cttcctacag gcactgtccc tcactcatta63421gacacttgaa taataaggat gttcatatat ttattggtgt tggtatcagt tagacagttg63481aatgatacaa atgttcatat atttcttctt attcaatagt ctcacaagaa cactattctt63541gtaaagtcat taaaaactgg atggtctttt cataattatt tccatgattt gtcatctaaa63601gccagtgttc tctcctcctg tcaatctgat agctttaaag ctaagttctg ggtgggtcca63661agtcatgcct gaaaggttta tcaaatgaca tattgcagtc atatggtcgg agcacaaaca63721cctctgaatg tacaatattt taaagcaaaa cagtttatgt gtaagctcta tgaggttacg63781gaccatgact atcttattta ttaccaaatc cccagctcct agaacagtgc ccctcaatat63841aaatctgtca aatgaataaa cgaagagttt gcctgcagta gtaaacttgt tatttgcaca63901cactcgaggc ccacctctat gtgtacattg tcagtgagtc agcctcgtgg atgactctgc63961aggactgtct gtataacatS cactacagtt accaggggac ccaattttca taaattgctc64021cagcatcaca ccctcctctt acagagactc ttcctgtcca ttctaatccc tgacacgttg64081tcatcctcac tcagattccc caatagatag aaatgctgtt aaatatactt gggtagagag64141ggataggcat gctcaaactc Sttttgggaa aaaaaattgc aactgtcaga aatgtgttag64201ctatcttcac agattatgaa acataaatat caattatctg ttcacagcag tgaaagcctg64261catatttttt taagatagca agtataaaac ggctataagt accatgttga gtagagacct64321accaccgaag tagagacctt cactgaaata gtgaagggat ggttgtgttg cagggtcaga64381atgattaccc actggttgac actccctcca ggactaaagg cagcatcacc agcgtccact64441ctgcttctcc actgcttact gttaaggagc aaggcaatag cattatctaa gtaggaacta64501cttcattctt tcaaaacctg gaatcggctg atcagaagaa gaaaaacagt ataaaaatac64561agaaagacaa gattctctgg ctgtcctaat gaatgctagc tagctataat agcatggata64621agacatataa ccaaacatat aagatctatt aattaagggg aatctctatt tgtattaact64681catctatttt ctctaaaacc agtatttagt tatctcccat acattggcat attgtgtata64741tttgcagaat tcaaaatgtt actgatgtga cttttttcca tcagacatct gagctatccc64801tcaactaata gttgagctgt tcctctatag ctcagtatct gagttagaac tcgaagtaaa64861aaggtataaa taagtcatgc tataaaattc aaaggcaatc agatgtttga gactatagtt64921atacagaaaa gtgtccttgt tcttgggagg aatacatcga ggagtttagg gatagagggc64981tatgatgtgt gcagttttct ctcaggtggt tcagagaaaa aaagacaatg tgtgtgtatg65041tatatttgtg tgtatgtgca catagagtga tactgcaaat gaggtggaat gtttacaatg65101agtgaatgca tgtggttttt tttttttttt tgcactaccc atgaagcttt ccagtgtgtc65161tgaaataact tccagataaa acttttttta aaggcaatca gaacagtggc aatgaataat65221tcaattattt catatttgag ctgtctttcc tgccaccccc accccctata acactacata65281catacatagg ctcacataag tgacacttac tatacttttt tgcctatgta atgagtgttg65341gcgaagtacg tgagtgggaa attcagtctt ttgcattcaa gctctaagta attctaagag65401accttttaga taatgatttg acttttaaga caacaatttt gaggttataa tatgatgtca65461tttcatataa acagaactgc ccttttgtcc tttcagattt gattgaaaat ggcccatgga65S21gtacaaccac ctgggaacat atcctcgaga aagacagttg aggcttattg cctaaaccac65581aggctactga aaacttggcc aaaggcgact actctagact ggtgacttca aaagtgctga65641tgaatacagt gaaccatgaa agatgcatta tttgttttga acattttact atgattgatg65701acccagattt ggcaagttag ttcactccca gtggagatga aagtttcact gccttctttc65761tttcaacatt cttgttgaga cagatttcac ttttattggc caatgtacta acaaatcact65821tgcatttgca gcataatgaa ttcattagca acactgtgga tcaatgctat acataatatt65881cctgagtcaa cattaactct taattaaact tccttattat aatgcctctg gaaattttcc65941ttcaggctac taaacttcaa gccaacagtc taagtgttaa tcagtaatca tgctagtaac66001tttttgagat gggtcagggc cagggccagg gtcagtgatc catcatgaat ggcaggttta66061aaaatggata tacgtgatca aaaataccca taagttgacc aaagcattct aacctttggg66121ttattctaac actcagtgta tcagccttct gagcaagcca attttttatt gccttaaaaa66181gtctaaaaga aagataaaaa cagagataat cagttttgtt tggcaatggc aggggtgtgg66241gaaatgaaaa agaagaaagt taaagatgag tgaaaatagg atagtcttgg cactttggta66301tgaaattgaa gtacttattt aaactgatga atattgtaca gaaatataca gagagcagtg66361aggggctaag aacctaattc caaggtaact acaaggaaaa aattattgat ctggattgtg66421accagaattc aagagtttga ctgttgtcat tgttgctgtt gttattaagt taaaaaaaat66481gagaaaaaaa tatacttttt tctagtatac ttaccaggaa aggaaagaga gaaggaggga66541gggaaggagg gagacatgga gggggcagag ggagagagag acaaagacac tgacaaagtc66601tggaaaaaga cacaaattca gatttaagat cccaaaatat gctacatttc tgcccccttc66661aaaatattaa actttgctaa aatacactgg aaattttttt tattgtttat tttttaaatc66721aactagcaga ccaattagcc aagatgatat tttcatcctt ggtactcttt caggtgagct66781ctgtgggcta ccaccagaaa gtcctagcca accaagctct cactgggtca ctctgtgcta66841gctagactac atagcctcct aaaaaagcac Rcagccctga tgctggtcct gccaaagtgt66901ggtttgctgt catgtcctac aggctacccg tttcccagtg atttatcata ataaaccaaa66961tgggaatgaa atacccagaa atatgccata aatctactag tggtgaattt tcaatattct67021gcacaccatg gtgatttgtt aattcagttg gatctctatt aaWcctctct aaaatgtcat67081taaRccatct gttttgactt gttaatcaaa caacttttaa aaatgtattt agagtatcag67141taacccttga attaatgcat ccatcagtaa taatcccctc tccaacttta gatttatttt67201taagctctag cttttttccc caccattcca acaaatagcc tgacttccaa aagtaagaat67261caatcacttc agttgtagaa atgtccagag ggtgccctac tttcgaaaca ggaagtaact67321tgatccagca gtcccacttc ttggtatata tccaaaagaa ctgaaatctg gatcttaaag67381agatattttc actgcagcat atttgtaata gctaagatac agaggcaacc taaatgtcca67441tcaacagatg aatggacaaa ggaaatgtga tatataYata cacacacaca cacacacaca67501cacacacaca cacacacaca cacacacaca cacacatata caatgaaata ttattcagcc67561ctaaaaaagg aaggaaatcc tgtcatttac aacaagttgg atggaactgg aggacatcat67621gctaagtgga ataaaccaga cacagaagga caaatactgc atgatctcac ttacatgtat67681aatccaaaat agtcaaactg atggaagcag aaagtagaat ggtagttgcc agaggctggg67741ggaagatggg aattggtaga tgtggtcaag ggttacaaag ttttagtctt gcaaaataag67801ttctggaaag ctgctgtata acataagtat acaatcaaca atactatatt gtatacttag67861aaatttggta aaagggtagc tgttatatta agtgtcctta ccatgaaagg aaaacaaaac67921aaaaaaaccc aaaaagatgg gaggaaactt ttggaggcaa tgaataagtt tatggcattg67981attgtaatgg tggttttagg gtgtatacct gtctccaaac atcttgcaga ataaacatat68041taaatctaaa gtttccttgg gaaagaagat gagaaaataa ttgtcaagag actgtacacc68101aataaaatag tcaaggagta caatgaaaac ttaggaatcc catttcttcc tttgactcac68161actgtttgat gatatcattc acatcggcat ttggaagtta ttgagacatt tcaacataag68221attgtcctta tgatctatga tttgggactc tcttataaga aagtccattc tataccaatt68281tgttttgttc cttggtaact agaccttctt taattggatc taagaattaa tattcctatc68341tcataaagaa gactaaaagg atccaagtag atggagtttc aaaggtggtc cccataaaag68401catttttacc ttaagcaaag atgtcccaat ttttcctgct tgcttttcgg atgctgttct68461aaaaaaaatg taccttattc cttctactaa aagaaaacct atcaattcat tgattcattg68521aacaaatatt tattgaacat gtagtatgta ctaaacactg ggtaagattc cagatatgca68581aagaggaata agtccctgcc cttaagaaaa ctcacagtgt ggtcaagcta acaattctag68641agcaactgtg tgataagggc tccaaaagca catgcaggaa cacagagaga ggcactctta68701gtcttggagg ggcttcctac agtgggcaat ttttgatgtg tcacaaaagg aggagctatt68761agggcacaag aagagcaagg gtgaagtgca gaaaggagtg aatagatggg gaggggaccc68821aggcaaagag aataacatca gcaaaggtgc aacttcatgg gaacacagta catttggaag68881cctgcccacc atttgttaca gcagaatgca tgtgtgggtg gagatgaggc tgcagagatg68941ggctggagag gattatgaga gatggatgac tagcaaagga agttggtcat gtccttatgt69001ggtgggggac catggaaaga tttttattta taagacgtgg tttattcttc attctgtggc69061aaaaagcaga tactatagtc tgaatgtttg tgtccctccc cacattcata tgcgatgaaa69121cctcatcacc aatgtgatgg tattaggagg tggggccttt gggagataat taggtcatga69181gagcacagcc cttataaggg gattagtggc ttataaagga ggcccaagag agctgccttg69241ccccttccac catgtgagga caaagccaga ggcactatct aYgacccagg aaatgagccc69301tcacaaaata ccaagtctac cgtgccttga ccttggacat tctagtctcc agaactgtga69361gaaataaatt tatgttgttt ataagccacc cagctcgtga tttatttatt tatttattta69421tttatttatt tatttattta tttagagaga gagttttgct ctgtcactcg ggctggattt69481cagtgccatg atctcagatc actgcaccct ctccttccca ggtgcaagtg attctagtgc69541cttagcctcc tgagttgctg ggattacagg tgcttgtgac cacatttggc tgattttttt69601gtatttttag tagagattag gtttcatcat gttgcccagg ctggtctgaa actcctgact69661tcaagtgatc tgcccacctc ggcctcccaa agtgctggga ttacaggcat gagccactgt69721gcctggctat gatattttgt tacagcagct tgaatggact aagacagaag gaaaaatagg69781cctttctgta gcgtgagctg aaagacagaa aatagccata ggtttctaaa gagagaaaaa69841gatatatgtt tgacaatatg tttcaattag tacttttttt gaaatgcagt aagttaccta69901taccttattc catttctaat ctatatgatg gcatttaaat attgactagg tttctgatac69961agtttttgga gtctgaatgt cactgcatgg atgaataaac caaacagatc ggattcatat70021gggtttgcca aatgacaaat ttttttccat gtaagattag aggaaaaact gatttcaccc70081aatttcctgc cttatttata ttagaactga agtcaatgct gttatccctt tgcatgttct70141tttgtattta aaatctgata tagaattgtg ctgttacaga agaaataatt taatgcattc70201tgccctctta tttctcatga gttttcattt aaaagaaaac aaaaaagaaa aaggacatgg70261acttttcttt atttctagac tttataaact ttttagttat caaataaaca catgtattaa70321ttaagtaggt aaaatattgc atatattaaa aggtacttgg agWctcatat gttgtcagtt70381tttcatgact caaaatttat gaaaaaccat ctaagactat cgtaatgaag ttcaattgta70441gatcttgaag tgacaaaaca tgaaccacat tgacttgagg tccagggctt aaaactgcct70501atttgagctc taggttaaaa gcatgtgtga aatgcaaagt ctgacatctg cacagctgac70561tattgtgaag tctcagtatc attgttcata agtaaagctt gtccctaagc cataccacaa70621gcattcccag aggatataga tttcatYtga tttaacatga ttgttgatat tggtagtgta70681tttcacgtga acttgtgaaa tcattgtcta tacagacaat tgagacacta aaactttttt70741ttaagtattt tttgttaggg gctagatctg aggtttttta ttcatttgtt cttttgttca70801ctcatttgtt agttcagtta tttactcaaa aatgtatatt gagcaattcc tatatggcag70861acactgacag atgctggatt cagtgatgag caaagcattc gtggtttcta tgcccaagga70921tcctatcccg tggagtgtag agtcaagcaa agaatgtcaa caacaaatga aaattttaat70981cttattaatg ttatatgcaa aaatgtaaca cctccaaaaa agacaattta tttcctatta71041aggaatgaag gcagtccact gaggaagatc aacatgtaag cacatgtaaa gcaaaataat71101caataggtaa tgtagttttt gaaaaagaag gggctttaag caggaagtcc tgggtttgga71161cttgggtttc aaatctagct atgtactctt gggccacata cccaagtctt gtaagtctca71221gtttcctcct ttttaaagtt agcctaaaac tacctcgctc atctaatggt gtgagaatta71281ggtaaacagc caggtagctc atcaaattgt aattattata attgttattt tttgagtcat71341gaaagttttc acactgaagg gaacatttca acttgacctg gaagagtaag tagtttatca71401ggcagaaaga atttgttagg gtattccaga gagaaggaac aaaatgtgca aattcaagta71461gtcagaatca aaatggtttc ttaaaggaat gacaaacaga tcagtgcagt tggagcctaa71521agttatctaa ataatccgtt agaccttttc tttaactgat aaaataaagc aagcattcca71581aaaatcaatt taaatccatc ttcctcctta tacctctcca ttccccatac catggaaaca71641cagttttacc tcttttacaa tgagttgtca gcatgaagag acttggttca ttaagattag71701caaacttcac agcattgaac aaaagataaa gaaaagttta tagcaaatac gttccatgtg71761aaagcatctc cagcaggttc agaagatgca atgaaaagac taaaacttga tatagggata71821tttcagtggt gctYgtacca gcgtcctaac attttgttct accttagtaa aatctatccc71881ttattactca tcctatctgt agactctctt atggaacaag aagctttttt ttttttttcc71941ctaatcccgt ggggaagccc tctccttccc tgggtgattc ctgagcaacc aggaaaacag72001cagtcacagt caacacagct agtacttgca gaaaatctct cttctgtgat gctctgaatg72061actcacagtt ccagatggcc ttgtcagcct ttatccgcat tccactcttg gcaccattaa72121cctggtctaS tgtggttgca acaaataact tttcttgtta tgaggaccag tgttttgaaa72181aatttaaaat gttataaaat taaaatgttt atatttggaa attatttcca aatataaaag72241gagcctgtct tcattataga ttatttggaa aaaatgcaga ggggtgcaaa agaaaaatgg72301aaacaagcca tctttttttt acccataatt ctaccactca gagacaacta ctgtgaacat72361tttgatgtat ttatctccag tctttctaga aggtagatca ctgtaagaga tttctgaagc72421agaagtacta agtcagaagg aataaacatt tttatacctc ttaatgtgta ttgccagata72481gtttttgaga aatattacag caatttctac ttttagaagt actgcttgag agtgatgtta72541catggtattc tcactaacac atatacaatg ttataaatat gtccaaaaat aaaacttagc72601aactatgtta tctccttgtt tcaatttgaa cttattacaa gagtgatcaa tttttaaatt72661taaatgttat ttttagcaaa gttatagatg caaatagttt agagaactaa gtagtaccac72721aaggattaaa aaaagagatc tcctgcagtg catcccccac ccacaataca tacatgtatc72781ttccactccc cagagggtaa ccattttcaa atattttagc tgattcattt gctatactcc72841actctatctc taaatgatat aactttacag ttacttctta atagttcatt tttttgggca72901ttgcttattg atacttcata gcggaagata aggatttacc tttgcaacac ttcacacttc72961tcatcaccca tccttctaat atattatagt cttacttaga ttgatagtca ttgtgtttcc73021atgagcagaa ccaaagaaaa actataagca gctaaactat gtaacatacc ctgattacct73081ttttttcttt gttttccttc ttgaaaattc ttgtcttttg ttagtttctt tgttccctta73141gatgtccata tatacttatc actaattcaa tcccaaactt ttcccatatt acaaaaatct73201aagtatggct caaacacatc aagaatttta ttaaattcat cttcttgaag aaatctcatc73261cagaggcctc tttgacctgg attggttatt ctccatgtct cttgctcagc tgtcactttg73321ggatgttctt tccttattat cccaagggta atgtttttag agtttattcc cttgttttgg73381tgagcacgtt ttccagtagc ttcctgagtc agtatgcatc agagatacat tttttaaagg73441ctcgcacctc agaaataatc tttattccat gctcactctt gatcaatagt ttggYtgagt73501atagaattct tggttgagaa tcactttcct tcggaattta aaaggcatca cttcattctt73561ttctaggttt caaaacgaat cttcagaagt ctgatgccct tttgattttt gatccttcta73621tacgatacga taatgatcct tagaacaagt cacaagtctc ttttttaata ctttatattg73681tgctaaatgc tccaattaat gagttctgga aatttttctt caattttgtc ctcctgcagt73741tttctctttt ttctagaatt tctgatttta gatgttagat ttcctgaact ggtcctctga73801tttcccactt tttcttctgt attttctacc tttttgtatt tttgctccat ttccatagag73861atgtcctcaa tttacctttc aacccttcta ttgagttttt aacttattct atcatgtttt73921tactttccaa gagctctttt cctattctct gagttgtttt ttttttttcc atagcatctg73981cttttgtttc gtggaagcaa tgttaatatt tatgaataca atatcaagtg tatttcttct74041cctctctctg atgatacctt cttcctgcaa catctgtact tttttatttc tcttcttttt74101tttttttttt ttttttgaga tggagtctca ctctgtcacc caggctggag tgcagtggga74161ccatgttggc tcactgcaac ctccatctcc tgggttcaag caattctcct gcctcagcct74221cctgagtagc tgggattaca gttgcctact accacgccca gctaattttt ttatattttt74281agtagagacg gggtttcacc atattggcca ggctggtctc gaactcctga cctaaggtaa74341tccccccgcc ttggcctccc gaagtgttgg gattacaggc gtgagccacc gcgcccggcc74401aacatctgta ctttgaagtt ggtctttttc catttgtttt ggtttctttc acttactttt74461tctaagtatt tgataaatct tatctgtcta ctcatattta aggctagagt actaaaaatc74521agattggaag ctctgtttgc aYaggtaaga tttgtcaact acatccactt tttgatgatc74581caactgaaca gtttcattca gaaatacctt gcaccattat ctttgggttt tttctcttgg74641gttggtgaat tctccaaagg ttatatcaat ctcctgtcca gaaggcttaa gcatagttgg74701aagctgacta ggggaagaag gttgggactt tcaaccttcg gaattcattc aacaaatatt74761tgagcatcta tatttggcag cctctattct agccaccgga gacacagtgg taaacagaat74821ttaaaaagcc ttgtgttatc atgaacacaa atatataagt gtttatttaa tccctctgtt74881ttcagaatgg cactcagtct tcaacctgcc taggcccccc ttgtctaggg acggttttac74941attcatcagg aagtataccc cttgtatact tgtttttcag cttccaaaat tttgttgctg75001ttatctccct tcccactttc tttgtccttg tcatttatgc ctataaacat ccattgatgg75061ttttctgaag gcagaggagt taaatggata tgttaattac tatagatgta atcagaggtc75121ttcatgttgt ttttttgttt tctgttttac tattctaact tggcatttat agatcttctt75181tgtgagtagt ctgaatttgt ctttaatgat ttaacattga aacagtattt tccttactta75241tttgcataag ctctttcttt gttagtgtat tagccattgR cctgcaatat cttttaggat75301gaccgattct gaagcctgct gactgagttg cttgtggttc ctgtcattta gaatgtatgc75361aggtcatgaa tcgcttagat ggaacagatg gaatgaaact tgctctaaat attttaccaa75421aataaataca tttaaataat gtaaagaaaa atcttcaatc actaggcttt gaacttataa75481cagaaaggta tctgctttta actatattaa ttcaacaaac tttattgaac agttggtaag75541tatgaagcat catctctctg agaacaaaat accaaggaac tgagtcccat cattacagga75601ttctcaggag taaatgggtc aatacatagt tataaaatga tgagggctga tctatagcag75661aagtacaaag ctgagaacaa ctcacttgac ctgctaagct ggggaattca ggaagggttc75721agatctaaag agcagacatt tgaggtggtt cttgaaatat gagcacaatg atggttttac75781caggctgcaa aggtgacaaa gtgcattcca ggctgataaa agagggcatg caaaatatgg75841caggtacaaa aatgtgtatt taaggaagaa tgagaagttt ctggaagttg ctgaagatac75901agaaaataaa gtggggggcg gggggggcgg gtggttggag atgaggagga gatggtaggc75961ttgattcaaa ttatggaaat gtatttataa tgcaccaact tgtaaagaca ctgttgttcc76021ctacccagca gccactagaa tttgttcagg tgtcaggcgg ttggtgcttc aagggagatc76081aggcccctcc caggaccagg atgaaccatg attacttccc agccaatttc atagcatttc76141tcttgccaat gaatggctta gatataagca tatgatgaat ttgtttctaa tacagatctg76201agaaagaaat ctgttaagga acttctggta aagtttttat ctttcttaaa aagtgacaga76261agaaaaggaa gttgtataaa tatacttaga gctgctgtag tcatcttgag accataagag76321gataaaactg agatcaaaaa ctactgtgct gaggatgggt gactagaaag aaggaaagaa76381tctggattct tgatgcatgt ttgtactact agaatcattc tatcactacc ttcttattat76441ataattcaat aaatctctta ttatttaagc tattttaaat gaagccttct gttatatgCa76501gcctaaacaa atatactgat tcaagctccc agcaaattct gtcacacata attcaaggaa76561cgtttgttaa taacttcata ctattatatg gggaataaat gattagtcaa gaaagacttt76621ctgttttgaa aaattctgga aagatgataa tacagtatgt agatttattg tcatggctaa76681tatacatcta catataacat gaattacctt ggagtagtaa taaaagggca gagtaataac76741ttgtgcagag ccctagacta gaaaagttga aaatataaaa tggaggaaaa agtgagttat76801gagattcagt aatatgaaag tataagaaat aaaagaatcc aaaagccata gaaggttgaa76861actgaaaaga attttagaaa gcgtctaggc caggtgtggt ggctcacacc tgtaatccta76921gcactttggg aggccgaggc aggcagattg cttgaggcca ggagttccag accagcctgg76981ccaacatggt gaaacctcat ctctactaaa atacgaaaac ataactaggc gtggtggtgc77041atgcctgtaa tcccagctac ttaggtggct gaggtggaag gattgcttca acctagggag77101gcagaggttg tagtgagcca agatcgtacc acttcattcc agcctgggtg acagagtgag77161acactgtttc aaaaaataaa aagagagtct agcctaaacc ccttaattat acagattgaa77221aaccagtcct ggagaaattg gaagtcctca aagagtttac cattaatggt ggaaccagga77281cttccacaca atgttctgac ttcctttaga gcacttttta ttatatcata tagttcctta77341cttctcacta ttaatagaga ttattttact aagagtaagt ataataagag ctgatcagaa77401gacctgagag acataatgga gtttcaattc taatttgctg ttggctcctt gaaatgcttt77461gttgagaagg agtaaaaagc ttacaaaaca cacacacaca cacacacaca cacacacaca77521cacacacaca cacacaattt cttaattatg tctaccatgg gcatgggatg gtaggaatgc77581catgtaacta gtttccatgg atggaaacca cctaatggga aatagagaaa aagaaaaaga77641aaagaaattg tgtgtaaatt ttcagctcat tttggcttag attacatgat gaaacttatt77701tctttgaaaa actcatttga ttttgaatta gattatatgg aacttctcct ttgtcaattt77761taatttcttg tcttgtttta gtttgctttt ctgagcagta gatatcctcc caattggaga77821ttccgcaaaa ttagtactta gtcatcttgg ttcctttcaa gtagaaaagt ttcttttaaa77881tacttcaaat cattggtatg cacatttgtt gcaaaaaaaa acctcattct ggaaaatgtt77941gcttatttta ttatccaaaa aataggtatt tattaatata ctgcatttct tttaaataaa78001ataaattaca gattttcttc cagcatccac ttatttggaa ttgggtacat atgaagaaaa78061gacttcttat aatatggaat tatttcaaaa gctattatta cttcttataa atataaagca78121tacaagaaat tctcaccatt ttctaagatt tacattagaa agatataagt attgtctttt78181agaatactgt ttttattttt ctaaatattc cttataactt acttattaat tttatccttt78241ctttgttata aatatccatt ttttttaaag acccatacta tcttttccta tgcaatttaa78301cctaacatat tttctgtaaa tgaggttatt tagttatcca tttttctacc tcctgttgct78351tggcagtcct caaaaccatt gcagatcttt ctagagagca gtttttaaga acagtgcttt78421acttttcaac tcttgatcaa cctgatgaga attctttgaa taaaccagaa ggaaggctaa78481agagacaaaa gaatactata gtttccttaa agttaatgag ccagaatcct ttggcccact78541ttggcattga acaatgtgaa taaaatggcc actctcacat cagtaattta cattttatac78601agtgtgtact ttacactgat atttacaaag aggaaaaaca acagtttttt acatgtaaga78661ggagctcctt ggcagataaa agaaaaactt actcccatta gtacaacact ggagtttaaa78721tctagagaac aagtacttca gaacctagta gaaaaagtcc ctgatttgta ctttgtatga78781acaattaggt ttgagaatat tgctatataa tcacagaaaa tactggctat tatactacgt78841gaagtcttca gtgacaaaga gagaaacaga aaaaatagtt aatgccataa caatgaaaat78901gtggaatgtg aggaacgccc agtgaccgta aatatctacc ttaataagcc tgacaatttg78961tatacagttc atgcaattaa caagtgtgat aaatatgatt attactctca agttgaaatc79021aattttcttg gctaaaagca aagaattgtt attgagcaga tgggattact tttctttgcc79081aatttatctt cataaaactc aatcaatgcc ttgccttaaa aatgtcaaat aactcagatt79141tcaggataac acatacaaac taatctcttc tgcctgtctc tacctgatca ctccctactt79201caaaagctcc aacaacatag tataactgac acaaatcaaa gcaaaaacta tttttctcac79261tgctacatgg tcttatcaat aatccagtat ttcaatatct aataaaagat accacaattc79321aaagcagtaa tgtgccccaa gctaccgatc cacaacatat atattgatat ctaaaaatat79381atggatataa cttgttatct actaaataag tttctttgca gtgtggtgtt aatagccaga79441attttaaata cataaaaact tgggttcaaa tcctaactct gccacttaaa tgctatatga79501caattggtca agttacttaa cctctctctg gtctcaagtt tcttgtctgt aaagctgtaa79561tagcttttag agtgctcttc tgaatattaa aaaggcatta tactcttagc ataatgtcta79621catagagtaa atatttaaca acaaaataac aaatattagg tgtgttattg gagaattgga79681gttttaaata aaggagttgt ccctaaggta cattcaattt aactatgata tttaaaactt79741caatttttca cattattttt ccaggaaaat atttcactct tatttctcca taatttgttt79801tgaattgtaa aagagatttg caagcggctg aagcagttac actatactgt atatctgcag79861gatgggcaac tgattttttt tttcttcttt tttttttttt tttgagacag agtctcactc79921tgttgcccag actggagtgc agtggtgcga tctcgctgca acctctgcct ctcaggttct79981agggattctc tgcatcagcc ccctgagtag ctgggactgc aggcacacgc caccacgcct80041ggctaatttt tgtattgatt ttcaagattt gtcaagagct cctaatattt tcttttctca80101aacacatctt aggactacca tgcatatcag tcagtcagct actctggagg tctgctgcaa80161ggatacacac cttccattcc cacccatcag atacttgtct cctttctccc ccactccaag80221acagcaacct tccagctcta gataaaaaga gctagtcttt cttgcataag aacaacaaag80281acaaaaacca ttttggtagt gtatactgca gattttaacc aaaacttctc tgaagacctc80341tgatttccta aaaaacctct tcatcccagt gcagttgctc tttcctaaat gagcaaccgc80401gcatctggtc aaatttggtg aatattctgt gctccagaaa caactgattc catccccttt80461aatctcttct tctcttatat ccatctccct ccttgttgtt tctctccatg tttacaacta80521gttcattgat ttaaaaacca atgtaataca caaggaagta tgcacgacaa tgtttagtgt80581agtatggttt gcaatattaa aaaaggccat cagtaagaaa atagttaaag gataaacttg80641atatacatac tatgctgcaa tttaagaaaa ctggtataga tttatacgta ctaaaataaa80701ataatctcca aaacatagta agtgcaaaga tcaatcacaR aataacatct gtagtatatc80761acttttgatt tttaaaaatt acccctaatt ctaaatgttc atatatataa atattcagtt80821aaaaattctg aaaagatact gctatggttt gaatgtttgt tccatccaaa actcaggctg80881aagtttaatt gccattgtaa cagtattaag aggtaggact cttttttttt tttttttggt80941gacagggtct cacttcaaca cccaggttag agtgcagtgg catgatcata gctcactgtg81001gcctcagctt cccaagctca ggtgattctc ccacctcagc ttccagagta gctggaacta81061caggcacatg ccaccatgcc cagctatttt gttgtatttt tttgtattga tagggtttct81121tcatgttgct caggcaggtt ggtctcgaac tccttacctc aagtgatcca cccacctcag81181cctcccaaag tgctgagatt acaggtgtga gccaccacat ccagcaagag ttgggacttc81241taagaggtgt taggtcatgt gagctttgcc ctgatgtaag ggttaatcct gttatcactg81301gagcaggttt gttataaaag agtgagacgt ttggtcccct ttcctctctc tctcccaatc81361tgtctatctc tctccctttt gctttctgcc atgtggtgat gcaacaaaag gacccttaac81421agatgccagc accttgattt tagatttccc agcctccaga actgtgagcc aataaatttc81481agctcatgat aaattaccta gtctcaagta ttctgttaga gcagcacaaa atggattaag81541gcagatatac accatattgt atccatcact aagtggatac tttcaagaaa gacagcaaga81601ctaaggagca tgaaaaagga ctttctcata ttctgaattt taaaaatatt ttatgacatg81661aatatattta tctattacct atgtaataaa actagacatt aagagaaaaa tctcatggta81721gaaatcttag gaaatagaga aaaattagag aaaattaaga aaaagcatgc ataatttcac81781aaaccaatgg tagccactgt aaaaaaatgt tatttcattc taatacattt ctacacacat81841atgcacacag tgcatttttg aaaacataac tgagtctttt ctaattgacc tcttactcta81901caaaatttga aatagccaaa acaaattttt gattcctata aagagatagc actagagctg81961gaagagatgg ctcatgcctg taatccctac actttgcatg actgaggcca gagaattgct82021tgaggccagg agtttgagac cagcctgggc aacatagcag gacccatctc tacaaaatta82081ataataataa taataataat aataagctgg gcataatggt gtgtgcctat tgtccttgct82141acccagaggc tgaggcagga ggactggttg agccctggaa gttcaaggct gcagtaagct82201atgattgcat tacactctac ccagtgtcaa ggaaaggaaa ggaaaggagg ggagaggagg82261ggagaggaga ggagaggaga ggagaggaga ggagaagggg aatgggcagg ggcaggggca82321aggcaaggaa aggggcaggg gcagaggcaa gggaagggga aagggcacta ggacctatga82381gccaacatag gctatggctt ccactagtac aacttaaaac tcagctgaag acatgacaca82441tagaaaaggg ttgctgtgtc tgtacacaca cacgtttccc atgttcccaa tcccagtctg82501tggtcagtga aagtgaagat tgcctcagag cctgcattat ctcaagctac tgacctaatt82561gctaatgctt tactctggYc tatttcctgc Mtgacctcag aatgtgtcag tgtaaattcc82621atagtaagac agtagttgca cattttggag tgtggattct gctttgaaac acaaataagt82681gtgatgaacg tgaccctggc actctgtagc cctcagtttc ctcaacgcta aattgatcac82741tacagttcct tctagtgtaa acagtcccac gaagaatcgt gctgaatgga tgactacata82801atggcctgct cctagagttc ttaaatcaat ccttaaaact ggctgcaaaa tgacttcact82861cctttaacag tgtgggactt gtctctgttc tccagaatgc tcaccagatg gtgaagaagt82921atctctctac ctaccaacat cgtcatattg cttcttgcca ctcgctactc aaaaaYtgtg82981aaaaacctgt gggagcaagt atcagctgaa aagggtggct ttctccttag gcaaaagctR83041cagggcaaaa cgggggcccc aaacttctat cacgtcaaag acatgaaaca gatgatccct83101agttttgatc ttctttgaag tttattaaaa acaagcttga atctgtacca atcctgacag83161gtgtgaatgt aagactcaca aatgagaaat gctaagcttt cctaatgttc aatttaatct83221tatagaccat gaaacatgtt ataattaaag atctgaacta ttaatatgaa ggagatagca83281tatattctta ccccaaatat gactaactag gtaaaatctt caaaatataa tcatggcctg83341attatcagcc attgtggagg agaattttaa aaagttcttc attgacatcc caagtttatg83401ttttagacac ttctaatcaa acatgaatag attaacttca agtaaaaatt aatagtcaca83461ttattgatta tcatgattgg aaatgtattt gaccagaaca atgaggaaag agcatagagt83521cctgctatct tcaagtatga atttacactt ttaactgatg tcaagtcatc catagtatga83581aaactcattt atttttattt gaaaaattta aaaccatcaa aatggatagt gtgggagcca83641aataatatat aagcaatatt ttatgagaac tacaaaacta ttaagagcag taactagaat83701tcggttactg ccgttcctta tttcagaaga gaaagtcaaa tgttttctga tatttaagaa83761gtaataactt cctgttgtto agttatgctt tctataatta tatatgataa gcaacagaaa83821aataggtctg gttttggctg taatgtgtat attcaattca atattaattt ggactttaaa83881tcattttgct atcaaatatt ttgaacctca tgaccaggaa gtaatcaggt aaaaaaaaaa83941aagaaaaaaa gtgggtttgt tacctgacct atctcttaag ttcaaacttt ctataggtat84001ttttctctac ctttgtccat atggttatac aattatcact agatgcttga attactaaat84061ggttttgtat atcttttcct caaatttata tttgtcctat tattggctta gtctctcaaa84121gtattacttt tatgatattg ctataatggt cctctatagt ataaagttga gcccacacca84181tttatcctgc cacttaacaa tgtccttaat gtagattata tggtttggcc atgccctaac84241caaaatctca tcttgaattg taatccccat aatccccatg tgttgcggga 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caatattata85141aagatatcaa gtcttagatt aatctatgag ttaaatgcag ttacttttgc cctaaaatgt85201taaaaggctc ttaattatgc aattcgaaat gtgatgtcta ctttcttctt gaaagcattt85261ttcctggaac cttctgatga ctctaactta ggctgcctgc tttctaggcc tactactaca85321cagttgtcat actgggattt attttcataa acatctgggt tggttccaat gctctttgta85381tcctaggttt tctgtatagg attcccgttg ctttgttttg cttgaatata tcttcgagta85441atacttcctt ttaattagga agaatctgta ggaggtaaag ttgtaaactt gagtccttcc85501atgtttaaat acatctttag tttgtcttaa cacttgatag tttgactatc aattttgggt85561tctagttctt cttcctgaga actttgaaac cttgcctagt ctgcattcac ttctaatctt85621gctgatgaga agtttgatac ctttgaaaga tccttttttt ttgttctctg gaaggattaa85681tttcttatac ttagaattcc aaaattttca tcagcatgtg tatacacatc tagatatgta85741tccttttttc cttgttcggt gttggatgaa acttttcaat ctgaggactt gaattactct85801tcaggtcaag gatttttttt ctgttatttt cccacatcct ttcccattcc tccacttcta85861ccacattctt catatctttt ttacttttcc atcRtatttt atatccttgg ctttttgctc85921tatattctaa gatatttgct taattcaata ttcaagaatg aatattactt gaattgcatt85981ttatccaatc tttatatata catatatatt cagtattctN ctatttatgg aaatcagatc86041atacttaatg gttatattct ccccctgaat atctctgaaa atttaatatt gacaaatttt86101tcccacactt ttcattgtct ctgtttcttc tggaaagcag aagataaatt gtctcaggaa86161aataaatttg tcctgtttat ttattagttc ctttttgttt aggctactgg tttttttgtt86221tggtttggtt ttttgtcttt tttcaaatgt ctggtgatcc tttcttgact gggaatattt86281gtaatttaag aactaggagt ttcttaagta gttggcaggg atatcataag gagctctgta86341gtacttataa actgcttata agcaacttaa tgcaatttca atcaaaatct taatgggttt86401ttttgggggg gacttgacaa gtagattgtt tgtataattt agcacaacga tgtgagaata86461acccaggaaa ttctaaaaaa taagattaag agggaatatg ttctcccaga tattaaaatg86521tatttcttaa aatccataat aattataaca tggggctttt tgtctagaaa taggatgtaa86581agattaaaaa aggaactaac cataaacagt agaagtggca tttcaagcca ataaggaaat86641aatagattat gtaataccta ggattctgac aatttagaaa atctaggaaa agaacatcag86701agccctgaaa taaagtaaaa taaattccat aattattaga gatataaata tatgatgtaa86761aatgattaaa tactagaaga aaatattggt gttggaaaag aattgctaag gatttataaa86821atatatttat atagagacta tataaacaat ataaacatac aggctacata gggactattt86881aaacttctat ttattaaaat agagtatctg taaaagtaaa aatagaaatg aataaatggc86941aaaaaaNtgt aaaaaacaaa cataaatgaa aagttaatat tcttaatctc taaagaacac87001tctaaaatca ataagaggcc aggggtggtg gctcacacct gtaatcccag cacttcgaga87061ggcagaggca gtcagatcac ttgagtccag gagtttgaga ccagcctggg caacaaagtg87121agacacctgt ctcctaaaaa ataaataaaa ataaaatcaa caagaaaaaa caaatcagcc87181cacgaataaa taataaaata ataaaaagca aatatgtata attgccatta gacacacaaa87241acagatttta atattcttga agctaaatta attcttatta aaacaaaata ctatgtgatt87301catcaaataa agagaacaat taaaatgata aaatatagca acggaaataa tgtagaaata87361gagactgctg atgaagtata tataaacttt ctgcagggca atatgacaat aatagcaaaa87421ataaatcttt aaaatattgg gcaattcttt agtttgacaa ttctaattct agaaatatat87481agtaagaaaa caacccagcc ttgctataaa gactctacac aaagatattc atcacaatag87541tgcttataat gtgaaatctg gggagagctt caaatattta ataatagaaa attgcttaag87601tgtagtatat tcatgtaagg aaatgccatt aaaatgttat atagagaatt gtatttaatg87661gtaagaaaag tgttcatgat gcaatatact gtgaaatttt aaaagcagat tataaaatat87721taccttcagt ataatctcat tgttgttagt aaaactcctt ctctctctac atacacactc87781tcacacacag agacagaaaa attatctctc aatggcataa ttattgacag ttcgttttct87841cccccttgct tattattatt ttgtaataga tatgctatag ccactcaata aatatttgtt87901actaatttca aaaagtatgt attattatat ccaggttgtt catggaattt atcatgcaaa87961caactaccct cttgagagag tcaaaagtgg acactataaa ttatgaattc atataaacta88021tatcaggaca atgggcataa actgagtgtc ccaggcacgg caaaatgtgc ggataccctg88081gagatgtatc ttgactttaa gaagtttaca atctttcttg gggatagaag attaaaaaac88141atgaaaccat tagaaataat ctcccacaat tagttttgta aaagcaagtg cttaattgta88201cttgacaaac attagatgtt actggaggtc taagaagtaa gagctgaata ctcgtcagaa88261aagctccctg gaggaagtgg ggactgagtg atacttttag aataggtaag aaaaagaata88321atgagaactt ttcaaatgga ggttggggtt gtagaaggaa aagaatcaag tattcagagg88381tagctgataa cgatgttgta tatataaaat caccctgact tttgcaaggg gtccgtctat88441acagaagagt aaaaagtaaa caatctatta acaatgtact atcactgcct ccactttaca88501caggagaaaa tcgaggcttt agaaggttac ataacctgcc aagggtcaca tagctaaaag88561tggagagctg agatttgaac ctaaggagtt ggtttcagag tctatgcttt ccaccctatg88621ctgtactgcc cactacagtc aagctctggc ttcttgtata aatctgatgt cactctttgt88681gggactgctt ataacatttc ctcacccaga atccatacct cctcctttct gctctgtcag88741agctctttgt ctattcacac acagttcaaa gaataccttc tccatcaaat ttttctaaca88801attccaatct tggaattctc tcctaccttg gagttgagaa caccactctc ctaaatttct88861gcctacttct cagacactac ttctcaatct ctttgttgga ttcttctttc tctatatttt88921tSttttttta gtctactcat tgcctgtgtg agtaccttca cccccaaaac tacaatacct88981acctaccatt gtgctgaaaa ccccagctta cattgctctt ccacattcca taaatttcta89041tctggatgtg cacagacacc tcaaacttca tatttccaat actggcattt accctatctg89101cagtttttac tatcttatgg acagcagatg ccagaaatct aatcactgaa accagaaacc89161catgtacaat tcttgagtcc tccctctctc aagcctaaaa tcctggaagt caccaagttc89221tgtctatttt actctataaa taactattag attcttcttt catctgaact cccttagttc89281aagccctctt tgtttctcat atgattattg tagtaggctc tgaactggtt ttcctggtac89341ctgtctttcc cctgcctact ccaattctac ctccacatca acatttctca aatttgaggg89401gtcatagact tccaaggaca tttccacaat ccctgagaag tatacagttt ccatatgaga89461aatcactgta gctaaaagtt aaatactttt cttcagttga ttatgtatag ctaaggcaat89521aattcaagca ttagtaaata caaagccaaa atgcaggcac attacgcaga aaatgcctgt89581tcttgggttt ttaaaaaata cgttaaaaaa ataaggccag atgtggtgac tcccacctgt89641catcccagca ctttgggagg cYgaggtggg atgattgctt gagaccagga gttcgagacc89701agccaagaaa acatagggag accttgtctc tacaaaaatt tttaaaaatt agccaggcac89761agtggtgcgt gcttatagtc ccagctactt gggaggctga ggcaggagga tcgtttgagc89821ctgggaggtc aaggctgcaa tgagccatga ttgccactgc tctccagcct gggtgacaga89881gcaagaccct atctcaataa ataaataaga ccacaaagga aaaaaattct tacagagaat89941tattgaagta taaattgtgt caaaattgaa gaatataata aaccctaaga ttaatagtcc90001tgtccttgag aaagatcatc aagtgatgcc cccatgcttt aaaaaatatt ccaagctttt90061tagcataata tctaacattt cttagcagtt cctaataggt tacttctctg tagttacctc90121tctcactcct tccccatcac ctatagtgcc acaatctgta acctgtttga ggctctctca90181cacctttcat actgcaatat ttgctcgaac tattgacccc caaccttact catctttcct90241ttctaactaa ctaacttctc ctcatcctca aagccccagc tcaagaattt tcatttctgg90301aagaatctct gattttcttc tcttctctag tcttgaaatg gtatgtgtga acccacagct90361tgttgtaatg tcattgtcct ttctgtttaa caccctcagt tgctggtcct tgaagtctgg90421gactgtctta atctacttta aagtcttcaa gccaagtaca attcctaggc atgcaataca90481tgtttgttaa atagatggat gacctttatt tatatttatc tttccctttt ctgctacaat90541tagttaactc attcatttct tcattcacta ataaccactt atctgttatt ttctgggaat90601acaaaaattc ataaaacatc atccttgcct ccaaaaaaca ctttattatt gtgccatcct90661tctctctctt tctctttctc tccttctcta attatctagt tgtgtaggta ttttcttcaa90721aggaataaca ggtactcaga ggaacactta tacactgttg atgggagtgt aaattagttc90781aaccattgtg gaagacagtg tggcaattcc tcaaagacct aaaaacagaa ctagcattca90841acccagcaat ctcatttctg ggtatatgcc caaaggaata taaatcattc tattataaag90901acacatgcat gtgtatgttc attacagcag cattaacaat agcaaagaca tagaatcaac90961ctaaatgccc aacagtagta gacaggataa agcaaatgtg gtacataaac accatggaat91021actatgaagc cataaaaaag aatgagatag tgtcctttcc aggaacactg atggagctgg91081aggccaatat ccttagcaaa ctaacacagg aactgcatgt tctcacttgt aagtgggagc91141taaatgatga caactcatgg acacatagag ggaaacaaca gacactgtga cctatcagag91201ggtggagggt gggaggagtg agaggatcag gaaaatcaac taatgggtat taggtgtaat91261atgtgggtga tgaaataatc tgtactacaa accccatgac acaagtttac ctatgtaaca91321aatctgtaca tgtacccctg aacttaaaag ttaaaaagaa ataaaaaata aacagaatag91381tagggattca ttacaatatc ttctctcctc ctcataattc ttaaacctgt gtagaagttc91441aatacatatt tgtggaatag ccttattacg cctttaggga atggagcaat gccttgccta91501ttaatctata cttctatcag agtttcctgc tgtatggaaa acctgagtgt tacacttcaa91561acaaatgagg caatttatac atttttgttg ttgttgttgt tgttgttttt ggcataaatg91621tgctaagtga gctggagttt cagaagagaa actgaatgtt atatgtgaat ccaggtcagt91681agcttggctc tgactacaat actgatttca ttcaagataa ggaaactaat tggtatcaat91741tttagttgac attatatgtt agttttataa tattcaggaa tttttgaagg attatttgat91801ttttattttt atagatgttc ttgctcttta acactaaata atgaggaaag ataatagggc91861taacatttat taagcattta tgttggacag gcactgcttt aagtattttt atatgtatca91921actcattgaa ttttcacaac tcttagatct atttgatagc tggggaaact gaggcacaga91981gaacctcaag taacttgccc aaggtaagcc agctagttag catggaccag tgattcaaaa92041acaggcagtc tgtactcctt acaactgtat tatgctgcct ataaaaggac cactagacta92101ataattatga aaccagattt ttaatcttaa attagccata taatagtaga gtgcatttaa92161ggatgtcatc tgagtttcat tgtccttgta ccccttacag cctgtgagaa ggaaccttta92221tatagtcttt cataaactgt aaagtgttat aaattcaaag atttcttata atatgttaaa92281attactttta agagttgaga agtccaaata aaagcagaga gatgagagga aacactagca92341ctaaatgttc agacacccac tgaccaYgtc aagctgcaca ttttgttgct aaacctaagg92401gagagattag atatgaggag agtgggaagc aagaaggtat gaagtctggg tatttaggga92461ctaatagaaa tgattttctc gattagttta agaacattag caattactta cgggataagc92521acagttaaag gaatttctgg aaggaataaa actataaaaa ttagtcaaat tgttaaaata92581tcagaactgt gtaaaagcat ataaagtttc atcatatctt tcttttgaaa aacaaacaaa92641cacttcatgt tctagccagt tgctaatagt gatcagttga tgaatacacc tcatgtttca92701cgcatataaa attttacacc atgtctagtc cataggcatt agtgtaggag tcagaataca92761acctgaattc tgttcgcagc tttgtgcctt gtcgataaag cagtggacat ctctccacag92821ggagatatgt ttcctcccgt gatatagagg atgttgattc acttgtctcc tctctatttc92881gaaaagatgc tctgaagatt agtgagacaa tggctgtaaa gCtctttgca ctgtttacaa92941cataaatcat acacagacat actggcatga gaaacgctat catcatctct tttatacatg93001agaacaacca taaggaaaac aaacctcaga gacagtcctg tattataaaa atgttgggta93061gagatgccaa aagttgtagg gtaggaaaca gcaacaacaa caacaagacg gaatccaaag93121aatatttgca ttctataata tattctacag agtYtcagac gggaccttcg ttgagtgctc93181ccaagtatta tcagtagcca tgtttttttt ttctttttct tttttttttt tttttttttg93241gtaaaaggga taaatagtga tgtcaggaga tgctgcaaaa tatattccag tgataagcat93301atggcaagca attaatggat gaattcgcct ctcttattgc catgttgtga caaatactct93361aacttatttg gcctttggct ccctaaaggg tgctcagaaa tgctgtttag aaagtacttt93421tcatgaagag ctacaacaac aacaaaaaca aatacaattc aaatatctac taaacatatg93481aaggagtact cactctcatt agtaatcaga gaaatgcaat gatcccatta tagagccctg93541tcatttgaaa aaaaagaaag aaaatccaag tgttttttat tagaacgtgg agcaacagga93601attctcatta ccttctcaac cactttgtca aatgctttct gcttatctgc tgaagttaaa93661gatatgcatg acccatgaat ccactcctag gtatattccc ccacaaaaat gtacgcttat93721gtgcatcaag atacacgcac ataagtgttc gaaatatctt tattcataat atttccaaac93781tggatatgtt caactgcata aagaaagaag attggacagt aaattgtggt tcctttatac93841aacagaatgc tatatatcat gatatatatt atgatgtgca atcctcagct acatacaaca93901ttgatgaatt ttacaactat aatattgcac aaaaggagca aaacacagga gtatctacaa93961gatgagtcca tttacataaa atgcaaaaca aactaaattg aactgttgtt ttggcatgca94021tacatacgtg gtaaatcata aagaaaagta ggaaaagtaa aagtaaagtc aagatagtgg94081tgacctatct ggagaggatg aaacaggaaa ttatagggtc tttctgaggg gtgatcatag94141taggtattta ctttagaaca atttgttaaa cttaaaattt aaattttaca tactttctta94201aattttgtta tatttcacaa tttaaaaatt tataaaatga taattttaca aagcctaaaa94261gatgaattat ttgggggctt ttacttctct ttcatctgta caactgctga tgaaaatcac94321caggtgtgta taacatgaag catctcctta aatgacatgc atttattggg aaaaaacaca94381aagtccaaat ggtaaaatgt tagcaaggta aaacactgaa gatttttctc cccaaaactg94441ccaaacaagt ctggtttaac tgaaattgac agcaaagaca acagagcaca cttaattgaa94501ttttaatctc agtgatctct aagccatgtt tgaaacataa acagacatgt cagagttctt94561tatgatgttg gacatgaatt cattttcata attcaaaggc atactttgct tatgaatctc94621tttaacaagc tttggctgaa tattcttttc ttccagatgt ttgctgttgt atacacacag94681cttccatctc tttgcagatg atttaaaaca tagttagaaa gagtacattt atttaacaaa94741agagtaagag tacagaattc aaatagatcg tctgtgggtg tatataatga tgagtacata94801agtctcatgc agtcctcata aagacagcat ctattaatct gaagaagttt ctcttactaa94861tttgcaaacc taaaagcatt ttacattact aagatattaa taaataggtc aattaatact94921tttgatagag tagagagact cctaaataat ggacatgaaa aatgattttg taaaagtaYg94981gtttcatttt aaatccctgc ttaagcaatt tgtaggaggc aagatagtgt ggcagttgag95041aggatggtct ctgaaatcag atctgaattt gaataccacc tctaccattt actaacctaa95101acaagtcata ttacttctct gtgtctcaat agctacttcc tgaggtgttc ttacaaaaac95161acaaataaat aatccatgta aagaactttg cacagtgcaa atacatagtg agcacgcatt95221gagttttatt tatcatcatc atcatcttgc tgtacttttg taaactcacc ttctcccgtc95281tttttctact ctaaggtgct cttccaagct actttcctcc tcagctatcg ttcccctgga95341tttccagtaa gagagggtga aatcatgcct gcttatcttc tttctctttt actgatactt95401cactgaagtg aaagtaaagg aataaaaaca caacacaccc acccacaaag gcacaaataa95461taaaggaaac aagatcagca aaggagagat ttctactgat tttttgaaat cagaaaatag95521ctgaagtgcc ttagcataat cgaggaaatg gttacggaga gtaaattcca agagaaagtg95581gactaatgtg ttctcccgaa tccagaaaga cttactgctt ggaggcagca gaattaagga95641aggcaggagt ttagcgaggg gctgaaagtg tattaaaatt atatggagcc tttggatcca95701aactaactac ttcccttacc tactggaagc ggagtctttc ttttttggag gaaatcggct95761agagagattt gaaactgatg atactaggca ctgtagcaaa ctaggagagg ctgcaggttg95821cgaaataggt gcttatttga aagcctatag agtttgcaat aagaaaccca acttttttat95881ttgtcatgct ccccagacat tagcagtcag ttatatgccc caggcgcaaa tctcgcaggc95941agaaagtggg gtacccccta atcatgacct tggggaaaca tttcaaagaa cacaccggct96001ttgattgaac aacctatgat gcaacagtgc aaccctacag ttgacgagcc ctatccatga96061tcacagaact tctgacattg tttcttgcca tcattgtcat tgttgctttg ttttgtgtgt96121gtgtgcatat gcacctgtat atgtcttgct tttaactaag aatgaacagc ctcttaagga96181aactctccat aatgaagaag agaaactaga agaagcaaac atcaactgaa gaaagaaatc96241tacaggaaag agagagacag aggaaaacct caagaggata ataatctgtg accttagata96301aaacacactt ctgacataag aacatatacc attaaaaagg agaggatgag gctgggcatg96361ttggctcatg cctgtaatcc cagcactttg ggaggctgag gtgggcggat catgaggtca96421agagatcgag atcaccctgg ccaacatggt gaaaccccat ctctactaaa aatacaaaaa96481ttagctgggt gtggtggcat gctcctgtag tcccagttac tcgggaggct gaggcaggag96541aattgcttga acctgggagg cagaggttgc agtgagccaa gattatgcca ctgcactcca96601gcctggtgac agagcaagac tccgtctcaa aaaaaaaaaa aaaaaaaaaa aaaaaaagga96661gagaatgaga gtgctaaatt atttttaaat catgaccaaa ataaacattt taatagtaag96721gttggaaaat aaaaatgtgt gtgaacaaat cttctagaag accaaaaaac aaaaagacaa96781aaaaggaaga aaacaattaa gaaattaaag gatatgatct aggagatcca actaagataa96841tgagaattca aggaagaaag aacagagaaa atagagggca taaaattatc aatgaataag96901agcaaacatt tcagaactga aggactcata tctctggagt gaaaaggtct attgcgtgcc96961cagggcaatg gataaaaatg cagaccaaga caattgatca tgaaatgtgg gaacttcagt97021aaagaaaaga aggtcacaaa aatttctaca cagaaaaaga tcaggatttc accaatagaa97081aatactggag tgatgcctac aaaatgttca aaaaaataca tttttaacat agaatccaat97141tgcagttaat ccatgcctga gacaaaaaaa ggtttaaaca aagggctgcc tctgaatagt97201atatagaaaa gatttctgaa cagaaaatct taaaaactag cttttatccc caacttggat97261actaaatata gagacaggca agaattaggg gtcttcttgt cattcttctg agactctgga97321gctcctgaga cttctttttc actaacacca ttgaatccgg gaatcaacaa gctgcacaaa97381gttataaaga ttgccagact tcatgtttct ggaaaaaaaa aagtactatt ttttcataca97441gctgagacct ctgaaaagat ggctcaatgg gcaagatgcc atgagaaatc aaagccaaat97501actcattctg aagtcagttt tgctcagact ttgtatactg ccactcaatt tttcaagtca97561tcagaaacat aactaagaat gagtgacttt ttgctatYaa ctaatgaccc accattcaac97621gatcttgtat gacaaagtag aggagtatct tcttattttt aggcttatta aattacaatg97681gaaaatattc attaacaatc tcataatgag gcattctaga tgcttattct tacctaaagg97741gaatggaaca aaaaataacc aaaaactaaa aagatgaaga caaaagcctt tcttggtatt97801atagtattct tttacaaagg atatggttta tcatagtaat tgattccctc tgttacacta97861gagatactat tatattaaat gcctaaaggt taaacttagg taacagtgga gctatagttc97921tttcagaaat aaaataatta aatagctatg tatgccaaga aaccttactt tgaacatttc97981tattgtacca tctcattatt gctggctgcc tgattagcaa gcagtaaact tgggtaatag98041ctttcctctg atatcacttc aagtctactc gagttctaga attacccaga ctaccaggac98101tttacttgca caatatgctg aaatgtttat aacattatgc tttcccctcc taattctcaa98161gaccattttg ataactggct aagactggat aatatcaaca aatatgaaat aattataaga98221atcattcttt cttaaaataa gaagagtttc cagaaacaga aactaaaaca gaattcaggc98281taagctgcta aataggctat ctcagggatt ctcagctcat tcttgatgag gatagattgc98341tttttatttc ccttaagtgt tccgtattta tttcacaaat attacttaac tgtgtaccat98401gtacaaagcc gtgtgctagt taagctggtt actgtggaag aaataaaggg agtgggagca98461tctagctttt ttcttcaaag gagatggggg aatctgtggg agttagtggt aggggcacct98521acagaggaaa tWgctgaaaa ggaggagctg gggaagatga ggatgaggaa ctaagttgtg98581aataaaggaa gggcagagca atggtttttt taataatatt ggaatgggat ttgtttttag98641cactgctccc ctttccctta acagtcccct tgagctacaa ataaatgtaa ctggcaaagt98701ggataataag acttcagaat cttctagcta accatgatca atgtgtcatg


Following is a genomic nucleotide sequence of a GPX3 region (SEQ ID NO: 5).

>5:150384801-1504848001ggcttatgtc tacaatccca gcactttggg aggccgaagc aggcagatca cttgaggtca61ggagtttgag accagcctag ccaacatggt gaaaccctgt ctctacaaaa aaatacaaaa121ttagccaggc gtggtggcac acaagaggct taggtggaag aatcgcttga acccaggagg181cagaggtttc agtgagccaa gattacccca ctgcactcca gcctgggtga Yagagtgagg241ccctgtctca aaaaaagagg aagaaaggaa gggagggaag gagggaggga ggaaggagca301catacttgtc tgaggatcag taataatacR tataataata acatctgact ttcattgaaa361acatattatg tgccaggtag tattctgagt gcttaaatct attgattcat tctgtcctca421caactacaag gtagtcactg ttactattct tttttataga acagaaaatt gaggcccaaa481gagatcaaat aacttaccct gtccctaatt agtaatggag ctaggactca gaccatggta541agctggattc agagcctttg tacttaattg caatgcctct tScatatgYg ctaggtaggg601aacaaggtga tagcagaatt taatagtcag gattgatgca gtattcctga actagtatag661aatgagctag attaaaaact cagcaattag aattcagtag cgaatcaaat cctgagataa721gtaggatttg gcttatcctg tggccaattt tcctcgtatt aaacatataa attcatgggc781cttcacaccc ataaaagaat aaattagtat tataattttt aaaatatgat taaaattagt841gctttctgaa gtactggtta ggtgtttctg tttgcaaaga gaatttatgg ttttgtaaga901ttagtttaat gttgatggtg gaatagacaa gagccaaaag acactagaag caaagagaaa961aatgaaaatt aaactatagc aatccagcag ttagttaata aggctgcagc tcagatattc1021ctgttcctca tccagtcctt actttttttc tccaatcacY gttgtYaccc tggtcagttt1081taattctgct aaataagctc tccccactga ccctgttgca actgtccttc tttgttcctt1141tttactattc ctcaagatta tttagtgttt ctgcccagtt tgcaaaatcc tatttgtata1201tagccatata tactttgttc attgtcatat tctgtttctg tttctactac tgcaattttt1261aaaaaatgtg gttttctttc ttgaaatgct cagggggata gactccattt Rgccttgata1321tttcttgtag gccatatgta tattatgcat gaaagtaaag attcaatctc ataatatgac1381aaaaagttat gagtcataat acattagcag atatatttac cagtatatag ttaattgtgc1441ttctttctag aagtctggca agacttccaa ccacatgcag aggcaccagg agaaccaata1501aacacttttg aggcatgttt cattaataga ccagggaact gagacagagg aaaggKgtga1561caactgtaat gctcttgaaa atatatttca tctgagccca gactttattt caaaaattcc1621aaaaatgtgg ctgttatggt aggaatttga actaYttgga tttatttagt ggcaatagaa1681gatatgccac aMaaaaaaag agcatagtga atgtgaaaaa gcctccttcc agaagtcaga1741cctcattatg caaaagagaa ccataagaga gaaaagccct taatatgtac taagtgtggg1801aRaaccttca gcagggaatc aaatctcatt atacacctga gaatccatac tcaagagaaa1861acctacgagt gtgttgaatg tagaaaagct ttctcccaca agtcacatct gttgaacgtt1921agagaattca caccagggag aaaccctatg agtgtggcga gtgtgggaaa gcctttttcc1981aaaacttaca cctcagcatt tacaggagaa ctcatactag aggaaaaccc tatgtgtgtg2041atgaatatgg gagagccttc Wgcctgaagt cacacctctt tgtacatcag agaatacaca2101caggagagaa aWcttatgtg tgaactaagt gtgagagagc tttcagtgaa gtRtcatgcc2161ttattagaca tcagaaaatt tacactagag agaaacctta tacatgtaat gagtgttaaa2221aagttttttc tcaaaagcct gacctcatac attacagaat tcacacaggg aaaaaaactc2281atgtaaatgc agtcaatgtg taaaaaaaag ccttcagaca tagatcagcc ctctgtcgac2341ataagaggac tcataaagaa aaacatccct gaacaagaaa taaatatggg aatatcttta2401actagaactt gtagtgatag aaagccttca gtcaaaagca aaccttatta tttatcaaga2461aatcttactg aggataagcc tgtttaatat atttataaaa gcgcgcagtt atgtttctat2521agaaaacata ttccagatgt gattcctaaa tatttcttga ggatattaca gaaaatacat2581ttttattaga gaataaatgt tcactgtgga ccacaaaggc ttttaaaata ttaataagtg2641aactagtcag aacaaactta gaaaacRata tgtggacaac ccacaagata tgaatgttac2701tatatgtgcc actacttatt gctgtaagtc ctggctgcac tacattttgc tatgcatcat2761ataaaataag ttatatgtgt tggaattgca tatgtgaatc taaaaatttg taaatataaa2821ataattacta tatatagaat gccatttact aagactttct acattaaata ttaccatttt2881tcccctaaag aaaatacaag ttataaccaa aaatacagtg ttcagtaaga gttctaaagt2941gtaaaataaa cttttttctg ttgctttctg gtatgtatga cttctgctgc ttcttaatga3001gaagtacata aaggtgttaa ttacataaaa tatataaata taaactagat atcatataag3061tctcagtagc aaaagaaaat agtcatggcc tcttacaaga ctcactgcaa tttaRaaagg3121aattcttggt gggtacaatt acccttttta catactgtta tggactgaat tgtaccttcc3181caccaRattc atatgttgaa gccctaatca ccaatacctc agaatatgac tgtatttgga3241catactgcct ctaaagagta attaaaataa aaccattagg atgtgtccta atctaatctg3301actggtgttc ttacaagacc tagagagtag gacacacgag gagacatcag gggcaggtgt3361acacagagaa atgaccatgt gaagtggcag caagagggct gctatctgct agccaagaag3421agaggcctcc aaggaaacca acccttttgc acattgatct cagacttcca gcctccagaa3481ttgtgagaaa ataaatttct gtcatttaag ccactcactc taatattttg taaggcagcc3541ctaggaaaca aatacaaaca ctactgctct ttttccctgg agtactttgt aagcttgagt3601atacaaagta taagtactac gtaagccaat aatatgatag agtgcttgct atactgcacg3661gcatctctat ttggcatttt ctaattcacc ttgtgacaga ttagtaagag agatattttc3721ataaggattt tacaattcac aaatattata aagacttttt gcagagagaa ttgttcattt3781ttaaaattcc atctaacagt aggggtaggt attctgtaaa tttccatgtg agtatccatg3841ccattaaaaa tcaacttgtt ccttatttat aaattaaaag tggggcctca ttcttctaaa3901gcaaattttg acagggagtt aagattacaa ggcagaaacc tacaagaggt gttaagagct3961cttattctgg atttagacag atgtagattc tgaatctgct ctgagcctca atagcaccta4021gtttgttgga tcattgcaag gattatacaa tatcatgtat gtatggtgct cataagatgt4081tagctatttt atattattta aggatataat tcocattcta gttatgaaga cagacaagga4141aacaactcta attaggatta tattagagag aactgtaggg agtcatgtgt atcattctgt4201ttcattctca caaccatgtc agtctttcag actcaggtgt gggcctggaa ccactgccct4261gaattgcccc tctacatcta ttctataatt gcttgttcag aagcaatacc attgctgata4321ccccaaactc cttatcttta tctcatctac tgatgagacc cattgcttgg agggtagtta4381catggaaagc cattcacaaa acaccttatt aactttgtgg gtgaaaaaaa agtgtatctt4441aattgtatta agccactgag atttagggat tgattattaa tagcaaatag caatcatttt4501ctagtagaaa gaaattggtc ctggaagtgt cctgctaatg taataaaaac ctaaaatatg4561gcataggcct agtagttgag cagtgagaaa actgatgtca gaagtggaaa gatgtttatc4621tatgttttgt actagccaaa catttggttt gggccaggcg tggtggctca cacctgtaat4681ttcagcactt tgggaggtca aggtaggcaa attgcttgag cccaggagtt caagaccagc4741ctagacaatg tgatgaaacc ctgtctctat aaaaaataca aaaattagcc agatgtggtc4801gtgtatacct atagtcccag ttactcaaga gcctgaggca ggaggatttc ttgagcccag4861gaggttgagg ctacagtgag ctgtgatttt gtcgctgtac tccagcctgg gtgacagagc4921aagaccctgt ctcaaacaaa acaaaacaaa acaaaacaaa acatttggtt tgattgtctc4981ctctacacat gcttactttg ttgacagctc cagaagataa ttagaaaaca gagtattagt5041aatatttgct gttttactgg ctgtatttgg aagctattgt aagaaaaaga taaactcaga5101gaaaattagt ggattataag caaaaatgaa agaaaataga gtcctgaaat ttgagacctc5161atggagttta aaaaatttga tttctagact tcaaatgtta ggagaataat ttaaatggtt5221ttgagtgtat caaagaccta ataaacattt gctagtgaaa taaagtgact cagaagaaag5281attatattaa gaaactgaaa ccttctcgtt caagcttgat aaccttacag tagtctgtta5341ttcacctacc ctagctccat gatggagaag ctcaatttta ggcagctaca gccaagaaga5401ctggggctcc catacccaac ctagctccca cttgtagagc agaggctctt gccaaggtaa5461gagaggctaa gagtattggg acctcaattg ccctcctcct cagcttttct ctatagagta5521gatgtttcat gccaggaaag gcaagccaaa aaaaagatca ttctcccagc tcccactaat5581aggatagagg ctccagactg gcaggagtac attaaaaaga Yctcaggcct tcatcttcct5641accaagatct cacttgcagg aaggagtatc cctgctaaga agcttccccg gattccactg5701gtagggcaga ggtgtcactt caggaaaatc cggcKttccc ctttgtcccc cgcttctgtg5761caagagtgta gatgttatat ccagggaaag aagcaagatg ggagggccag aagctcctca5821gctcagctSg ggggctgact gtatttaatc ataacatgaa gggttgcatg aattaaggca5881ttgttgaaaa tagagatctt agtggcaagc acttaagaga attctaatag tttcataaaa5941caagtagcaa caaatgaaac agcaagtcac ccggtttaac agagtgaaca agagaaagag6001ctaaaactgg aagtctgtgc atatgtctat gtttcacaca ttcaggacca accataacag6061gtactagctg aacttgagtg gaattgaaag aatttcccaa gccacacgct gatacattag6121caaagagtgg aagtcttact agctcaagga gtgtaagcac aacccctgac caaacactgg6181ctaaatgtta agatattttg acccaacggt gacttctagg aagccaggct tggggtaaaa6241gctacacact gtggggtggg gggcggcggg gggaaataga gtttacaaag ttggtgcaag6301caagccacta aacaaactaa caaaacagag ccacatcaat aatccctaaa ggggatgtgt6361cagaatccag agttgctaca atatattatt tcaaaaacta ttagagatgc aaaagaacaa6421aatagtataa cccttgtaaa ggaaaaacag catcaataaa aactgctttt gaggaggtct6481agatgttgga cctgtaaggc aaagatgcca aagaagctat tacaaatatg ttcaaaaaac6541taaagaaaac catgttcaaa gaatgaaagg aatgtatggt gacaatgact catcaaatgg6601agaatgttag tagaataaaa agtgtttaaa gactcaaata aaaattctgg agttgaaMag6661tagaatacct gaaatgaaga ttcactttag gtactcaaaa gtagatttga gctggcagaa6721gaatcagtaa gcttggggct cgatcattcg atattataca gtcttagaac agaaagaaaa6781aataatgaag aaaacctgag cagacttctg gtttctagtc tgacatgtaa agagcttgga6841agttgtcaat cctatcatca caaccagaaa aaagtctgaa aaactggaaa ttaacaattc6901ttagatcctt caaagaatca aggtcacagg acaaaccact gccccagaaa ctagagagac6961aggtagatgc tgagaatcac aggttcactg acagcggaag tccaccacta aagtcaatat7021attttaggaa cacttaaact acaattgatg aattgctaga gactagcaat aaaagtgcca7081gcattctagt tgatgaaaat gttgtgacca gaggcttaca tgaacctaat cctgtattcc7141tcttggagca attattcagt atttactaat acagtgtttg tggtggattt atttaacata7201agtactgtga ataataaaat caactgtata tgaaatcttg actatccatt tacatgtagg7261agaatcaaca aatggtattc tccacaaatg gaatcaaccc ctagaagttc ctgagaaatc7321cctgttgagt gggaaaggac ctagagccaa ggagacaagg ttggaggtga ctggtcctct7381tcctttgttc ttccactgaa attacttgag aagcatcatg acacatcctt atacacaggg7441tatggtggaa aaataattgg cagtcaaaaa gacttaagtg tatgaagact taagcatgat7501acacatggag aaggtgatgg tgtaaagaat gacaatggcg tctgagtaac attctgaagg7561aggagggaag ttcaaaaggt gggatggtgt gcctggatga gacacatgag ggagaaggat7621tttctatggt gcttctgtta gtttagcagg tagaatgccc ctgtgaaggg tacaggaagc7681atgtggcaga gtgggtgcct aagtctgggt ttagggagac tttagaaaca atttgaaacc7741cagggtctta ccctctgttc acctcataga acagtaaaat cccttggatc aggcaaactc7801tgatgaaaaa cccagactgc catctctctc ccagatggcc aattttcctt ctggtgctgg7861cgaatgatga agttgtcttc aggaaggcag aattctgctg Sgtgctctcc tcttctgagg7921agttatacca ccacacagcc tttgctccca gaaagagtca ccatcttgtg ttctaacatg7981gatcccttgt aagcccatac aaaccactcc atccatactt aactgctttc tccacaaagg8041caactgagtc taggagccaa tggactatct cactttattt tttaaaattt acccagggca8101ctttttcatg ttctttcttc tccctggaac ttactagcat tatggaacac aaggatgtgt8161ttgtggtcat cttctcttta caagataggt cacatagacc cataagtagg ctgtgtatac8221ttttcttaca aaggaggtgt cacttacctt gggaatacca gccagccaca tatgaaatcc8281cagacacagg agacccctaa gaaaaaggcg aggctgtctg taactgcctt agcaactaag8341ccaccagtgg attcaactct taaaattaca gcaccatgga aacacaaaat cacagaattt8401tggatttggg taacactaga gagctcacat aattaaatac cttaatagaa aattctcatt8461tactaattag aagtttttaa ccatgtagtg taaccatgta tacactattc tcaaagagaa8521tgggaatatc ttcttcagtt acttaatgaa aacatacaag gaatctgaaa ccctaacata8581ccagaatcca tgggacaaaa ggaaaattat ttgatcatgg 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tggataagaa9481agagaaatgc tgaagcagaa tttatttcat ctgctttaga tgaatttagg aatcccttgc9541aaggcataaa actaattttg tgatcctttg agtaatatgg atttctgagg aaattctaga9601ttcagagaag tgctgggcca gattttggtt aaggcaatga catggaaaaa tttttcaaag9661aagaggtaaa aatatgtagt ggagtttttt tgtttLtttt ttttcataat caggagtttg9721agagggtata atggaagttg ttaggttttg acgggaaggc gagggttaaa gaaagacagg9781gagagagagt tagcagctct acagcaaaca caagttttat gtctagcaca agacctgcgg9841aggttgggga ccagcttaat gccaaagccc actgccgctt acaggctggg gtacttatag9901gtgtgggtgg gaggggtctg ggcagtatgg cttgctgcct ggcaggatgt tgataagatg9961ttcccatgat gagatggttt ggtctttgtc ctggcaaaat gtgatagtga tgttccttgg10021gctttttccc agcagaatat ggtaagaaat tcaggtggtt gagcaaaatg tttctcatgg10081cctgaatccc catggaatgt ttcactttga ccaatgtctg cgaaatgatg gggggcttac10141aaagtggtac agtttggatt aacattcttg ccttctactt cagtctaaaa ggaagagggg10201cattgttgat tatctagctg cttcctgctg aataggggca ctgtaatcag ggcttgggtt10261ttgaagcagt gggtgtccaa cttcagagtt gttttcctgg agatgttgat accagacttg10321gtggggaaag atggtatcaa tgtgtttctg ggtggctgcc tagacaaggt agttctgcct10381ttgggagata aagtgggata tgaaggtaag tatacatggg ccaattgtga gtattaggag10441gaagattagg ggccctaaga aaggggtaac cagatatccc tgtgccaagt gtagctgaga10501tgcttagtcc tgctaacagg ggaatgaagt gtatagccca cttggtgtgt gtggaggagg10561aggaaatagg gattactaaa gaacctgaat ggtttgattg ttaggcaaaa tgttaatgtt10621tggagattga aacaccaggg tacatgttcc tgaccaactt gccagtaggc aaagaagaga10681gtttgttcca cacagaaaga aaagactggg ggttgacagg caaagttgta agtgaaggca10741gtgagccatg agaagccggg ggttaaatcc tgaacaaact tttgtcccaa cttttttgtt10801tttccaggtt gaataactgt taacaaggat agtccctgtt agggcctgat agggatattg10861gtggtgaagg ctgtctggtt ttagacagag agagagaaat gggtttttgt taacagccat10921tgcggtcctg acagggaaga agaataaagg ttgcagttga gggaattgtc tgtgcatttt10981tttagggagt tcccttaagt tggatgcatg gagaacagtg ctggcagaga agggaggggt11041tgggaaggga tgttttatgg aattcagttt gtaacatgtt tagtttacag gccatgagac11101gaaagagggt gccagccctg cgtgcgatgg tgcaggtagg tttgatggat tgcagggaaa11161ggtgtttagc caagcaagat tataaacagg ttttgggaag ggactggttg agtaggtgag11221atgcaggttt actttggatc aagtttctgt ggttaggtta acaggaaggg ctgtgaactg11281ctggatttgt gtggacaaac aaatttaaca attggaagaa agaggagagt gtgactgatt11341taagaggtaa tgtgtgaggt tgacaaagga agcccaactg ccagaggtta tgggatttag11401agtatcccac agcaaagaca aaaggggaaa aagaagattt gagtacRagg gaaattttgg11461aaggtRccct gcagccatag ctcctgggtt aatgtgagga attggagtgg actatcoagg11521gatgtgggga gggaatatca ggaaagatct gaaacaaggt gtgagataac agatttgaac11581ttggaggcag agagtgtaat ggaccagggc cttctggact ggcaacttct ggaattcttg11641ttaagcatag tgaggttggt cctatgaagg aggaagaata ttttgggggt gagaaaactt11701gtggatgtaa gtctggtgct gtttttagtt tggaatggtg gatttagtgt ggaaaggatg11761ttagttttgt tgccacagga gtagtcagga ttacctggtg aggacccgtc cacttaggtt11821ggagagggga gaaggaattg gtgatttaga cccagttccc tggttgtagg ggcagggagg11881agtgtttgga ggatggactt ttaggctggg gcaagtaagc atttgcgtac cgtcttatta11941gatgttgagt gaggtataat gccagccaag tatcctgtat caaRgaggtg gaggggcggg12001ctgggggcag atacagggag attttygagg ataaaagggc attggtacat gaattcaaat12061gggcttaggc tgaggggcgt gtgagcaatg gcttgtaaat tcatgagtgc cattggaaga12121agtgaagttc aggccatttt aacctctagg aagtttggtt atttgttgtt ttaaaaaggc12181attgacctat ttacttttat ctgaagattg ggggcagtaa ggaacatgaa aggcccattt12241aatgtttaca gcctccacca actgttggtt aacctgtgaa acaaatgttg gcccactgtc12301taaccggatg gaggagggga gtccaaacca ggggatcata tgggtgagga gaatagaagt12361gatggtgtgt gccttttcgg tggtggtagg aaaatctttt atccatccag agaatgtatc12421tacaattgtc agaaggtacc aggcccattt tatggggacc atgagggtaa agttgatctg12481cccgccctgc cctggcaggt gtccttgggc ctggtgtgtg gggaaaggag gtggtttgat12541agctccctga gaggaagttg tttgagtgca aatggaatat gccttagtaa tacctatgag12601attggcagcc atggcgggaa aatatatata agcttttaag agctagagta gggggcagta12661accggcatgg aaatggttgt gcacatatga aagtacagaa agttcctggg acttgggcaa12721gacaatttta ttattggggt agaaccatcc tcctccccaa atagcaccag cccgggtgag12781tgaggtttgt tcctcctggg tatatacagg gtgtatgctg ggaaagatgg gcaataatga12841tgaggtttta agggctgcct gctgggctgc agagtttgct 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ttggtcagaa13741tgtacacaca gtgaatgggg ccagcccctc cacacctgtg ggtatttctc atcaggcagg13801aegagagact gagaaaagaa ataagacaca gagacaaaat atagagaaag aaaagtgggc13861ccaggggact ggggctcagc atacagagga cctgcaccgg cccggtctct gaattccctc13921agtatttatt aattactatt ttcactatct cagcaagagg aatgcggcag gagaagaagg13981tgatagtggg gagaaggtca gcaagaaaac atgtgagcaa aggaatctgt gtcgcaaata14041agttcaaggg aaggtactat gcctggatgt gcacgtaggc cagatttatg cttttctcca14101cccaaacatc tcagtggagc aaagagtaac agcagcattg ctgccaacat gtctcgcctc14161ccgccacagg gcagcttttc tcctatctca gaattgaaca aatgtacaat cgggttttat14221accgagacat tcagttccca ggggcaggca ggagacagtg gccttcctct atctcaactg14281caagaaggct tcctctttta ctaatcctcc tcagcacaga cccttcacgg gtgtcagcct14341ggggggcggt caggtctttc ccatcccacg aggccatatc tcaggatgtc tcagtgggga14401gaaaccttga acaatacctg gctttccagg gcagaggtcc ctgcggcttt ccgcagtgca14461ttgtgcccct ggtttatcaa gactggagaa tggcaatgac ttttaccaag caacctgcct14521gtaaacattt tgttaacaag gcacatcttg cacagcccta gatcccttaa accttgattc14581catacaacac atgtttttgt gagctcaagg ttggggcaaa gttacagata aacagcattt14641cagggcaaag caattgttca gggtacaggt caaaatggag tttcttatgt cttccctttc14701tacacagaca cagtaacagt ctgatctctc tttcttttcc ctacaataca gagtagaagg14761cttggtggag ttgggcagtc ccagtactgg ggccattaaa aagggcattt ttcagctttt14821taaagtggga gttgatgggg caagctgggt tgaggggttt taggatgagc ccatgtgagg14881ccatatagaa cagcttggcc agcaagccaa agttgggaat ccacagatgg aagcatccca14941tgcagcctga gaaggagagg aggttatttt tcgtgtgggg aagaggcatg tcccaaatta15001gctcctttca ttgggttgga atggcctgag aattaggggt taggacaagc ccaaggtaag15061tgacctgcat ttgggctaac ctgagccttt gtgggtaaga ccctaaaatt tacttggtat15121gtcccacccc aagatagggg tagggcactg agggataaac aggaaagagt gggtgaaggg15181ggtgatgaat aggttgcata atagaggacc agtctgtttg tgcctagagg ggattctatc15241gactcccaca atagagatag aagaactgag gaggggctca gaatattctg gtaaaattga15301ataactagcc tcatatttaa tgggaaagac atgggcttag cagacactga cagcattact15361cttggttcca aggtggtgat ggtggtggga gtggeggatt ctgggcccta tcagtcttca15421ggtagaggtg gtgaagtggg ataaagcgtt ttgctgagca cagtctgaga tgtgctccct15481gtcctccagg gtgagggagg aagagaggat gacgtaagtg tcatgccagg taatttataa15541gattgagtga catacagaaa ttccttgtgg aaggaggtgg gatccatgga aaagaagcca15601agtctttttt caagctggaa gaggtcagct agggagaagg aaacataaac tcagattata15661ccttcggccc gcgtgacttc ccgcaagggg atgactttgg aaggcctttg ggtgtatgcc15721tggttttcag aggaaggggg ttaagtgtga gactgggtat gcggtggaga agaaaggggg15781aacagagggc aacaataagg gaKtgaagga gccggagctg aaggaggagg aggggatggt15841ggtgggagaa ggactgaagg aggggttttg ttgtccgggt tgaaattaga ggaggaaggc15901ttgtctgaag gaaggggcat ttttgggttt ggaggttcca gattagacat ctgagagtgg15961tgtctggagg aagttttgag gagccttgcc ccatactggt ggctggaagg gtgagaaata16021tagaggaggg gtgtgagtac cctggagggg agtaagtacc atgattcctc ttgggaggag16081ggacataaga aagccagggc atccctgcag ctcttcacag tcctctggag atcagagtga16141ctggagtggc gagcattctg agggcgtccc ctgagaaggc agaccatggt cacctggtga16201ccagggagac ctctcaccca gcactgggat tttctggtga aggagcagaa gcatgaKagg16261aatctggaga ggaggtaaag ggagactcac ccattaattg gagacggcgt tggacgtgat16321gttctgcaat gggggtgatc cttgccggag ccacccagaa agggggagaa agaaaaaaga16381ggctagagag tttgatcagg atctagaggt cagcccaggg ccaaaggaga gagaataaga16441gaaaaagggc tgcaaagagg gagtctactc aggatctgga agcaggcctc agtctaattt16501ttgctgcttg ctgctttcca ggttgcaaga gaagacttac ccgtttagaa cccaatctat16561gtcctgggtt tctgcgccaa aatgtagtgg agtttttttc ataatcagga gtttgagagg16621gtacaatgga agttgttagg ttttgaaggg aaggtgaggg ttaaagaaag agagttggat16681gctttgcagt aaatgcaggt tttatgtcta gcccaagacc tgcggaggtg ggggaccagg16741ttaatgcctg aacccactgc cacttacagg ctggggtact tacaggtatg ggagggaggg16801gtctgggcag tatggcttgc tgcccaacag gctattgata agatgttccc atgatgaggt16861gacttggtcc ttgttccagc agaatgtgat agggatgttc cttggacttt ttcccagtgg16921aatgtgatca gaaagtcagg tggtcaggcc gatgtttctc acacagagaa ccacttccac16981aagattaatt tccatactcc ttccaccact tgtttgaacc ttcagcttta tcctattaaa17041ttcaaaacaa tcttttaact ctaggcaaca atttatattt ccatggcttc ttataacctt17101ttagtaaaac acacacacac agacattttt ccaaacacac cttgcatgta aaaatatttt17161tagtagtatc aattacatgt tataatgatg actcttagca atcttacttt taatgtaaaa17221gctggtaagt tatgttaatt atgtactagg tgctgataag gtcttactat tccagcatag17281ctaggggtgt ggccaactcc acatgtcccc aggccttacc tagctgtaaa gcaggcaagt17341caaacaattt tcaaaagcca aagaagcagt ttatgacctt aaggcactta gcaaacctaa17401tatttgaaca taatttagat gacatgtttg tattttgaag acatttgtga aaactttaca17461gaggagataa acagtgactt tcacgtctca tttagccagt ttgcacagag agaaagaggt17521cagagtctga ctggtaggaa attcttatcc ttttgccagt aggccaggtt tctgggtttt17581ctctccctga gcagccctag tgaMcctgct caactgtatg caaacaaaca cactaccatg17641aattaagaac atttacaaat agtttacaaa ttttggagaa attaggcaga gagagaaata17701tgacttaaat tctgtttaca aaagtatact caacatactt aaaatatcaa taagcctaaa17761ctccaaaaag ttagtttaag gttaaaaagc tgatgtgttc cattaactcc tgtgggtctg17821acaaaggtag cctaggaatt ccagataaat ggaacaaatg atgacttgct agaaatgcac17881aggaaacaaa ataactatcc acaaaaccaa ataaaagcct tctagaagca aaaataaata17941aacaggaaag caaccctaat tttttcttac tcaatttacc ctggaggcta aagtgttgcc18001cagggcccca aaagagccac ataataaata ttttattcct gatacacaat tcaatatcct18061taagttcacc aatatcatca tacatcctgt gcaatcaaga agttcacttt aggcccatga18121ccaataagca ctccagtgcc agcactatcc atgcaaaaca gtaaacatag tgtgaagcag18181tgcaagcata tctgggaaat ttggctccac actaaatcca gcttcaagct taactatata18241aaaaaaagaa ttgccaaact gccaatgcat ttctttacaa tagttattat tttactttaa18301tcaagactaa gagctttaac tacgaaaatg ttaactagcc caatgtctcc aattctttat18361catgttttaa agaatatttt attatctaaa ctttttccac atccttctcc cctaatcact18421ggttctttac tacattgttt cacaaataat tttttcaaat gtgtaatttg aactaactbt18481tagataactt cttaattaga caaaattatt ctttttctca gtaataacac aaactttttg18541gcacattttg tatacagaac tctgtgttaa ctagaagtat tatccttagt aacctaaaat18601tttagtgaaa ccctaaaaag aaatactgaa ctatcagata tgggcattta tagataagaa18661caattccaca atttttagaa acatatttcc ccatatcaca acccttcctt aattggaaat18721gacccaaata ttcaatgagc atcaaaatta attttaagct tttaatttac acaaaaagtt18781tacctaaaac atttatccca tttactgtac tcaattcttt catttttaac agtttatcta18841gattacttct gtaaactgag atattagaca ctatcactta aagttagtta tttccttgct18901aaccatgttt ctaatagcca gtgaatatca agtgctcacc taaacctgag agtctcagaa18961ttaaatatat aagtattttg ccaataactc agaagacgta gctaacatta aattgctctt19021atttgtcaaa aaaaaaaggc acattttgtt ttggctgggt ttgtagtttt ataacattct19081atgccaaaca ttgacatctc aaaatattta gcaaacacaa acataaaatc cagacaaaat19141gtatgctgac aattctgaag gcatttctat ttttattcta ccaataattt taaagccagc19201ttgtttagta aagttatact taagtcactt taacttaaaa atcgcttagg cttattaatt19261tatgagcgct cttttactta taagccaatt tggcaaacat aacatataag tgtacataca19321aataaacaca tctagacatg tatacacaca cacaaatgaa gatctaatag cttgaaaccc19381tagccatgag atagcaacac aagcttaccg gttttacttt gtttgcccca gtaggtaatg19441caatgaaggc tgtgaaccaa aattttgggt aaagcaattt ccatggcagt ttgatttttt19501ttgtttcttt ttcttttttt tttttttctt tgagatggag tcttgctctg tagcccaggc19561tagagtgcag tggtgcaatc tcggctcact gaaacctctg cttcccaggt cctggttcaa19621gcaattctcc tgcctcagcc tcctaagtag ctgggattac aggcacgtgc caccatgtcc19681agctaatttt tgtattttta gtagagatgg ggtttcacct tgttggcctt gttcatgtct19741tgaactcctg acctcgtgat cYgcccgcct cggcctccca aagtgcaggg attacaggcg19801tgagccaccg tgcccagatg gcagtttgat tttttttgtt tttgtttttg agacagagtc19861tcactctgtt gcccaggctg gagtgcagtg gcgtgatctc agctcccact gcagtctccg19921cctcccgggt ctaagtgatt ctcctgactc agcctcctga gtagctggga ctataggcac19981gcaccaccac gcctggctaa ttttttgtat ttttagtaga gatggagttt agtagagatg20041gggtttcacc acgttggcca ggatggtctt gatttcctga cctagtgatc cacctgcctc20101ggcctcccaa agtgctggga ttacaggcat gagccactgc acctggccct agcagtttga20161tttttaaagg tgaaacctcc ccagactcca aagaacacta agaccaaaca gtaccaaagg20221agaacatcac tctttcacca ggccctctgc ttagaatagc agcaccaaag cctggatata20281tgcaatggca atgccatccc agttttccat tcaacagtaa actccgcatt ccaaacaata20341ttggggccaa atagcattgc aactgcgaga taaaattcta aggagagttt aatactagac20401ctcagaacct ctgccaaggg catcctcttt ggagaggttg aggtccggag gattcccctc20461tggggcttcc cctagtgggg cccaatctta agagtgtcag acgtctctga ccttaggtgg20521gcaccagtcc tgcttgcatg ttttccctct aaagggaatg gcctactatg agctttcatt20581ttgtccctgg atgaaggcct tgacttttag catccttata atttgataag gccacacttt20641cccatgtttc ccattccatg aacttaataa ctggaggctg gatgtgtttc ttttgctctt20701agccagttga ctagggaaac ggaagaatta cgcataagaa aaggtttaag ttgcctgaaa20761caggcgagtt tgctctgagc tgtgccacac atagggatca gggaccacac ccagaaaaga20821tttaaaaaag agtccttctc ccttctgggc agggcaatta tccccattca ctccatggtc20881ttcaggcaat attggggatt gatcccagcc aatttccctc aatttccaaa gagctactag20941gaaacagctg ctaaaagacc aataaagaag aaaaggaaaa aaaaaaagaa aaagacccag21001gtcccttagg caaaccaggt ggtggcggtt aggcttcttc acatgaaaac cccttagtat21061tcaccagcca tggccagaaa cctgcagttt acctccatgt ttacacgctg ctcaccaagg21121gtcccgagtg ggaaaggaaa agagagagag agatttccct gtatgtaaaa agggaaagga21181gaaaaataaa tcccaaactt tgggcttacc ttctcctggc tggctcacca aaatatgtta21241ccagtggagg gtgtccaggt gcttggcatt ttgaacaaag aattggacaa aatgcacaaa21301caaagcaagg aaagaatgaa gtaacaaaag cagagattta ttgagtacac tccacagtgg21361gagcaggccc aagcagccac tcaagggccg ggatacagga tcttcttggg tccaaatacc21421cgctggaggt ttcccattgg ccacttggtg ttcacgccat gtaaataaag tggtggcccc21481caatcagtct gattgtttgc agacggaaac caatcagagg ctgaagtgaa gttacaaagt21541tacactctta ggcaaacgcc tggttgccaa aagcaaccaa tcagaggtat tttctttttc21601tttttctttt tttttctttt tgagacggag tctttctctg tcacccaggc tggcgtgcag21661tggcccgatc tcggctcact gcaagctcca cgtcccgggt tcacgccatt ctcctgcctc21721agcctcccga gtagctggga gtacaggtgc ccgccaccac gcccggctat ttttttgtat21781ttttagtaga gacagggttt caccatgttg gccaggatgg tctcgatctc ttgacctcgt21841gatccaccct cctcagcctc ccaaagtgct gggattacag gcgtgagcca ctgcgcctgg21901cccagaggta ctttcaatta accatctgcc atgcagaaaa ggtgggagtt tgcaaagaga21961gtagcctctg gtccttttgt tacttaggca tggaaagtta gggttttcct ttcaatgtag22021ttctacgaag tcagcgtgaa atggccttag gtttcctatt ctcctgcctc actggtatcc22081aagggactct gccattaggc tagctgtgga gggatggaga gagagctgag gcctcaaatg22141ccagtattcc ttccttccag atttgcgtgt aagaccagat aatcttccag accaaacagt22201atctgttgat gagtattagg ctcgaatgag aaggagagag aagtggagca ctggattgaa22261gagaaagcaa aaaaccttcc tagatcaaca aggaaatagc ctcttctaga atccagatag22321ggccctggac tcctgtggga taatgtagtg ggtgaaaaaa ttggtaRtga agtcctcgga22381tatggggatg cacttggaag tcttgggaac aaggaagaga gacatcctgt ggtggtgatt22441tttagatcca acacccaggg gcttgggtgc ctttgggggg attagtagaa gagatcgaca22501cattgaggga ggttcaggat aactgtctga aaatgagaga tttttattgc ttatactgat22561gtcccaatag ggtctgtatg tgcttcaaat aggtagaaaa gaatgaagtc cgagcctgaa22621gataacaata tcagtcagaa ttttaggatt gtgaatacct gtccacagaa atagctgggc22681cctgagcctc tgctgatgat gtaggaatRg aggcagttaa taagctttaa agtcataggg22741tctcagggct agggtatggt gaggacactt tgccacccct aaggttcaaa gcctcttgga22801ctggaggagg ttgttaacag atattctagg cagaaaagct gtgtcaggtt gtggtgtatg22861aagagggaga atttgacacc aaatggtcag ctggccatct gctcacctgt tcccctgtgc22921tccctactcc cacagggtct gcttacagaa caaggcacag caaggaggca agacacaagc22981aagaaatgtg cttgatgtta cccactgcag tccttcttcc actctggagg attctgaaga23041ctcagaagag ggacaggcaa tggattcagt ctaaacccca ggaccaggac actgcctcag23101cttcgaagcc tggatgcaat gctccagggt ataaccactg cccagaagca cagctagtac23161aagctgcagc ctcaatccag gcaaggagcc aactccaaca ggtcaggctc caagggatga23221agactgaaaa catgaatgtg ttgtgccact aactctagcg tttgcttttc cttgtgtttt23281tgcatgcatt gtagaccttg gcatcagcat ttggctagct ttaagacaga aactgagaag23341ccttttgtgt tttatgcgtc aacttgactg ggtcacagca tgcccaaata tttggttaaa23401cacgatttct aggtgcatct gtgaggattt tctggacgag actaatattt gaatttgaat23461cagtggacta agtaaggcag actgccctcc ccagtgtggg tggccctcat ccttctctct23521gcctgacact cttctagctg gaacatttgt cttctcctac cctcggactc agactatgac23581tggaattgat atcattgact ctcctagttc ttcagactca gattgctctc Scgggacttc23641tcagcttcca aatcacatga accaattcat tataggaaat tttttWatat atcctattaa23701ttctgtttct ctggagaacc ctgattaata cagatttatt ttcctacact ccagtaactc23761tccactactc cctccctcaa cccctggtaa ctatcctact ttctgtctct ataaatttga23821ctattctcag tacctcatat aagaggaatc atgcagtatt tgtccttttg tgactggctt23881atttcattag cataatgttt tcaaggttta ttcatgttgt agcatgtatc caaatttaat23941tcctttttga ggctgaatga tactccattg tatgtatata ccatattttg ttcattcatc24001cattgataaa catgttgttc ccacatcttg gctattagga ataatgttgc tgtgaacatg24061agtgtacaaa tatctgagtc cttgcctttt tttttttttt ttggacacag agtctctctc24121tgttgcccag actggagtaa agtggtgtga ttctcggctc acggcaacct ctgcctcctg24181ggttcaagtg attctcgtgc ctcagcctcc ccagtagctg ggattacagg cgtgtgccac24241catgcctggc taattttttg tatttttaat agagatggga ttcgtcatgt tgcctaggct24301ggtctcaaac tcctgagctc aggcaatttg cccacctcgg cctcctaagg tgctaggatt24361acaggcgtga gccaccatgc ctggatcatt gcttttcatt attttgggta tatacctaga24421agtgggattg ctggatcata tggtcattct gattttttga ggaaccatca tactgttctc24481cacagtgtct gatgacctac agttttgagc ttagcctttc taaaatagtg gggaaaaaaa24541tgaaaagaaa acaactagaa gtggaagtaa tttgtccttc attaagccag atatacacat24601cctgattcaa gcttgaaaac aatatcacct ccttcgctga tatgtaagta cctttttata24661atttaaattt taagttatga ttaattagaa acttaaaatg tatagtctgt atatgcactg24721gatgtccaca aagtgaccct tggttgctaa atctttgaga aaggctgagt agacactgaa24781cgaatgtata tccaacttac ttgtcaactc ctccaagaac attccttacc ccctgaccca24841agacatgctt tctatgagct ccaacagtgc ccctagtctt caacagctac cacatctgtg24901ctcgtcacac tcttgtcctt ctcctagtct caactgtgag ccatggatgg cagaggccgg24961tttttaccct tcaggtctcc agttaggcct gtgatggttc tagggttttg tttaggctgc25021gagtctgatt ggggctagga caaagggtca aattcaggat gaaaatcagc ctggccaaga25081gcagtggata catagccccc atcatcccac ttctcagatg ctcctagaac tccagcccgg25141gatcctttat cctctgtata ctccaccttc tccccataca agaccctctg cagagagcag25201gcacaaggag cagataaatg atggtcgatg ctgcctgtca attcagatgg gcctggcata25261acggttaact aatgggtttc ttgtttgatt gataggttct ctcaaaacta aaggagttaa25321atttctttaa tagcaataca tgctcattgt taaaaactca tatcaactga atttcccttg25381aacactatta acatttagtg tattatcctt tcacatttgt atagatattt agaaaaatgg25441agtgtagtat atacgtttat atatttttgc ttagcagtac atcatagaca tctatttcat25501tatattcaaa tggctcaata atattcccct gtgtagctgt accataatct agccaaactc25561ctatgtgggg gcctggtttg tatttgattt ttcagtaaYa taaacaatgc tgagataaac25621ctctatcagc tagattattt ctattgactg attttaatac atgattggaa ttttaaccac25681aagggggaag caggcaacca tgggaagaca ggctaagatt taggataaag aaaaagaggc25741tgggtgcagt ggctcatgcc tgtaatccca gcgctttggg agggtgaggc aggaggacag25801ctcaagccta ggagtttgag gttacacaaa gctataatca cactactgca ctccagcctg25861ggtgacagag caaaaccctc tctctcaaaa aaaaaaaaaa aaaaaaaaaa cgatttagaa25921agttatctca catacataag cttaccccaa ccttgtgagc aggtagtagc attagtatta25981gcctcatttt ttggaggcaa agctgatgat ttcattatca ggcgctcttc tgtatttcca26041aataaattga cagcagtaca acattctgcc tacattcagt tcaagtccag gtgctgtgct26101ggggacacta tgaggcatgc agaaataaag aagacaatcc ctgcccctca gggggtcatt26161atcaggtgtg aggacagaca cacctaaata accaagtgcc cactgtaaca gacaggagag26221cccaggaagg taggaaattc acttcgatag tgaggctggg cacagtttta tggaaggggt26281atgctgacaa taagaggtaa ggtgtattta gcctttactc tgtgcatggc actgtgctaa26341gtgctttacc tgcataatct cattaaaact tccccacagg ccaggcaccg tggtttatgc26401ctgtaatccc agcactttgg gaggccaaaa caagaggatt gcttaagccc aggagtttgc26461aaccagcctg ggcaacatag cagggccctg tctcttaaaa acaaaccaac caaccaacaa26521acaaaccaac aaacaaatcc ccatagacct ggaaggtatc ctaccctttt ttacagagaa26581gaaaactgat ggtcagagag gttaagaaac cagctaccgt ggcacaacac tggaacgcgc26641gtccttaatg tgaattcagg aggccctaca agggttggta gactttcaac aggcagggct26701gggagagaga cttctaagag aggaaacaca gaaacgaagc cttagaggca agaaatacag26761gcacgtctgg gaatggcaag gggatcagcg tgcctggggt gtgaaaaagg aggaatctga26821agagatcaaa actagagaaa gaaaactgag tcagagtggt gaagactgtg agtagcaagg26881caaggagatc ccgctgtatt ttgtattcag gtgaaaccaa ctgaagataa tgacatcatg26941tgtgctttat gaggattaat ttggtgcatt gcMtaagaga acaaggagac tagttagggg27001cttgttaaaa tagtcctggc caaagataac tagcgaagga atgagaacca gaagacatta27061cagagataaa atccacaaga tcttattaga tgctggggaa agaggaaaga attgtgatta27121agattttcat gtttgggcaa ccaggagaat gtgagtgtgt acaccaggag aggggctgga27181cagaagggag aggcgagttc acttttcttt tatgagctgg aaggaccaca gggacctttg27241agtggagatg tttagaggag agttagaaac aggaagctgg tgatttagac atagtacctg27301agaatcagaa gaaacccagg gccgggtgtg gtgtctcacg cctgtaatcc tagcactttg27361ggaggccaag atgggagggc tgcttgaggc caggagttca agaccagcct ggtcaacata27421gtaagaccct ctctatatag aataaaataa aatttaaaaa aagaagaagg ctgggtgcag27481tggctcacac ctgtaatccc agcactttag gaggccgagg cggtggatca cctgaggtca27541ggagttcaag accagcctga tcaacgtggt gaaaccccgt ctctactaaa aatacaaaaa27601ttagctgggt gtagtggcag gtgtctgtaa tcccacctac tcaggaggct gaggcaggag27661aatcacttga acccaagaga cagtgagcca agattgcgcc attgcattcc aacctgggtg27721acagaacgag actctgtctc aaaaaaataa aaaataaata aaaagaagaa gaaatgacca27781agggagctgg ccagggaaaa acctacactt aagattcagc aaggcatgtt agaccctgat27841aacctgcaat tccacagcca ggtttctatc ccagagaaac aaaatcacac gtgcacaaga27901gagcgtatga aagttcacag cagcattgtc tgtcttggtg aaagcctggg tcagggagga27961gcaggcaaat aaaccattaa acatccacat tgtgcaatag ttaccaatta agtagatcaa28021aggtattgac atggacagat cttcagaaca tacagtggat gagaaaaaca acatgtagtg28081caataataat gtataaaaca ttacttatga aaaaagaaga aaagccaaac aatcctgtca28141catatatatt ttaaatgatg tatgtgtagg catagagaaa attctggaaa gctaaatcca28201tgctaattgt gataaagggg aggagttggg acaaacatga agagcagaag gggttaaatg28261gggttttagc atagttgtca ggttttaatt ttataagaaa aatgtaatca tctgttactt28321atgtgaataa aaattctcaa aatattttta aaaagaaaga ttcaatggga agaggaagca28381atggaataga caggaataca ttcctagact ctaggtagga cactgttact gggaacactg28441ggagaagttt ctggaaKgca aggtggaaaa aggatccact gcactcagca acgctgcaga28501gacagcagcc agcaggatga gtcctgtgag ctcagctggt tgtcaacacc tttcacttac28561agccactagc tcctgtgtcc ttgaaaagtc gccatgtccc accactgccc ttgaatgaga28621tggagacttt ctgttctttt ttgagttgta aacatccaaa agcatttcRt caatttcttg28681tatttagaca ttcccttcct ttcccagaaa ttccacagtg atattctcag tgttctcttt28741ccagtccttc aagctgtgta tgaaatctac ttcttcccag tccagctcca gcaaatacct28801gcctcctctc ttgttctcca ttcaaaaaac ttccaatttg aggtcatttt taagagcatt28861actgtggtgg tggcggtggt ggagtttata gaatttctca tgggacccac agcatggatg28921tggctaacac tgactgagca cacaaaggtg caggcactgt gctaacttca taggaagtat28981ctcggttaat cctttcagca accccagtag gtcagtacta ttataacctc caaggtcttt29041ctttcacagc tgggacttag tgtggctgag cgacctaagg aggtaagtgg cagtaagctt29101gtggtgggtg actctgtgtt tgtctcacta tgtgagtttg tcctaagtga tcaatagggg29161tggggactgg actagaaaca aggtctcagg tatgcagggg tgttcagttt accaaatgcc29221tttatgacca ttaattcatt tgatgtcacc acagtgcttt aatgacatgg gtcattaggg29281aaaataatga gatgagtcaa gctttgtaat tcccttaaag tggtcaagtc tgggttaagg29341gcttttaggg cacattaact cactatgtcg tcttgagcaa ctctgcaagg ggtgggagca29401gagggggccc cctttggccc agctctctac aaatcatcta gttcctagca gccactcctc29461ctggtctgca aattcttggc gaggcaccct cctgctctcc aaacccaccc attccaggcg29521atcccttaag tggcagagga gccaggttcc tggggttaat aagcaggctg tttatagcca29581gcagcagtca cgggacagcc agctggaagg tcatgcccct tctgaatgtt gaggtttctc29641ataaacattt ccccagtgag ccttctggga gatgaggatg actctgggcc cattgccctt29701gctggggcag agcgccaagg ccccatactc actttcttct cctttctccc gaatctggct29761ctcttcctct ttcctccttc ctctcctact ctgctgtcat tccttccctt tcttcagtgg29821aaagaggaca cgtttcacag tagacacaca ggataactca accttctgag cctcagtttc29881ctcctgcgta aatggggtaa taatgggRcc ttcatctcag gatgtaaggg aaagtgctta29941gcactgtgtt aggcacgcac agtggacatt taaaacatat tggtcatgtc tttccccctc30001caccctatcc ttttgcccta atcctggcca ctgccctgtt ttctttctat tttcctgctc30061cagccctgct cccatttcca ccctgggcac ttccacccca ctgaYtgtgc tgctgctgcc30121tgggagggta gacgaagaag ccaggcttca ttcagaggag ggctgaccac cgcagggccc30181gcctggcctt ggcacttccc catgagaccg caccctaggc ctctctgctt ttagtaaata30241gcccatggga acagggggtg gagggaggat gtagaatggg agaggccaag acattttaac30301ctttggcttc tatttgccct taatctggct cttccaatgg cttaatgatc agagatcatt30361gtgtaaattg ctgtgtgact ttgggcaagt ccccttcact ctctgagctt cagtgaagtg30421tgggaaggaa gtgaagagca gaagttgggt agaagtgcag gtcctggaac cagaccatct30481ccaccacttg ctagcttgga gtacataact cctctgtgcc tcagettcct caactataaa30541atgcaattta tagtatacct aatttataaa agcactttta aaagtgctta gaatagcgcc30601tagcccatag ttggtactaa attaatctca gctattatat gcaaatggag aggtagaaca30661ggggtatgtg tgcatgagag gagagctgga ccttctctga gggtattcta Ragtcctgaa30721aacccacatt cctccttttt ggataagaag aagacagaac cttgaacaca aagtacttct30781cccaaggaga ccataggaaa cttgtcaaag acttttaaag ccagatggac cccttagagg30841tcatctggtc Yaacttgtca tgctacagta agaacagggt ggaccagaga gattcggact30901tatctgggac cacagagctt ttgacgagtt atagaattgc aggtggtgca ttgcagggaa30961gggaggcact ttaagaggac agtgggatgg gctgccagag ggctggtggg atgctagagg31021tcagattccc aggctccatg acctccagga ttcttagttc aggcacttac cccataacta31081aagcactgat gtcaccaccg gcatctttaa taattataac catgtaatga ggagggacta31141tatcccaagc actgcaccag acgctttcac atgcattact tactccatac aaaatcccct31201tgRcaaatga ggaaacacgc cttgcccaag ctgcaacaat tacaaagggg cagagctggg31261ctttgaatcc cggtctctct gatgccaaaa ccagggttct catgcaacac tcttttcatg31321tttcccagag cctagtttga ggcttgagcc tcaataaata aggatcttgt atttgtctca31381ctgggctggc caagcagatc ttgtatttgt ctgactgggc tggccaagcg ataacactaa31441tgaatMagcc tgggtcccag tcacctttcc agccctttcc accctgaccc acaagccatg31501atgagagacc agaccctgtg taggaaatct ttcttccagg ggccctgcct ctgtgttatc31561tgeccccact gtcaatggga gaagcagtgg ctgctttcgg aacaggcagg ggaggagggc31621ttagagcctg gggtgacRct tctggctgct gggcctgacc tccccagact ttagccaggg31681ccctgacttg aatgggagga gcatgaacaa acagaaagtt gtaggagaag caagaaacca31741ggtaaggtga aaaaaacttt tcccctccaa aaatacgaag tttatagttg atgtgaattt31801gtcaacttaa tatagtgtaa gaagcataag gtttaatacg gtcttcctcg ccatgatggc31861aggaagcaca tctgttgtat tcactaccac atgcttagtg ccccacccaa ggcctgtcta31921gagtcagtgc tcaataaata aacatggaaa atgaatgaaa aaaaaaaatg gagggacata31981aggaagagca ctgaaacatc agtcagaaaa cctgcattac agtttttagc ttcatggctc32041acagcaaccc ttggacaagt cacttcggct ctgtaaacct cagtttctac aagtgtaaaa32101tagatatcat ggcagttcct actgcacagg gctttgaaat cacagacttc cgtaggagtc32161atggttccat aaccaactaa tgtcaagttg aaaattgtat ttcttcagag tgaggccggc32221tttagcaatc tatgcaaggg gtcttgctga accagggcca gaggaaggcc agaggtgtgg32281ttctaagaat gaggattaaa catgagagag actataaatc tgcttggaga accgcagcat32341taggagggta cagcggacct ggcaggcatg acagatactc tctgccctgg agagtctcca32401gccctgccca tgcaaggtgt cagttagtat cagcgggagc acagatgggc ttaaatcaga32461agatgttaca gattatctag tccacactgg acaatagccc agtgaggggt taaaggctga32521gagacaaaga cccagatatt ctaattccca gctcaatgct actcttccca caccaccatc32581aaaggagggg gacggtggtg agagggggta tttgaagaga aacagattgg acaaaggaat32641gaatgcctcc atgtagcaac agcttcaaag gggcttcaga ataggagata tcttgttaaa32701gaaggaggaa cgagaggggg aaatggttaa aaataacgtc ttacatccat gtggattatg32761tttccaacta tatcatgtgt agttattgca tgtaaggtac tatggtggag agttactgat32821ggggcatcag aaagcccatt tcattaccca gctctgccat gtacaagctc tgcgacctcg32881ggcaaatcct ctctctgatc ctcaaatttt catgtgaagc atgaagcaat agtgcctacc32941ccatagacct atcctgggga ccaggttagg aaagggaagt ggagggaggt tgtatcctct33001ctaaaatgct ctgcaaatgg gcaacatggc aaagcggtca caagcaagcg tgtgaggtag33061accRtcactt agcctttctt ttcttttttt tttttaagac agagtttcgc tcttgttgcc33121caggctagag tgcaatggca cgatctcggc tcactgcaac ctccacctcc taggttcaag33181tgattttcct gcctcagcct cctgagtagc tgggattaca ggcgcacgcc accacacccg33241actaattttt gtatttttag tagagatggg gtttcaccat gttggccagg ctggtctcga33301actcctgaca tcaggtgatc cgcctgcctt ggccttccaa agtgctggga ttacaggcgt33361gagccaccac gcccagcccc acttagcctt tctacgactt tgtatcctca tctgtaaaat33421ggatgtggtg ggaatcaaat ataatgcatt tgcagccttt ggcacagtcc ctgacacata33481caaagcctgc aacatcctgt tagttactac cactagttgg gtttaaagaa ttttctcatg33541taatcctcac aataatccta tgaggtagga ttattattat tctcatattg cagatgggga33601aaccaagacc taaaaagaat tgcttaccca aatcaatagc taattagtag acagcaaagc33661caactagaac ccagatgccc tatcagatca ggcaggcaaa gatcagaatt agtgagtagg33721gcaggcagca gcgggaatgt ctgtggagtc cagacaataa tgcagccaca aagccagagt33781tctggtagct gcagaggcat ttccaacttt aaactctggt cagtctggag ctcagtcaga33841acaaaccttg tttcatcttt gatttaagga gctgagaaaa ataagctctg gaaagagaag33901aggggaccct gtgttccagc atcatctgcg ttatttattc actaggctga ttgcttcKcc33961tctctgggcc tcagtttccc cagctgtata tgaaaggttg aactagatta atgcttctca34021aacttgaatg aggttctgag tcacctgatg atcttgtttg aatgtagatt ctgattctca34081gtaggtctgg gaaaaagcct gagattctga atgtctgacg agctcccagg ccatgccagt34141gctgcagagc taaggatcac tctctgagga gcaaggaact agatcagctt gaaggacatt34201tctggtatga taatgcctat gagagcaata caccaaagac tgagaagtcg agcaaaaaca34261aattctgccc aaagtgcctt acagtatttg ggggtccagt gtgagggcca ggctatttcc34321catggaccac agaccccttt aaaaaggggc ttgatatcca gcactcagtg aggcattcag34381ctgcagggcc agctctccag actcttcttc ccagcccatc tcccaccctc acctgcactt34441cacctcctaa agggaagaga caaaattttc taagccattt ccctccccta tcagggctgg34501ggagggagcg gcttgttcct aatgaagaca aaggacaagg cttaagggac acttgagaat34561ctttttctgt ccttcctttt cctcattcat tcattcattc ttcattattc aactatttat34621tgagtactct ctacgtgcct ggtattctcc taggggctga ggttacagca gagaaaataa34681gacagatgtg gcctctgacc tcatgttgct tacattctaa ttgggaggaa aatgggacag34741gccataaata ggtagatttt aaaaatgaat gagatcatct aaaatcacaa aaagcaataa34801aagaataatg aaacaaagtg atggggtagg gggcttcttc tgtctattgt cctcaagaca34861aagtccaagg ttggaaaagc tcatctccac ctgcccttgt ttgcttctcc agcctcatct34921cctgtcactt tttgccttga actttccatt ccagccacac aggacatgga gtatcaaggc34981tggaagacgc caaccagcct ttgatccagt ggttctctca gccccaatca ctctttctct35041ttgtccctac ctcttcctct ttttccctct ttctcaccca actaacccct cctgctcttt35101cccagcttac tcgccactcc cactggaagc tggccctgct gccactgatc tgggctagga35161atccgtctgc gccaccttcc cWgatgacag catccatcac ctgtgcagcc gtgttaattg35221gctgtccttc ccccaccaga ctgtaagtgc ctcaagggca ggagtcctgt cttattcact35281ctgaatcctg aatcctcagc agttgctgca atgcaaagca cagagtaggt gcttaaggaa35341cacctgttga attaactgac actaagttta gtatatttaa gagctcagta atgggctggg35401cgcagtggct cacgcctgta atcccagcac tttgggaggc caaggtgggc agatcacctg35461aggtcaggag ttcaagacca gcctggctaa catggtgaaa gcccgtctct attaaaaata35521caaaaaatta gctgggtgtg gtggcaggtg cctgtaattc cagctactcg ggaggctgag35581gcaggagaaa cgcttgaacc caggaggcgg aggttgcagt gagctgagat agcaccactg35641cactccagcc tgggcgacaa gagcaaaact ctgtctcaaa aaaaaaaaaa aaaaaaaaag35701ctcagtaaca tgagacaaag gcatctacaa gacatggctt tggagacaaa gaataaattg35761ataaattgga aggaaaagaa tataacaatt cctcagtcct ttctggagtc cacattctag35821tggctttcag ctctacactg tatcaggcct cctacaaggc ttaccaggca gactgggcag35881aaattattga cccccattca acagctgggg aaggtcatgc ctcagagagg tgaacctact35941tcagctgaag ttacccagcc aggtggtggc aaagcatgtc caaagaaagt tagggaccag36001agacgtcaga tccaacccct ccctcttgca ggggatgggg taggggtggt aatctgcaga36061ctctgaacta agtgttctag ctcatttcaa actcagaata accatttgag gtaaacagta36121gccatagcca caaaaaaagt agacacatga tttgcccatc atccaccttc cccctctaac36181ccaattgtcc ctgggcagac cgtgcagagt accaccccat tcgtcctcaa ggactccctg36241cctggggtca actcatgaga aactgtccac ccgcagattg actgggacag aaaaaaccct36301agacttttaa tttccttatt tcacagttgg agacaatcca aagcttcgag agaaggaact36361agtctatata gcacatactg agacagggtc agaactccgg agtcagaact ttctgaagta36421tagcccacaa gtccccttga catgaacctt ttgagttggg aaagggctaa gaatgatgtg36481aacatgacct ggccatttgt tagctgtggt caggctgggc gaagagaggc agcccctctg36541gtagttctac tctagaactc attagtcccg ccagtcctca atggtttgtg cattggtagg36601tagcccatgg gaagtaggat gtgggttgct tactgcttag tgactgttta tgaagattgt36661tattgctact acagcagtat agtctcccag ctgaacaata acctagaaag tatggagagt36721ggccgggcgc agtggctcac ccttgtaatc ccagcacttt gggaggccga ggcaggcgaa36781tcacgaagtc aggagttcga gaccagcctg gccaacatgg tgaaaccccg tctctactaa36841aaatacaaaa aattagctgg gcatggtggt ggtgcctata atcccagcta ctcaaagggc36901tgaggcagga gaatcgcttg aacctgggat gcggaggttg cggtgagctg agatcatgcc36961attgcattcc agcctgggag acagtgcgag acttcgtcgc aaaaaaaaaa aaaagaaaga37021aagtatggag agtaggtgga gaggggctag cagagacata ggtagggcac cttaccacta37081agaaatagag caaagggtag gtgctttatg ttccagaagc atatagatcc aagaggaggg37141aagggacatt ttggctgaaa gcttggaact atatctagca tagataaatg tgattctcat37201aggtgcttgt atttgctatg ggaccctgga ccaatcattc agtctcttga agccttagcc37261tctcccataa gagggtggaa tgagctagtc tctagggatt cttcttttta taactctccc37321tctaagtggg ctttgcaggc agagggagtc attaactcct gctatggtct gagtgttccc37381cctcccgcat attccgatat tgactttttt tttttaagag tctcactctg tcttccaggc37441tggagtgcag tggcacgatc tcagctcact gcgacctcca actccctggt tcaagcagtt37501ctcctgcctc agcctcctga gtagctggga ctacaggcgc acaccaccat gcctggctaa37561tttttgtatt tttagtagag atggggtttc accatgttgg tcaggctggt ctggaactcc37621tgacctcatg atccgcctgc ctcggcctac taaagtgctg ggaatacagg cgtgagccac37681actgcgcctg gctatattga catcttaacc cccaagtgat gctattagga ggtgggaact37741tgggaggtga ttaggtcata aaggtggatg gagcactcat gaatggaata aatgccctta37801taaaaaaggc ccaagaaagg cccctcaccc catctaccat gtgagggtac agtgagaaga37861cagccatgta tgaggaagca ggtcctcacc tgatcccaaa tccttgatct tggacttccc37921agcctgagaa ctgtaagaaa taaatctgtt atttacatgc cacccagttt atagaatttt37981attatagcag cccaaacgga ttaagacaac tccatttcag gtaagcccaa caaacctagt38041atttgccagg ccaggtcctg ttgaggctta attgagaaat gtgtagcaaa ttgttagtag38101tacaggcccg agaccatgat ccttagaccg ctacacttgg cctgtggtca gctcttggga38161acttctattt cagaaggatt tccaccattc cccaaactaa taagagtagc tcattatgcc38221taaactggac aaacaatgca gtttctgttg actgcctaat tttcttctgg gagtttagaa38281ttctggtatg tgcttagcca aggatgccta tgtgaccagc ccctaacaaa aNcctggcat38341tgagtctcca gtgaacttcc ctggtaaaca acattttaca catgctgtta cagttcattg38401acaaaggaat gaagcacatc ctgtgtgctt aattcagctg ggggatgatt ctgggaatct38461cgtggctgtt ttcttccaga ctttgtccca tgcacctttt ccctttgctg attttgtaac38521cttgtgctgt aataaatcat agtgtcagtg tacttatatg ctgagttctg tgagtcctcc38581tagcaaatca ctgaacctag aggtgatctg gggaccccca acaggagtta agcctagatt38641tcacagagtc aatcataatc ttgtgccagt cccttaagag tatacagctg aaaccagtgc38701tatccaacag agatataatg tgagtcacat gtaattttac attttctagt ggctatattt38761taaaaaccaa aaagaaacag gcaaaactaa ttttaagcac atgttttctt caacccaata38821tattattatt cttttatttt tattttcgag acagagtctc actctgtcac ccaggctgga38881gtgcagtggt acaatcacca ctcactgcag cctcaatctc ctgggctcca gtgatttgcc38941cagctaattt tgaaaatttt tgtagagatg tggtctcact atgttgccca ggctggtctc39001aaactcctgg gctcaagcca tcctcttacc tcagcctccc aaagcgctgg gattacaggc39061gtgagccatt atgctcagct aacccactat attaaaaata tatttaaaat atttccatat39121gcaattttat taaattaaga tattttatat tcttttatca cactaagtct tcagaaaaca39181ctgtgtgttt tatactcaca gcacagatca gtttgtacta gccctactcc aagcgtgcaa39241cagccacaca cgcccatggc ctgcctgcta tattggctta gaggttaatg gcaagggctc39301tggagacagt atatgcggag gctaaagaca ctctgtctag gatgctgatt caaccatgtt39361gatttctgat taactccagt tccaggaaag ccgctaaggt tttcagttta tctactcttc39421cttgtgtaag agcatgtcct taacataaat attcccctta ggtgaaaaca aacttaatat39481tctcacactt cagttggcct acacatccct tcaataggga aatcgcccct tccctatgct39541atataagccc tgggctgagg aggggtaata gcttggggat ccactatctc acttcacagc39601cacctaagac ttctgtggct tctgtttcta agtccctaat aaatgtttct ttctgagaaa39661ctgggtatgt cagcttcttt cttcagcttc tcagcctcct ctgactggct ggcgcggggg39721tggggtaggt ttacagagat ctgctcacag cagaatagta tgtgtgggtc agaatcccgg39781ttctgtgact taccaactgc ataaccttaa gcaaagttgc ttaacctctc tatgtattag39841tttcttcatt tacaaaatgg ggataataat gttggctacc tcaagaggtt gcagagatta39901attaatctaa ggcagcacct ggtatagata ggatattgag tgaatgctgg ctgctactct39961ctttatgcta aagcttggcc catggagatc aacttgtcta acacctcgtt ccataaatga40021gaaaactgca gcccagagtt tggaaggcac tagtttcaca agcaaaaact acagccaccc40081acctctcctc ttgatgaact ccctgtcttc tggctggccc tgagatcaaa tttgccaatt40141atttaggaaa ttggcagctc cagggcccca gctcggttct gcaatttctc tcgattgcaa40201aacaagggct actgtttgaa gttggcactg aagtgacgca ggctgggcct cacttctgct40261tccacctagg ctcatcagtt agagtggctg atcccatctt tgagttcaga acctgaaatg40321tttactaacc aataataagg ctggctttcg ttgttttaac tttttacaat cctttgagtt40381tattaatttg tgttctatct tccttgaaga cacagtgcat cagcactttt tgtaaaacct40441ctttttaagt catcttcggt ctctgttcac ctaccaagta ggtaagtagt gagctcccta40501tagaggtctc taaaaaatag gatgaagagg ttccgagtgc tcacttgtct ggaatgcgga40561agacgtgttc tcagactgga agcaaaacta gcttatgatt cttctacagc ttctccttcc40621atccctccct tcccattttg gccaatgcaa atcatctact ctcctctgac aagcctactc40681atcataaccc gcacgtcttg aatcttccta gaagatgaaa tcagaccagt cttgcgggct40741ctacatggtt acaacttgct aacttgaagc tctcattatt ctatatgcca aatattgttt40801tccttgacat taatttattt gatagatatg tatcaagcaa ctactatgta ttaagctctg40861tgctggtgct ggtgYctttt tggatcttat aatttagtgc agaaaataga caaacaagaa40921atgatgataa agtacaacaa agggtcgatg tacaaagtgt caaatactct aggaactaca40981ggaaaacaag ggaaccatca cgaaacccct gtcttaagac gtgacattag tggagatatg41041aaaaatgagt aggatagtac cagttaaagg gagacaacct ctgttccaag cacagggaac41101agcagagatg aaacctggaa gtgagggaga atggcagact gcaagaacgg aaaaatgtcc41161agtgtagcgg aggcagagag aatatggaga gtgtggcaaa agaggaagaa gcagatggat41221tttgagggca ctttctgaag tgctaaggaa tttagacttt aacctgaggg caatcagaag41281cagcctggtg gagaacgata tatttcaaaa catagggtcc ttgaaaacaa gtcaaccaaa41341tgtatttaaa aggctgctga tgaaaagatt gggaagtatt gttttcattc tcattgtttt41401cactgtcatg ctctttgtgc caatggttag acctcctttg aaagctcact gcagcatgaa41461agcccttctt aatgccaggg caggctcccc aagcctcccc accccactgt ccatgtcatc41521agttttgtac tcctgttttg tatggctcag gctttcctta tactcttagg aatgaaaagc41581cacagacacc accactgaga gactgtcaaa gatccttgtt aaaYaggtgg acaactgaga41641tcagagaagg aaagtaattt tattactttc Ygtagcaatc caggggtagc atctcaggtc41701tctggctcct tcttgtctcc cctaaagaaa tagaccacca gggctgggat taaggtgaga41761caagtgagac atagagggtg caaaatgtag agagatgccc gctgccaggt gccagcctgc41821acttRtgtga ccctaggtgc cttcccttcc ctcaccctgc tggtatctgc tggaaacacc41881tttgagagca gggactttgg cttttagaca actctttagc atctctcatg gtgttaacat41941gttgctaggt gcctattttg agggtcacta gatgcctact gatactaatg aacaatggat42001ttctgacaaa ctgatgtgca cacagatgtt tatattttag ggtaaatacg aaccttaaaa42061gacaacagaa caacatggag agggcctgag actgagtcta gagacctgga ttctggttcc42121ctccctgcca tcagttggtt atgggaactt ggataaattg ctcctcatct ctaggcttca42181gggaaatgag gtggttgaat aaaacgtatt gagcacttac tgtgtgtcag ccattgttca42241tatgctccca ggctttaact cagctaaaga cttcctggcc tctgtggttc cttccacttc42301aacaggctgt ggtttgaggt gggaagactt cgtagagaat gcaaaacttg agagacatct42361tccaaattcc cagggggatg ttaatacctt taatcatagt aaaggtatgg tttctcaagg42421catttcttgg tcagaagaaa gttccagaag gcacttaatc ctaggactca cactaccaag42481gctacagcca ggccaactgc ctcacaataa ccttagaaca tgtctgaaga cagattttca42541gcttctgccc ctagagattc taatgcagtg attccaaagt ggggtccagg aatctgtatt42601aaaggcttcc cagttgactc tggtggtcag agagatttga gactgattcc atcacattcc42661ccatctgtga acgggatcat acctagacag cccagcccta gaactgcctg gtctgatcct42721aagtgttcca tggagatttt gtttttttaa tgtaatgaat gattaagtca gcaaatactt42781tacatctctt gtgtgctagg ccctgtgcca ggtggtgatt atgggcccta ttctcaaagg42841actcctggtc tccgtctgtc acttacttta gaaacaagtc atctagccag agccagaagg42901gcactggaga tcactaatcM atcccatcat tacaYagctg aggaaactga ggcccagaga42961gtaactgcaa catgttaaag actacacagg gagcaaattt Wttttctgct tYtaagccag43021gtggtttggc cacagatagg ccaagaagaa tacgaacaga caagccttgc tgggtttccc43081actcagttta ttactattag accattccct ttttccccac tcacatttct gcgcatttcc43141atggtcttca tagaatctaa gcctaaaaat agagttttcc ttgagtcttt gggtcttcat43201ttYtgaagac tctcatgtca cagaaaactt taattaaata aatcgttatg cttttctctt43261gctaaccttt ttctacaggc atgtcagctg tgaYYcttat gatggggagg aaaggcaccc43321caccttctct gtccctacag tccYaatgcc ctacccagaa tggggttttc aaaatcccag43381gacacccact ctttgtttct taagcactaa acctatatat agtaaatgtt tctggaagtt43441taacttcagc tcttgctgaa attttaaacc ctcaatttcc agaggaccat cgccaggtgt43501ttttaaaaYc tcgataggaa taagaaatgc ttcccagaat ggagacttSc atcagttctW43561gggagctatt agcccccWtg ccctggctgt aatggagacc gctgtgtctg cctcctttcg43621cactttggag ccaaaagagR aagggaccgc ctcccacgtc cacagggacc tgacttccac43681ctctctgccc agatttgctt atgtcactgt cgccccggga cggggaggtg gggagctgag43741ggcaagtcgc gcccgcccct gaaatcccag ccgcctagcg attggctgca aSggtcYcgg43801cttggccgcg gattggtcac acccgagggc ttgaaaggtg gctgggagcg ccggacacct43861cagacggacg gtggccaggg atcaggcagc ggctcaggcg accctgagtg tgcccccacc43921ccgccatggc ccggctgctg caggcgtcct gcctgctttc cctSctcctg gccggcttcg43981tctcgcagag ccggggacaa gagaagtcga aggtgagtga gcctccgggc cgggggccgg44041gagaaaaaac ctagcccctc ggtgtccagc gctcagtgca atgcacccct tttcccaggc44101tccccgccag atgggcaatc cccaggtgcg agagacctcc tgaacccctt ttgccgcccc44161ctccgccgcc gggaccccgc ccccgaccgt cgtcgtctcg tagttccatc tgttggagag44221ccgagacctg gtgcttcagg cgggcagaat gactaaggga ggaaggtctc tctccccgag44281ctcgcacttt ctccccRctg ccacctcgag Rgtcgccttg ctacatctat gtcacctccg44341tgcctgagct gctccccttd agtagggcct aagagggagg gcgtcacaga aaaaaatgcc44401cagcgtctgg gtgggctgtg caagttccca gggagagaga caaggagaaa ggagagaggc44461agctgggtgg tcctggtcct gaagaactgc tgtggggggc tcttctaccc caagaatgat44521acaggcaggt agaaatggcc acttggattc agggcattgg tagaagaggc agagatctgt44581gctagaaRga gctctggagt gacagtgcag aacactcagg accctgagtc cttacctgct44641cctggacccc cgtttctcca tctgcagggg agagtttggg ggtgggagtg catggggcac44701aatgaagctg agggcctcag aggggatgct tggagaagct gaaaaatcca caagctgttc44761tctgaaattt cctcYcctgg ggcagcctca ctacccagga cccactgtcc tcattagcct44821gaggaaacct ggtagttgga gaaagctggg gactgctaat tcagaagaag aggtagaatt44881ctctagagcc tcagtctatt tccagcaggt gtgtggccca Yacctggagt ggggatactg44941aggccaggag tgggatgacc cagcatgctt atctcctttg acagtatgta ctggggtggg45001ctctgYagac ctctcctcta cccagggagt gggagtgggt ggggaaggag gcagaagcca45061ggtgtaggga tagactcaaa gcgagcgatt tctgtctYca acttcccaac atgcataact45121cacatttttg caagctctga gcttttgttt ctaaaatcct ctgggtcttc actttaatta45181agttSttatg agtctaggat tccgtttcca aaattctgtc cacttctcag gaagcccatt45241ggaagcacag ggttccttcc atgttactca ccccttttcg gtcctcagcc taaatccgat45301taatcagcct ctccttggag tcagtctaaa tggatgtgaa gccacttcgt ccaagtcccc45361tcctttttat ccatccctgt tcataatccc caactcagaa ggcattttcc aggtcaggaa45421tgggatcgat tttcaacatt gaggtttggg gtgggccata gacaggccag caccRtggag45481tcagtcccaa ccttcagttt tggaaRggtc aaagaagata caattgggcc ctgcctcaag45541aaSgctagtg gggagaacgt ggactccatg aataactcat catagctgtg tcttctctgc45601Mgcactctgg ggaaggataa atggactcag agagaatagg atggggatgg tYtagaaaag45661ttttagggtg aggtgtgatc atatcacata caaccagtca ggacttgctg gctaatgaaa45721gcctgggcat gcccatctct gctcccaagt tcttaNagtt cagatgtctt agctctgggt45781taggacccaa ccactcacct tacccccaac cccagggtaa agagaYaggg ttatggggca45841tgtggagaat ggaatggacg aaaggtgact cagccccaga gaggtgtttt cctcctacca45901attgaaaggg agatgctagg gaagagacca ggtcctcctc ttcttgctgc gtcacctccc45961cagtccaact tcaSgctgcc cacgctcctt gtctctacaa aaggactgca gaagccggaa46021agagtgacaa ctgctgacgt gcaYgggatc ctagtaactg ctggtttcta ggtgactaaa46081cctggcagag agaatcatgg aaccacaggc tgacagagtt aaagggccct taagacagcc46141ctgaacctga ctccatctta caatggagga gctggagccc cagcaaaggg ggtcacatgS46201catcagagac acagcaaRgc Ycagcactca ggtctcctga ctcccagacc acttctcaca46261gcatcatatt gataggagtR ataagacggg agaggagaaa gacacaagac cagcagcccc46321agccagccag agtcctgNct gagtcccatc atccaactct caagccattg gaaccctctt46381ctcttgcccg gctgtgggag gattcaggca ccctcatggc ctctcccctt atctcctctg46441gccactgttt cagatgcggt gctctgggat tccacgtgcc cagagaaggg aagggggctc46501atagaggact gagttgcagt gatcagtggt gagcacagcc gtggctctcc acccatgggc46561caccttctga cccccactat ccYttgacat gagatttcgt tccaagagac tccaggcctg46621ttttgctctg ccagcagatt cccacaaccR ttttgggcag cagcatgctt atctccctgg46681acatatgccc agacagtgta agtgacttgc tcagggccac Rcagccagca aaaaatagaa46741cctaatgaaa tagggttctc cttgccacac ccccaagctg aaactgtgcc cagaagctgg46801tccttctStt tacaagttcc cattattagg acaacctgta atcttttttt cctccatgtc46861tcagagttca tttttggatc atggcagagt taaaaaagtg gagaggctat agacatgcct46921ggctttctgg ccactagatc tttgtggcgg tctagggtgt atttgttgtg ccccagtttg46981tctgcatttt aaggcggaac tggccctggc tgggaacgag gaggtccagg agcagtagga47041atgttgatct taggtcttgg gcctgcctcc agcacccacc aaaagtcacc ggatgtggaa47101tattagactc atgtaaagca ggaagtttgc accagagcca agaagagagc ttgcagctgc47161cagggaatgg cctggcggag gaagcgcagc ctcgcccagc tcagcagacc tgcttcatga47221cagaggcagc tcttctgcac tMtactgggg ccacgccctg ccagcatata tcactccctt47281cacctggtca ggcccaggta ccttgcctca acagcaagtt ctccagaatt gaggggaaga47341gagggagtga atttgcttct ctaactccag ccacctgtct ctgccctctc ctggtctata47401atgctacttt gcattccatt tgtttattgt ctgcccacct ctcaaaggat atcagggcca47461caaaggacct taaagaccac cttatacaat ggtttcaagg tttctccttt cYcatcacga47521ccagcccacc tgccaaattg tgtcaatgat gcaatgacat cctttcaaga atagtctcag47581aattttgttg tctgtgtcaY gggcagagta ggctcatagg ccacatccta ctagccagca47641gtgaccccaa tcccctctct cccactgatc atgatcctat caagccatca tggttgacct47701ggttgRagag ttggttcagt tcaaggttct cattttataa atgaggaaac tcaggtccga47761agaaaagaaa gggccagtcc aagaccacac agggagttaa tggcaRaggg acatggagcc47821caggtctccc agcccacagt ccactgcact ctgtccctcc ttgtcctgga ggctgactgt47881gagcagcagc tggggaggga ggaaggcata agggtcatca ccagcctgct cagacccgga47941acattaacac atgcaggtac tgttgctttt ccctaccKca ccacagccct ttcccccatg48001cctggctctc agtcctgctt YcctRtttgg taacaacagc ttcatctttc ctgtcctgca48061gattgggagc ctctgaatca ccatgtccat acKgcctctt cctcctttct gttcagtttt48121tccttcacac tggcctagtt caggttctca tcctcaattg cctggattat tccaacagcc48181acccaaccag tctccatcag cccgtctagg aacccagtca tcagctttag ggcagtctcc48241ctgagagccc agtaaatgtt ctgaaattga catgtgatgt ggaagtaatt agcaaaataa48301gtcattctcc agggttccat agcactcact tattaagtgc ttaatattaa taagtgctta48361ttaggtgctt aatattaata agtgcttttt aagcacttaa tattaagtac ccRaaaagca48421cttattaagt gctttcataa tcattatctt aaacaaggaa ttaggagacg tcagtgctag48481tccagttcca attctcggtg attactttga gaaagtcact ctctctgttg ggatctttca48541ttcttttgaa aacggagatg tccaagttcc tttccagctc taactgctcc ttttatggcc48601tgtgttccag atggactgcc atggtggcat aagtggcacc atttacgagt acggagccct48661caccattgat ggggaggagt acatcccctt caagcagtat gctggcaaat acgtcctctt48721tgtcaacgtg gccagctact gaggcctgac gggccagtac attggtaaga gcccaccctt48781cctccctgct ttatttgggg ctgtatggca tatttcaatc acaggagctt ttctggtgca48841tgggggaaag ggtgatggca atcacgagag tccaagcccc ttttctcagc tccactgtgt48901tccgtggttt tgtgaagatg attatataag ccYgaggtct gattgccttt ggacatgttc48961taggagattc ctagttatcc ttcttcatct ctgggcacct caacaaccct aaaggcagag49021ggatagagat taggtttgtg cttagagctc cctttggctg gagcatgaga tggtaactga49081agctccatct tgctgaSaat atctYatttt ccctcagccc catctgcttt ggtgcttctc49141ttggcagctc tctggaaagc aggcaattgc ctcgaggccc cagagtgtat gcgtggtgta49201gcgggatgaa ggagcaggct acacttctaa tgcccattct aaaataaact ttgaagatga49261tctagtttag ccttcccctc ttctcaatct acacatggga aaccaagact cagagcgaag49321atacaactta aacagggtca caaagctatt agcggtggaa tggggcattt ggcgcaggtt49381tcatgatctc ctgatatgct tactcctttc tccctagctg gggtagaata cagaggctag49441gggaacaggc aaccaaaggc aagcgacagc acccagggga aaacgctttg gggctgagca49501gtctactggc agggggtcag ggaggcaagg gcaatttgac cctccatgct ctgcctggca49561atcacaggcR aattcccgga agtgaaagga Yggcggtcac gtggcccagt ggctgtgagt49621gctttttctg ggatgcttct ctctagcctt ggaacagagc agagtgcgtt tgggcaagag49681atgggctggg tgctgctgca aaaSWgacca ggggacactg aggaaactgg ggagctgggc49741cagggcctca tctgtgttcc tgatttgcca aagattatgg gagggttgta acctcacYcc49801aaagaagttc tctgccttgt atccagggat ggatagttct tgctccagaa aactcaatcc49861tgagggttct gaatgagtgc tctagctggc ccaggtggag ggccttggca atgggcaggt49921gactgacagc tgacttgagg aagggtatta ttcttgtcct ccaaacctcc aatccatcca49981gattagagtc aagaggatag gacctgagtc ccagcattgc tgtgaactca ctggtgatcc50041tgcgcaagtc cctccctttc tcgggcctca gtagttccag cRgcacagcg ggtgagccgg50101gggagtggtg tggatgagac agggctcctc gccaggatac tcccacRtct gctctttctc50161tttggcccag aactgaatgc actacaggaa gagcttgcac cattcggtct ggtcattctg50221ggctttccct gcaaccaatt tggaaaacag gaaccaggag agaactcaga gatccttcct50281accctcaagt gagtactcac tcagcatcct gagaaagctc ctctcacatg gcccacatct50341tgttatcaac cccaaWtcat ggtggacatt tatcggccac caagaactac tctcctcttc50401taggatcccc agtggaatga gggaagggaa gggacaagag agggagaagg acagggacaa50461ctggttgtga tgtgcatccg cagggagcac caaggttgag ggacactgaa aagggaccag50521gctagaaagg aagaccgtgg actcacatta tgcctatgcc cactgcacat tcactggctc50581ctgctgccca ctgcagaata aatccagact cccaacaccc tctcccctgt tctgtccctt50641cctctcattt ctgagccctg tgcccacctc cttgggaccc acctaagaac atttctcaac50701aggtatgtcc gaccaggtgg aggcYttgtc cctaatttcc agctctttga gaaaggggat50761gtcaatggag agaaagagca gaaattctac actttcctaa aggtaagtga gctgccacct50821gtgctggctg gggctgcagc ccctcctggc tccagcccac agcgtcaggg cccatgccac50881ctcccctgct cctgggctct tggggaattt cttggcacct gactattgtt ccaactagag50941ggctctgcag accctgacta gggtctcMtt ggcccatttt acagaaaggc ccagaaggac51001ccagagtgaa catactaagg gtctcacaMt cttctagagc cacagctggc gctggcagtc51061ttctaactcc caaactgggg ctcttYtctc agggccaggc tattccccag gaaggcctgg51121gaaggaagag ggtcaggggg cctcaagcaa ggttgacact cctctYatcc ctgctctaga51181actcctgtcc tcccacctcg gagctcctgg gtacatctga ccgcctcttc tgggaaccca51241tgaaggttca cgacatccgc tggaactttg agaagttcct ggtggggcca gatggtatac51301ccatcatgcg ctggcaccac cggaccacgg tcagcaacgt caagatggac atcctgtcct51361acatgaggcg gcaggcagcc ctgggggtca agaggaagta actgaaggcc gtctcatccc51421atgtccacca tgtaggggag ggactttgtt caggaagaaa tccgtgtctc caaccacact51481atctacccat caYagacccc tttcctatca ctcaaggccc cagcctggca caaatggaKg51541catacagttc tgtgtactgc cRggcatgtg ggtgtgggtg catgtgggtg tttacacaca51601tgcctacagg tatgcgtgat tgtgtgtgtg tgcatgggtg tacaRccaYR tgtctRYcta51661tgtgtctttc tgggaatgtg taccatctgt gtgcctgcag ctgtgtagtg ctggacagtg51721acaacccttt ctctccagtt ctccactcca atgataatag ttcacttaca cctaaaccca51781aaggaaaaac cagctctagg tccaattgtt ctgctctaac tgatacctca accttggggc51841cagcatctcc cactgcctcc aaatattagt aactatgact gacgtcccca gaagtttctg51901ggtctaccac actccccaac cccccactcc tacttcctga agggccctcc caaggctaca51961tccccacccc acagttctcc ctgagagaga tcaacctccc tgagatcaRc caaggcagat52021gtgacagcaa gggccacgga ccccatggca ggggtggcgt cttcatgagg gaggggccca52081aagcccttgt gggcggacct cccctgagcc tgtctgaggg gccagccctt agtgcattca52141ggMtaaggcc cctgggcagg gatgccaccc ctgctccttc ggaggacgtg ccctcacccc52201tcactggtcc actggcttga gactcacccc gtctgcccag taaaagcctt tctgcagcag52261ctgagcctac tgtgtgtggt gcttcttcaa tggtggccgc ccccgcctgg gtgggaagtg52321aggaggagaa ggtggggcag ggtaaaggSg ggaggatgag aaaagaacaa atatgacaac52381aaaaactttt tacagtgggt gcaaaggtaa ttgcggtttt Ygccatatgg caaaatccaa52441ggctacctcc ccaccccaca attctccctg agatcagcca aggcagactg caagggccat52501gtagccctat taggggtggc atcttcatga gRgaggcccc cctgccacaa aaaaggggca52561aaaattgcaa ttactttttc aacaacctga tagttagctg cagtggcgca ctccttcagc52621tacttgggag actgatgtgg gaggctccct tgagcccggg agtttgaggc tatagtgtgc52681cRtgactgag tctgtgaaga gccactgcac tccagcctgg gcaacacagt cagactgtct52741cttaaaaaaa aaaaaaaaaa aagagagaaa ttagacaatg ctttgagtcc ctgctttttg52801gctcctacct tggcccactc tgcttctctc actcagcatt tggagtttat aaaaccagtt52861ctgatctact ctcattccct cccacagttc tccaagtcag ctgaggttaa gatgaggtgt52921tctgtttgac ggatgaggaa actgaggctc acagaagggc cacgccttgc cccaggtctc52981ctgatgagtg aggggcagga ctggaattta aacccaagtc ccctgagtcc tggcctaggc53041tccttccact gccccggYtg ccctaccctc agggaggccc tgatacgtca ccattactca53101agagtaatgg tgaccatctc agggaaagga agaaaagggg aacagaagga gggacccagg53161aaagcagggg gttgacaggg gaacatYagc gcataaatga acatgagtca gaatgttgat53221cttcttcaac ttggatttat gtccatgatt cgtgcaaata gctatccagg gatggacagc53281caccctaatc tgggcttctg gcaccacagg cctccagcta tggggtccag ggtctgaacc53341tcagggcctg gcagcttcag gctggcgccc ctcggcRgac gtggctggca tggccttctc53401ccatctgtga tggcttcagc aaggctactg tgagtggtgg tggagagggc cccagagcca53461gaatatccat cattctcttc tgttctggag acaaacccac acttcccaca gctcctcaca53521gaggggtagg ggtgtgcgtg gggcaggtcc tgctacagag cttgaagcaa aaattaaaca53581cacacacaaa ttggtcatgg caactagagg gcctgaaacc acttccggga ggttttgaag53641gaagggggtc ttggctgcct cccactctta ggattgctgc tcctggaggc ttctgcaaYg53701gatggtgggt caaagccgga tgaggcctct ctccactcag cagcagggaa ggagtttttc53761ccagtcactc ccagcagagt acaaatgaaa gccttctggg tggagcctcc ccagtcctgt53821aaacagctca gttcagggac tggtRtacaa gctggccacc catctcagcc tctcatccag53881ctgaggctct ggccacaccg tgcaagtggc ttctagtttY ttggcaatMt gagatcagct53941ggctctgcaa gatgaaggtg gagccaaatg acacaatctg gtctcactga ggcccctcac54001ggtcattttt tggagactct aaataaacaa aaattttgag gacttcatga ttatgtggta54061gagcgagttt caaagtctct tatggaatgc agtgcaggaa cagtgaaaat aacagctagg54121gttactgggt gctaccaagt gccagggcta agtaccttaa gtacgctggt catgtaatct54181tcacccagcc ctatgaagaa ggcaggttat tatcccattg taaaagaggg aactgggaca54241ctaagaggtt ttaaatgact tgctcatagt tccaggtcca ggaaatagtg gggctaggat54301ttgaacccaa tctcaaatcc tggagcagtt ctggggaggg agcccctccc attataccaa54361tctctaccac tcatcaaagc agcctccaag gggctccact gaacttgtag ggttcttcag54421ggaaaaacag aaaatgactg agcagcccaa tcccttcttc caatcaccaa atcctccaaa54481ctgcaacccc tccaaggtgt ccgtcccatg gcctctactc acacacctgc aaagggacac54541tcgccacctc ccagagctgg ctccatttct gcacaactgt gtcccttaga aagaaagttc54601ctcttcatgt tgcgatggac ttggcctccc tgtcattccc acccactagt tataattctg54661ttcccagaag tcccacaggc gaggtggtgc cttgtgcccc atgagagctc tacagggagc54721aatggcagtc gctaaggtcc caatcttttc acgagtggac acagctccag gctcttcagc54781ctttcatggt ggacaccatg gtcaggggag cttttcaaac agaaatatgg tcatgccact54841ctgctttaaa aatgtccagt gactacacat tatgctgagg ataagaccca ggcctcccac54901catgctccgc aggcctgcac ggtcaggacc cggctacgtc ctgaaccctg cgttgcccct54961ctctttccct accttgttct tggctccagc cacgctggtc ttccctccga tcctcaaatc55021agctccccta cttcccctcc tcccaccacg gcctctgcat ttgtcatgtt ctctgcaaaa55081gcatcctcca cccctacctc tccacctagc tagtgtcact cattctgaga gtctcaactc55141aaatgctgcc cccccggtct aggtcggctt cctctgctat ctgctcccac agaaaccggc55201tcttcttcct ttagggcact tgagtgcagc ctgtttgtgt ggtgtttgtt tattcatttc55261tgcctccctc attagacatt acgctgtata agggcaagga ctgtatctgc ttctgttctc55321taggcatcca tagcacctag cacaatgcct ggcattagat aatgcactag aatgaatggt55381ttcagccccc ctcactctgt ggttgccatt actctccatt caacactgtt ttggaaagct55441gggcctctcc tccaccaaga gcagaaacta acRacatcac ccccaaactc aggcaatgct55501ggcagataag atattatctc ccccagggag gaccaagact cagtattagg ggctcacctg55561gttctgtagg cctggctgtg ggagggtcca tcacttggga gctctgattt ggatttcgaa55621cccctccaca gggtagacgc caggtgtatt ccggctgcga caaaactggt gcttaataat55681caataatcaY acccaaaaat tacaatagca cctactgtgc caggacaata ctaaatctgt55741attagtcaag tataattgaa tctttataac aacccaggct ggcactccca tttcacaggt55801aaggaatctg aggctcagag gggataactt gctgaaggtc atctagcaaR gagaatggct55861aagcttggat ttgaatccag gtctttgtaa atccagagcc aatctcttaa gcgccatact55921atatactctg gtgtttaaag atgtgtacca agaagggtca tatgggagaa gctgaaaaag55981aggccagcca ggaggtttct gtaatggtcc aggggagagc tgggatgcct aaggtggggc56041tgtggcagag gactggggaa aatgggacaa gtgacagcag atctttggaa gaagaatgat56101aagaagggaa aagaggccag gcgcagtggc tcacgcctgt aatcctagca ctttgggagg56161ccaaggcggg tggatcacct gaggtcagga gttcaagacc agcctggcca atatggagaa56221accccgtctc taccaaaaat acaaaaaatt accgggcgtg gtggtgcatg cctgtaatcc56281cagctacttg ggaggctaag gcaggagaat agcttgaacc tgggaggcag aggttgcaat56341gagccgagat cgtatcactg cactccagca tgggcaaaaa agagtgaaat tccatctcaa56401aaaaaaaaaa aaaaaaggaa aagaaaataa aaaaagagag gagagaagaa gaggagggga56461ggggagagga gcggagggga ggggagggga gaggaaagga aaggaaagag agagaaacat56521ggtgaggctc tggaacctag ttacacgtgg aagttataag aaaaagcaaa cccaaactct56581gatacccatg gcctggggcc tggagggagt cctccttccc accctgcact cttactcagc56641cttctccgtc ctagaccagt gaccctgaac agctgtgggg cagccctgcg ggactgtggc56701cagatccctg cccctgggta gcagcccaga gccaggccct ggacacccac ctgccaccac56761Rgtgctgttt agttcagaag gatgcagttt ctgaacccct cacttaacct tcctctctgg56821aaggtgtctg gggcagcctS tgtgtgtgcc ctggagcaag ggagggacac agactcacca56881gatggaagag gcgcgagttg gggagtgggg gcgggtgctc catggccatg gggggagggg56941ggtagcggat ctgggaccag tcctcgaagc catggtgtgg caccatggct ggcatgggcR57001ggtaggcgta ggggtaggcc ccgcagagat gttctgggtg gggctccaca tggtaacgct57061ctcctgaggc ctgcaagaaa ggctgacgtc tggctttggc ctgcaacagg ctgcaMagga57121cacccatctc atcaccctct aaatagaatg ttagctctct gaaggctagc aggctgggta57181ccaaaggctg gtatgtggtc atgaaaggct gctacatggg tacagaaatc tggatacatg57241ggcatagaag gctggatata tgagcatgga aggctgcatg ggcatggaag gctgggtaca57301catgcatgga aggttgtgac atgggcacag aaggctggta catgggcacg gaaggctggt57361acatgggcat ggaaggctag tacatgggca cggaaggctg gtacatgggc acggaaggct57421ggtacatggg cacagaaggc tagtacatgg gcatggaaag ctggtacatg ggcatggaag57481gctggtacat ggacacggaa ggctggtaca tgggcacgga aagctagtac atgggcacag57541aaggctgcta catgggcagt gaaggctggt acatgggcac agaaggctag gtacatgggc57601agtgaaggct ggtacataga cacggaaggc tggtacatgg gcacggaagg ctagaacatg57661ggcacagaag gctggtacat gggcacggaa ggctgggtac atgggcacgg aaggctgggc57721acatgggcat ggaaggctgg gcacatgggc acagaaggct catacatggg cacggaaggc57781tgggtaaatg gacacagaag gctgggcaca tgggcacgga aggctgatac atggaaacgg57841aaggctgagc acatgggcat ggaaggctgg tacatggaca cggaaggctg gtacatgggc57901atggaaggct gggcatgggc acaaaaggct gggcatgggc acaaaaggct ggtacatggg57961cacggagggc tggaacatgg gcatagaaag ttggatacat gggcacggaa ggctcataca58021cggccaaaga aggctagtca catgggcacg gaaggttgct acctggacac agaatgtcaa58081cagtgatgac agctaataca ttgtgggcac tgcctctgta ccaatactgc tctaaggctt58141ttcctgtatt actcatcagt tagttagcag aggatgtccc cacgcccgag cacacactgt58201gcatccatca ggctagctcc atgaggaagg taagaggatg tcagtgctgc tacctccctc58261aagcctcctc acctttgctt tcctcttctg ctgtctgagg gcttctcttg ccttctcctc58321atctttgaat gcttttagct gagagaagaa gggagggaga aaagactgtc ggcacaggtg58381gtttctggcc aggcctggat ccagggccta accagccaMR aggactgacc ggctgatgct58441tccctctggg ccaccatgcg tgggccagcc ccgggaaagg gccctgaggg cggagcacag58501cccaggctgt tgctgcaggc cacctgcttg tcacagtggt ctgtgcacag gtcaagaggg58561ttcacgtgaa cctcgctgct tctctgctaa catcttttag ttccactctg ggagagtaaa58621gcccagaact gactgtggaa agtcagaggt agagatatct tagagtaaaa ctcgtaattg58681tacaaagaaa gagtcagaga ggggaagggc cttgccgagc tcaaatatga ttgcagagct58741ggagagaagc agtgagggtc ctgacatcca gcctcaccag ggccctccaa tccatgcccc58801ctctcccSac gaggacaggc cagttgccct tcctgggtcc agtcactctt acctgggcat58861ttgacagggt gacctgggcc tgcagcttct ccacttgctt cttcaRctct tccttctcct58921cattcatgcg ctcacgatca ctgcgctccc tctggaagtc ctcctcgaag atcttcacct58981ggtgtggagg gagggtgaag agagggaggg ggatggtcct gagtggggat ttctcctcag59041gcccagaYtc ccatgcctcc tgctggggtc acagatggca gagctggggg tcgccatggg59101gagtgggaca gctacacctc cagcctccac cttaacttca aacagagtag ttctgtgtcc59161ctctatctta cattctgggc ttcaagStag gactttattt gaacaaagga tatatggttt59221taaaaaaacg ttgaaagcca tcaaccagtg caatcctttc actccgctga gacccacagg59281ggcagtgatc acagaaccag agtgtggtgt agaccagagt ttggatctgc tggttctgag59341ggcagagacc ctacaaactc Ygctagggct ccagggtgcc ctggcagagg tgggttgggt59401ggggcctgcc tctgtctctt agcctgtagt ttcacatcct tagtgcagat cagctgagac59461actggctagg ttcaaggcag tttaggagga ttaaatagca cagagacaat gggagagcca59521caaccttttc gctttctttc accccaatcc ttctgtgtcc ctcagggcta gtaggtcttt59581aataccattt tagtacctgc caatctcctt taaataaagg agaaaagaac tccagttcag59641agtcttcatt tggcaagagt atccggctag agtttaataa cattgttctg tttttattgt59701ttattgcgta cagttacttt ctacttgtga caaataataa atggtttttt ccaattacag59761cagtgatata aagctccctt ttaaattcat ttatttagaa tttatttttt aaatactagg59821taaataatag cacgtgtggg gcatagagat ggctaaatca taaaggtggt agaggaacga59881cttaagctag ggttatggtg ctggaaagga taaacctaga gccagtgggg ggccctggcc59941aatggccaga aagtggatta ctaattacag gttccatgtg attccaagcc gtctgggccc60001tcaggaaagc tccagctccc acagagcacc tcccacctga tttcctcccg gaagcctcac60061ctgctgtttc agcaactcat tctgcgtgac cagctcctgt ttccttagga gggcccctgc60121tccttctggg ctcccaaatg ctgttggtgg agatgatggc ggggtttgga tgctcagtgc60181ttcctccagg gcctggaatc aggaaaagat gggaccatca gcaggaaccc ctggaaatca60241gggccctttg gaggggtcat cctcagggaa ctccttccta ataataatca tactaataat60301agccaccact accagtccta tttaataaat gctgccctat ttatttgcat tctacacata60361tcatttcatt ggatcttctg cacagtgcca tgaagaaaag actatgatca tcatcctcat60421tttacagatg tgaaaactga ggctcagaga cctgaagggg cttgtccaag gtcaaggtca60481cacagctagt aagtggcaga gcacagattc aagcccagca catgctccta cccagcaggc60541taaactgggg ttgtcatgca gaaggggaaa cctccccttc cctgaacatg tgtggctcaa60601ttcttagcac ccagacctag aaggaagatt aagtcctccg ggggaagctt cagtctcccc60661aacaactgcc ctgccctgag attcttcact ttcagcaacc cattcccatc caaaccaccc60721cttccatcct caacacttat gtacatagag aagactggat ttaatttctg cttagttaat60781attttccctt tctaacactg aaaatgggct gaaatatcat caaataacat tttgaaaata60841aaaaaatact cttaatctat catgttcaca atagattata taaacagtgt gcccacatct60901tcttaaaggt ttcagttaac cgtgtttccc ctttaactct gttaacatgt tactcagaac60961tctggaacat gtctcaagac tgggcaccct ggactttggc cccaggacag catcgcccat61021gggcctccct ggaccgaggg gagatagaga cctggcccaa cttggactcg ggcttccacc61081tggtctcctc agctccccta gacacgcaaa gaaactgcag gaccgagagt aaattcagga61141tgctccgagg ggaagttatg gctccacttt atcttcctac tccaccccac ttttaaatga61201aaagactgag gtccagcRac agggagatgc ctaggtcatg agcaaagaag gccacatgcc61261ctgcattact catccacatg gtgtctgtcc ctggctctgc caagaaaacc tccaaggtca61321tctttatgat cagcaacatg gacaattctc tgcctggatt tagagcccca agtcccccag61381ctcaggacag atcgcgtttc tttctctgga aacaggtcaa gggccccaga cttggcataa61441tcagtgttta caaaacacca aaaccaaaaa gaaagggttt ccccagcagg cctaggaatg61501ctcaactcat gccagagtcc actgtcacca gggtcaggag gcagagggaa aggaaaaaca61561attagcacga aacgaaaagc tgagccatga acttaactcc tccaggccct cagagaatgt61621ttcctttcaa agctccctcc tgtcagcttg catctttgaa atgtgctgga aagcaggcag61681aactagagcc gttcccaccN gggctcggat ggcaaaactg aactggagag gctggagagg61741ctaagctggg actagaccac tccgcttggc teagaccaga gggtttctgg tttcctcagc61801ctctaccctg ggggccccat ctccctggat cccactgcac aagggcgggc ccctcagccc61861gtgctcctcc actcccatca gtgtttgctg aacatgtgct tgatgccagg cgctgtacaa61921ggcgcccagg gtatacacct tggtgaaagt atgcacctcc caccaccaga tgggaagaca61981gaattaaata agtgatgacg agccatgaga aggagtgtca gagaagttgc tggtacctca62041ggagcataga ccagggcaac ctgaatgaga ttctgggaag gctttgctga gcaagtgagg62101gtaaaacaaa ccctgacaag cagggtgggc aggtgaggca caaggggaag agtgcacctc62161cagagggaag ggtgacacag gctaattcaa gggctgagtc actcccagtg tgggaggcaa62221tggcagagca ggcgggaaac aggatgccag ctcactgact gggggttacc cttcctaagc62281tgaatggttR ggggtgccag tgatggggtg ggcattgcag ctggactcaa gggagcccag62341ccaagggacc cgggccaagg cacccacctt gttgagccgc tggatctcct tttcctggta62401ctcacgctgt cgggtgagtg ggctcagctg atcctgcagg tacttgacct tttggcgcag62461ctccttggcc tctgctgtca gctgctcctt gtcggtctgc agggaataca aggttggtaa62521gctggctagg atggcctctc caggaggcct cggattctct gtcctgcctg gcccagccct62581tacgttctcc cctggYcatc acttcacaat gctcacatgc aaagcacctg gggtcggtac62641agtaatgtcc atccggtcct gccctcaatt attatgtgtc aatttaaaat aataattaaa62701aaaagaaaaa gcagtagctc agttgagtaa aagaccctgg attccgacac cagttcatcc62761actaagcagc tgagacccct ggcactgcca cagccctctc ttgtctaagc ttacctacct62821gtcacaggta cggggttcct aacgtgagtc acacagagac ctcaggaggc ctgtgagccc62881caaaactgaa tgcgaaattt tgttgtgtgt aatctgctag aaagaaaagc catagttctg62941accagattca catgggggtc ttccgtgatc cacagaaagc gataaactac ggataatccc63001taacagacac tgcagctcat acagccttgg agcctagagg agagatgaca cgcccagaga63061gaactgtgac ataaggcaga gagtgctcct ccagaaagaa acaaaatact gtggggctaa63121aagaaagatc accacagctg agggaaggct tccaggaggc ggttccatac cctctacgga63181accagcaggg cttcgccaca gccagccaag actgggatgg cctttagaca gcatcaagcc63241ccagccctgt aatacgatgg gaaacaaatg tccagagagg ggaagtgacg tacccaaggc63301cacacagtga gctggggcta gaacccaggt ttcctattcc cttgctctct ctccttccat63361gtcaaaggag gtgttgaaac taggggatgg cagcacagtg cagtggaaag accaggcaca63421tccccaaata aactatatat tcctatgtgt acatatatgc gagaaaggtc tggaaacaga63481tgcaccaaaa tggtaacagt ggttccctct agggagggcc tgggatcatg gcagtgggag63541gtagtccagg gaaactttca ctttgtagca tgtggacatt tcataactgt gtattcacag63601catgtgatta agagaccagt cgcaggggtt agttttcacc cagccctgtg tgacctttag63661tcagtacgga ctgcagaggg caggcttggt cagacctccc tgggaattgt tctggactcc63721ccatcaagag gctcccggat gggcatgggc tttaccgaaa ttcatcctta tctacagggc63781cacgccttgt catgaaacgt cctaccttcc ctgtagctga cagggaagag ccctcacatt63841ccagggattt gtctcaccta ccactgtgag caagggagag gggccaaaga gccaggatgt63901ctggctgcga gtcaccaggt atgactgtgc actcataagg aaagacagaa gtgttctccc63961taccacacct ccaaggtaag ggggtgtcac agacgtaggc tgactgctca aataaggccc64021ctggtgtccc atgctgacgg gaggaactSt gaaaggcaat ccaggttgaa aatgtccatt64081tttaagctag gcaaaagacc atgcccagtt cccatgaagg ggaaaacatg gtgacataaa64141taaaatctcc caagagtctg gcagtcaagt ggcctttcct ctttaagctg ctccaaggtc64201ctgatgggcc ttggctggtc tcattcatac atatgactgg gcagatacta ctacttcagg64261ggacctgttg tttcccccca agaaagaatc tggtctcact tatgcccact ctctgatctc64321tgtaacttct tcttcgtagt actttttttt tttttttttg agacagggtc tcattctgtt64381gcccaagctg gagtgtagtg acacaatctc agctcactgc aacctccgcc tcccgggttc64441aagcgattct cgtgcctcag tctaccgagt agctgggact acagacatgc gccaccactc64501ccagttaata tttgtatttt tattagagac ggggtttcac catgttggcc aggctggtct64561caagctcctg atctcaagtg atccgcccac cttggcctcc caaaatgctg tgtttacagg64621catgagccac catgcctggc catacatttt tcttttagag aaacagggtt tcactctgtt64681gtccagtctg gagtgcagtg gcacaatcac agctcactga agcttccaac tcctgggctc64741aagcaatcct cccacattag cctgagtagc taggtctaca ggtgcacact gccacaccca64801gtgaattttt taatttttgt agagacaagg tgtggctatg tcactgaggt tggtctcaaa64861ctcctggcct caagcaatcc tcccacctcg gcatcccaaa gtgccaggat cataggcaca64921agccacccaa cccggccttc tctgcaacac ttaacacact tttactttat ttgcttctgt64981aattagttgt ctggcacctc tttcccagcg agggcagggt tgagctgttc ctgtggactc65041tatgccaaag cacaatgcct gagacaggct ctgaagacaa atgccgggat gaatggataa65101atgaagctct gtctcatgtt gtagcccctc cccaacaaat caccatcact atgctgaaca65161cttggcagca tcccacccca ccaagtgcca tacagcaggc ctgcttggat cttttttttt65221ttttttttta gcaagagttt cactcttgtt ccccaggctg gagtgcgatg gtgcaatctt65281gactcactgc aacctccgcc tcccaggttc aagcaattct cctgcctcag ctacctgagt65341agctggaatt acaggtgcct gctgccacac ctggctaagt tttgtatttt tagtagagat65401gggatttcat catgttggcc acgctgatct tgaactcctg acctcaggta atccacccgt65461ctcggcctcc ccagttgcta ggattgtgag ccatcgtgcc cggccacctg cttagatctt65521ttatatggtg tgcttccctg tacagttccc cattccctac aattttaatg gaacaaaaag65581ttctgaataa aaacaagaaa atgtgaaaag ctgtagttaa tgtaactttc tcaattttca65641gatgggaaac tgcagtgcag ggaaggaacg tgcctgtgtt tttggtcacc tagctctttc65701gcactagacc cccgggtctc ctgactcctg cccctggctt gtttgctcca cagaactctc65761cgctaatgtg gaggggaact gactctgcag ggaccagcag tcacacttgc ctcctccatt65821tcaatcttgg acttggccag gaggagcttg cggtcaaagt cacgctgctt ctgctcccgc65881tcggcctcca ggtcagtcac ctgcttctgc aaatcagcca gcttctgacg cagctcagtg65941atctgggttc agaggcagag aggagtgtgt gaggcaagga tgtagagcac ttgcaggatg66001tgggcagggc ctggctgccc ctgggccctc caacactgcc cccaacttct cctctgggcc66061atactggggc tcagcgKgKc cactcYccaa ggttcaaagc tgctaaagag gcagMgagat66121gaagaccagg catgccctgt gggcgtggcS aggaacccca cattaccttc tgctcatact66181gctgcttcat ggaccggaaa tgctggtccc actgcttgtt cacttccagc agctgtgggg66241agagactgga gttagcagga gatgagcaga gaaggaacaa ggagagccat ctcctgcccc66301atgtacacca gcgtcccaag gtgtgctcgg tgtgtgtgaa tagtggctac agacactgtc66361tccatccctc agctctcgaa aactcaatgt tgctcaaagc catccacctt catccactgc66421tgcattttac cttgccagga aagcaagatt aacactaaga catggaaact acatMgtttt66481ggtgaataat tatggaacac acacacctct ttggagggca gtctgggatt atgtattgaa66541atttcacatt ttcatcaact ttaaaccaat aattccactc tgaagaattt aaccaataga66601aacacttaca caagtgtgca aatatatata cacaaggcta atcatctcag caatacctgt66661attacaaaaa aatccagagg ccaatctaag cacagaagat aggttaaaga aacgatagta66721taaacagaca atgtgcagct gttaagaaaa taagaaaata ggccgccagg cacagtggct66781catgcctata attccagcac tctgggaggc caaggtgggc caattgcttg agttcaggag66841tttgagacca gcctggagaa tatggcaaaa ccccatctct acaaaaaata caaaatttag66901ccgggcatgg tggcacgcat ctatagtctc aactactcag gaggctgaga tgggaggatc66961acctgaactt aggaggtgga ggctgcagta agccgagatc atggcactgc actctagcct67021gggcaaccaa agtgagaccc tatcttaaaa aaaaaaaaga aaagaaaaaa agaaaacaga67081aaataaagca cctaacacac ttcctcagtt tgaagatgac actatccacc atactcttga67141tataacaatt cctcagggaa gaaaaacaac cctacatcat caactaaata aaacaaaagg67201agtattggcc ctgcccctta agatatgtca taaggatcca caccaatttc aaaaacattg67261catatgataa aaaaaattac aaagaattaa aggaatatag catatgttat agatatgaat67321agatactctc aaaggcagtt aatttttttt ttggaggcag gcctaggctg gagtgcagtg67381gtatgatcat ggctcactgc agcctcctga gctcaagtga tcctcccacc tcagctcccc67441caagtagccg agactacagg tgtgtactac cacacccagc taatttattt tttgtagaga67501cagggtcttg ctatgttgcc caggctggtc tcaaactcct ggttgcaagt aatcttcctg67561catcagcctc ccaaagtgct gggattacag gtgtgagcca ccacgcctga cccagttaat67621tttttaaaaa agaaaagaaa aaataatctg taaagcagtg tgtgtatata catatatata67681cacacacgta tatgtataat tttattctac tttgaaaaaa actgagggat attcaacaaa67741ctgtaatcag ttgtggtttt ctctaggagg tggtattctt gatctttttg taatgagcat67801tatatcactt ttgaaatcag aaaaaaagac gcttataaca atacaaaaag aaatctaaaa67861ctaatatgca catcaagaag ctttcaaatg tgcgggagga caaggggagg caggctcagg67921gttctagaga agcacctggg ctgtgtggag aggggctaga cggaacagac agaacaagtg67981tctaccaaaa aggagctgca cttcgacctc gggtctggaa agactggact agactggggg68041tgtgaggagg gggaggaaca catgtgagat ccatgggaag aggcggaatg gactgcagca68101cagggactct gctgcgtggc ttctctcttg gcagcagagg gaaactaaga gcctcttacg68161aactggctcc tgcaccttag tgggactggg ggacatttaa actacctaaa gacctggcca68221tcgccttaat ggagtttagg aatccactca gtattctgtg gcaggcttcg gctgctggct68281ggtccttttc attcttgcct aagaaaattc ttgaaatggg agtctcaaaa tatctgcaaa68341gtagctacac caatagaggt aggtagctat tttttttttt gagatggggt cttgctctgt68401tgcccaggct ggcacgcggt ggcacggtct cggatcactg caacctcagc ctcccgggtt68461caagtaattc tccctgcctc agtctgagtg ggtgggatta caggcatgtg ccaccatgcc68521cgctaatttt ttgtattttt agtaggcaca gggtttcgcc atgttggcca ggttggtccc68581gaacctctga cctcaggtga tccacccgcc tcagcctccc aaagtgctgg gattacaggc68641atgagccacc gcacccagcc aaggtagctt ttaacgttaa aaattttgac agtaaattta68701tggagcctcc aggctagtgg gaagcggcct taatcccttc cttccatgat gggtcctccc68761taaagcatct ctcaagggtc cctccactcc tcatcggtga tgctaaaact tgcctaactt68821atcacaacct ctttccacca tccaaggtct accataggag cctgcctaaa ctgtagcccc68881aacaatttta ggccatgccc cacatgccac ctcctcagag tgaccactgt aggcaaaggg68941actgatcaag agaggacagt ccagggcaag gagtcagacc tcatccatgg gcaggcaggt69001cagtggtcac catgccaact cctcatggtg acctgggacc tgccagagcc aggaggocag69061ggcaagcctt tgtgctgctg gtcccgggag gtaagaggga tcctcccact actgccacct69121cggccaccta cctcactgcg ctgctgctcc agcatcttca ccttcttctc ggctgcRccc69181aaggccacca cctctgggac cttacctgcY gtcacactag cctggggaga agcacagagg69241agccttcacc aaaacctcaa tacaaattat ctcacccagt ctcggtgctc ctctaagacc69301cctcacccaa gKggccccag ccctctgtct ccctattcct cccacccagc aggacaccac69361taaccatccc agtcatgact acgtcccctt ctagaagtct acaagatgat gattccccct69421ccctgactca gggtggctgc caggccctct ccccttccct tctcccctcc ctacggtcat69481tctccctgtt taggtacaac ctctaaggta ctaccagcca ctctcctcac tccctacaca69541catcagccaa aaaactctct ggcctggaag gtaagacatt tgagatgtag atacagacag69601atatagatat agatatactc attctataaa acatatatgt tttataaaac ttttacaaaa69661gttgaagtta tataaaatgt ttatttaaaa acatttttag aaagatgcag aaataaagat69721ctgtgtaata cacatagatg tttcccagct ctgtcctctg taaggggcta aagcagagac69781atccagcagc actgagcaaa cctagtgctc agttggtttc taaataccat tttcttttta69841ttaaaaagaa acagggctgc tttgaggggc tggagcagat aaaatataag gtgagtttga69901tgcatcttat agtgatggaa agtaaggaag tgctcaaatg aataatacta ataacaataa69961taataaaaga gcatgtcaaa agggcacaag agacaacctg aaaaaaacat ctatggccaa70021aacgggaaca ctttgaacag caaaatacat cacaatagta ttggattata agtcacagta70081tgaaataaat actcttgagt tcatactgat agaacaaaat agctgaatca ataaataaat70141gggggagaag ggacagctct tccttacaaa agaattctga ttaataagtg taggaagaat70201gaggaaaata tgaaatcacc attccattac tacagtaata actRctgcag gtggagatcc70261accaatggtc actaaaatca gtgagtgaaa gtttaagaaa aaatagagta tttgcatagt70321ctctaagttt ctcctcaaaa ataaacactt attaattaca aagggaaaat tggtcacttg70381attgcagaaa cttgaaagac agcacttggc caagtgatga aggttaacag tagtaaaaca70441ctgacatcat gtacccctgg tctgctggac tgagaaatat tctgcacact ctgatgtaca70501cagaacgtca cctccgtgag attcttgcca aaacacgtaa cctcaatctc ctcatgagat70561ccaatcactt gtgaggcctc aatcgtgaca gcaaataagt ctatactgaa aaacattcta70621caaataactg gccagtacaa ctcaaaagtt tcaaggtcat gaaaagcaag gaacagctag70681gaactgtcac agactagagg aaaatgaggg agaagagaca actgaatgca atgtgggatc70741ccagactcca tgctggcaca cgacaggaca tgagtgcaaa tctggtgaaa tctgaataaa70801gtctgtagtt tactaagtag tacatgccat taattcctag ttttgatcat ttaacctggg70861ttctataaga tgttgccgtt aSgggaagta aaggaagggg ataggggaac tctctagact70921atttttgcaa ctcttctgta agtctagtta taccaaaata aaaaggttta aaggttaaaa70981aaaaaaatag caagtgctgg ggtgaaacag cagacaaggc cagtagtccg gagggtgtgt71041gtcgactcta tctccaagcc cctctgtgat ggacaccaag accctcgtct tctctgggct71101tcaatgcgat gagaagctca aacagaagaa ggtctgcagg ccccatccgg acttctgaca71161ttgtctgcca tcatcctgga gtcagattct ctctattctc agcgttctct ttccagcgtt71221ctctttccct ccacactgca cccccaagtg gcttcaggta gggctgggtg cagagcttgc71281cccctacagg ctcaggcctg taagcacacc atagcaccaa ggagcaaggt gagggggagc71341cctccaagga aggtcacccc ctttgagaaa ggggacagac aggcctgccc acttgaaatc71401tgcggcatct tggatgggag ctgtgcttag caaaaaggtc aacaagttac cggggaagga71461ggaagagggt ggattccagg ctctagggtg gtgcaccctg aacctccgcg agggagagag71521gagtccacgt ggagtcagca gagctggctg ctggccccaa atctccccta aagagcaaca71581gctaacgttc actgtttacg acgctaaacc tactttacaa gcattgcatc actgaatcct71641cacaaccacc ccttgaggca ggtgttacta tcttcatttt acagaggaaa ctgaggccta71701ggagtcttat gtgacttacc caaggttgca gtgctggtaa aaggtggagc tagtattcca71761cctgcatgca attccaaggc acactcgtcg cccctctgta acacatgcct ctaatgagac71821aggtgaccct ggggcacaag ggcaagtcgc tcccactctc aggaagggca ggaagagcat71881ctggctcggg gcattcaagg aagaYgagtg gagattaaag ggcacaggaa aagtaaagag71941acctgtccag ggaattccac acctgaggca gctcagagaa cccaagggag aacagccgag72001tctacaagtc ccttccacaa gagggcagac aaggccggat ctgatttggg gaataaaggg72061aagaaaagag gatctccatg ggctgggatt cggaacacca gggaagagca gactttcacc72121atttatcagc atgtttccct ggccgtaccc tacatctgcc tgatagcagg tcacacagaa72181atcctgatta tatgatgtta cttgacctct ccaaacctat ggccatagct atagaatgga72241atactagtcc cagccttgcc tactctatag gtagagatga ggcccaaata agaWaataga72301tttgcatgtc ctgggtaaac tctacattgt cacacagtaa taaggaatta agccattacg72361gtaattgcta ctattgcata ggtgtagggt gggttaaaga cattgagccc tactgttcag72421ctattaaacc ccattaaagg gtgaagtaaa aacacgttgg taaagagttg ggactcagct72481ctgcagcaag gggaatggta acgactgggc aaggggtgca gagtctgctc ctgcttggga72541cctggatgtg gccagtgctg ggactagagg ataggggagt Rggccagccc tgcagcatca72601ccagaccaca cagacactag ccaacaccct cccctctcca ctttagaggc tccagagaca72661caatcccagg agcttagcag aatccaaggg agcttgctca accaacctaa ttctgccagg72721aatatcaaag atgttaaact gacttttggg aaccactctc taagacagac cttgacaaac72781tggaatgtNt ttacggaatg cacccagact gagcaaacga ctcaacacca ccttctatga72841gcaatggctg aaggaactgg agctatttag ccaggagaag agaaggctta tgaggcccat72901gaagccacag tgactaccag cagcctctaa gcatggaggt caggccaagY aaagaaaaaa72961acacgtaaca gctagaacct tctaccactg gcactggctg caggagggag gaggctcact73021gtcactggag gtggtaagca gaggctgagt acctgcaacc aaggatgcta cagaaggaat73081ttctgaccac atacctgctg ctgtcYagcc actgccttct tgcctgtccc ttccatcttc73141ggtgagcctg gccgcccaga cRcaccctct ttgttgccat tgctcatcaa caacttcttg73201agctccaaat tttcctccct gggatggagg taaacagaga aatcacaatg ctgaccctga73261gttaagaaac ctMcagggct ccttaatgct cactatcgca tgagttgcag ctgagcccca73321gggagtactg caggatcctg aaacctgccc tcctggaaaa ccaaaaaggg catcttcagc73381taccttgctc tcaatctgtg gaggtctctg attgtcaatg gcagggtttc cccagctgtg73441gaatttctat gcacacaaga ccttccggat atatccaaac actgcattaa ataaccctgg73501atcacattct agtgagaaag tgacaccctt tccaattatc ttcacatttc ttgtgtagac73561cacggagacg gtgcgagctt ggtgctaaca ggccctgggc acctctctag ttactcgcca73621gtttccctcg ttaacacaga aggtgcaggc tgcaggccca gagccttcaa tgtgcaatga73681tccttagcct gaatttatta acatcctttc actttcattg tatttagagt tatcttctat73741ttatcacagg taatgctgtt ttccatttac tctagttaaa gttgccttta taattttaag73801taaaaagatg aatcaaatta aagtaaaatt ctaagtaact aataaggcag gtgatagagg73861agatcataaa attagtgatg tggattcagg tctgactaaa atgtttcttc tttctttttt73921ttgagatagg gtctcgttct gtcacccagg ctggagtaca gtggcccaat ctcggctcac73981cacagcctcg actgctccta ctcaagtaat cctcccacct cagccacccc caacctcccc74041caccacacac ccccaccctc ttgagtagct gggactacag gcacaccacc acacccagct74101aatttttttg gtattttttg ttggggctgg Rggaggggtg gtgatgtatt tcaccaggct74161ggtctcaaac tcatggactc aaagcaatcc tcccgcctta acgtcccaaa gtgctgggat74221tacaggtgtg agccacaacg cccaaccacc acttctttat gttctatttg ccagctgagt74281ttccgcttga aaaaccaata agtaaaatga ctttcccaag gtcatacagc agagacttgc74341attcttgcct tctaatccgt gacttttttc cccagcttca gtttctgaat ccatggatgg74401ggtcaYtagg gctataaaaa ccccaaaagt gcatccttgg ccatccaaaa gcaaataaat74461tacacactga ttcaaaatag ccagtggctc agtagttaaa cattacttct gtggccatac74521ttacaaagtt tatattcctt ctctttctgt tgattctaat aagaaacagg agaggaggga74581aaaacagagt ggcaagtcct gtctgtgaca cgggcctttc ctatgtgcct gagcccagct74641ggtacccacc agatgactca tcacYcaaac tgtccaggac cacagtgcag gcaggaattg74701tggccactca caggatggag agcaaggagg cccaagttcY tgttgtaaga ctccaatcaa74761gtccctgcct ctccctgggc ctcagtttcc cctctgcaca gtgagaggtc tgtctgcatg74821atctccaagg gcttgtcaag ctctgacagt caagatcagt gtttcccaag gcgtgatcct74881gtgcctacct cgttcataat cacagagact cctggtgaaa tgcaggctcc taggtcttgc74941ctaagacctg tcaattcaga atcttgcaaa ggaaggaagg gaaggcgtat aaacttgtaa75001tgcctttccc tgaccctcaa ccctcagtta agtctaagcc ccctagtcca gtgggggagc75061tctcatgttc tcaggaagac agagcaggtt gggatggtga ccagcaggag gcagcaaagt75121cctgagtcct ctggacagcc agttcaccgt taacagggga gagaggcaag tgctggagga75181ggaaggaagt acaatctatg ctgaccttct tctgaagctc tcaaggcact ctatacacct75241cccaaggtgg caaaagggcc agagagaaaa taccaaaaga gccaaggaga aggatcaaga75301gacgtaacct ccaaataggg ctctgggcac agggcctcag agccacggtc ctcaacccag75361aaatcagtgc tgcacaccag cYcctcctcc tgcagccccM actcctcacc ccttctctga75421ggggcctgaa cttaccgcag cctctcggca gcctgatccY gctgttccag gcccttatcc75481aacttggcct tcagagcctc gttctccttc cgaagctgct cacacagggt ctgtggggca75541ggggaacaga cagggtgagg gaaaggaggg gcccctccca ggtgcaggct gagctagagg75601atggtggggg gcctgtagcc accccagggc ccaactcctt atcccctttg cctggcctca75661ccccatccct ctctaaggag ctaagccact tggccaccca cgtgtcctct cccttgggag75721ccaactacgg agaagcctga ccaagtatca gccatggggc cttctgctcc tccaagacag75781acagctccat cccttctcct tcatccctgc tcccactgcc gggaccccta ttccccacca75841gcctccccca gctgacttct acYcttcttt gaagtcttag tttaaatccc atctcctcag75901agaagtcctc cctgactccc cgatccagct acattaggct aactccgtta tccttgctca75961cagccccccg cttttacgct tctcagcacc tgtggcagat aaagctaaag aactgttcgt76021gctgctgttt tcttaatatc taccccctta cccctaatta attcctgagc tcccggaggg76081ctgggacccc taaccatYct cttgttcact gccagatccc cagcccccag ctcaaagttt76141gtggaaggaa caacatgact gaacagccaa atgagcaaat ggacaaatga gcaggcgagt76201cctagggggg ctgaaaggca caccaatttg caggtgtgag aggtgcccag tgttgccaag76261gggaaaacca gaagacaagg cattcagtcg ggacctcact atgccctcac gccctcacaa76321tgtggctgtg acacttggtt cctcctctac aaaagaaaga caactgtttc tctttttttt76381tttttttttt ttttttttaa gacagagtct cactctgttg cccaggctgg actgcagtag76441catgatctca gctcactgca acctccacct cccaggttca agagattctc ctgcctcagc76501ctcctgagta gctggaacta caggtgtgtg ccaccatgcc tggctaattt ttgtattttc76561agtacagacg gggtttcacc atgttggcca ggctggtatc aaactcctga cctcaagtga76621tccacctgcc tcagtctccc aaagtgctgg gattacaggc atgagccacc acacctagcc76661cagggacaac tgtttcttct ctgcctcctc tatagggctg ctgagaggga cagatgagac76741agtgagagtg gaagtgtcca tgaaccatca gtcacttgct tatgtgcggg gactcatatt76001ggaagctctg tgaactgggg gcatggaaga ggggtcgcca gactcaggac ctcacaggct76861ggggggaagg gaaggtgctg actagcaatg ctagcataca gtgtcagcac agagttgttc76921aatctttcca cagatcctca ctgagcacct cacctgtgcc aggtacattg ctcggtgttt76981ctccatatac tgcctcactg gtgcctcaca acttcctcaa agctaagtaa ctcatctcta77041tgttaaaggt agggaaacca ggtaaaatga tacagtctaa caggtgcaca gctgctaaga77101ctcatcactg gcggggagta aaactccaat tggcagaccc cacactggtg tctctttccc77161ctgtgatgaa agatcagaga agggagagag atggtgccca aaggagggga cagcctttga77221gctgggccag gaccagggcc attcactaaa cagccatctg ctgccttcca cctcccaggc77281ctgttgcagg tggatgcaac catgtgacta gttctggcca acaaaagagg tgtagaaggg77341acaagcatca ctcctggact ggcctacgca caattctcca gtctcttttt cctggtagca77401ggggctgatg tggatgcctc gtattctaaa gggcaccgga aagttgggcc cctgtctccc77461tgggactcta aggaactgtg tagagcagaa acaaacccct gccacacaga ataggaggga77521aaacttttgt tgtgtaaccc agggagattt cagagttgtt tcatttctga ctcacaaagg77581agactcttgg gaaggctgaa tggaggacac agccttcaac tggaggtggc tggacaatga77641gggagatgag gcttagcaaa cagagaacca gctgggcatg gtggctcaca ccagtaatcc77701cagcactttg ggaggctgag gcaggaggat cacttgagcc caggagttca acaccagtct77761gggcaacatg gcaaaaccct gtctctacta aaaataccaa aaaattggcc aggcataagg77821gcgcatgcat gtagtctcag ctattcaggg aactgaggtg ggagaactga gcccaggagg77881tcaaggctgt agtgagctgt ggtcgcacca ctgcactcca gcctgggtgg cggagcaaga77941ccctgtcccc caacacccct taaaaaaaag aaatcaaaaa attattgtta tgagtccatt78001caatgcctag cagagagcct tatgctatac ctgaccttga atatgtttgt ttagtgaacc78061aagaaacaca tcagtgaatg aatgaggagg aactggatca atacacctcc acccaggcag78121taaaaatacc caagatgcca tgtctctggg cgaggcctcc agggaacaga atggcctgct78181cctagtccct aagggaaggc caggacaagg cctcacttgc tgtcctaccc ttgcagtcta78241gagagctgtt tccttggagt ctctgggcca atgccctggg tgcaaaccgg ccaatggata78301gaatcatcag aggtcacaaa gatcatcacc ttccatccaa ggtgctacga gagctatgag78361ttcatttgat catttattat tttgtccttt cattcattca ccaagtgtgt atgaagtgcc78421acgaactggg aYgcaacagt gaatacaaca gacatggtgc ctgcccccct caagcttacc78481ttctagcaga gagtataaga aaaaaaagag tataagaaaa aatgtattaa ataaaattat78541tacaaactat gataagagct aagaaggaaa taaacaagga ggggactgaa ataaaaaata78601acaKaggttg gcaggacccc ttttaagggg cctaggatct atccccatct caaagctgaa78661aagtggatgc gcaaagtgct ctcaccccag gcaccttcct accctgccca cagcctaggc78721actgtgccag gctcaccttg ccagggttca gcctggatac cttgaagcct cactgacatc78781ttaaaggggt tcccttctct cagcctggct ctccaggcct ctgcctctcg ttcagcctca78841cctcccaaca cacccctccc ctccaggtgg gatgggcatc ctccgtgctc ctctaccccc78901acacctctcc tcatactgca tctccaacct gattgccctt catgccctcg gcaaccaagg78961tcacgcaagg gggactccca cttctgccat cagcggggca cttgagtgcc tgctgacatg79021aatgagacca cagatcagag aatggcctgg gaggagagtc tgcagggagt aaggaggctt79081caagtcatgg ctctgtcact aaggtggcgg gcactcagat cacgagcagt ccctcagaag79141cctccgtttt gccatcttta gaatggtcac caattataac tgaacacttg cccgctgcta79201aagcccacaa ggctaagacc ccctgcccag tgtggatgcc cgtcatgaac tccgaatggg79261gacctctctt ccagcatgga ctaggttctg gactgcactg ggtgcttcat gtacatggcc79321tcatttaatg cagcaatcta accatggagg cacttctagc tcatgttact gataggaaca79381ttgggggata gagaggataa gtgacttgtc caaggtcata cagcaataaa gggtcactac79441tggaaccaag gaccatataa ctccaaggtc tggcctggcc tagcaaggaa atctgtccat79501tccccacagc acagggaggc tttcaaaagg aattcaatag gggaggcagg ttgggatggt79561ggtcaagagt atgggctttg gaatgcgaga gatcgaggtt ccaatcccta cttcaccatt79621taccagctgg gtgaccttgg gcaaaaaaag ggctgcttcc ccacctgtga agtggtgata79681atgagggtgc ctaccctggg gggaaagagg cattatgaaa ggagttgacc tttgttccct79741cccttcccat cccccaaccc tgcacatgag aaataaaggc agggctgctg ggggtatccc79801caaccatgac actcgcattg cccatcccgt atttccccat ttccttcctc ttcctcatcc79861ctccccacaN cttccttatc ctgttcatca ccctgaacaa aaagcccgaa gtctgcccac79921aacacagSct tcagaagtcc ccatggtacc agtggattcc caggagcagg aaggtgggaa79981gagctcgggg ggaagcacgc ctgcctgtct cgggctgccc tccccacgcg cctcacctgc80041agaatggagg tgcgctgctc attcttgtgc accttggatg ccagtcggtt gaactccagg80101gccatgcggc ccaggtgggt gaagagctgg ccgtggtccg gctcctcggc acacacactc80161agcgtggtct ccaggcgctg caggtgcagc atcaggttgc cgtcctcacg ggScaggggg80221cccagcRcct ggagagggaa agggcacacg gcccactctt caccaaggcc tgagtaggcg80281ccgccagtcc attctccctc tgcttcctca tttctcatga ctcagtttcc ccctgtgacc80341ccagctcagc cccgggaaat tctccagtta tgcaggttcc ctgtctgggg ctgactcaca80401gggcagaacc caggactcac aggccactgg tggctccaca gcagcggggc caccatcctc80461ccacacactg ggccttgcag agtgcctgac agtaagtcac ttgtctgctg gacctcagca80521tcctcatcta ccaaatgtcc gcacaaccct tccctccctt caacctcaca gggttcttag80581gaggatgaat tgacccctga cagtaacaag cccagaaaag ggacatcact gcacagtcag80641ccctccatat ccatgggttc cgcatccatg gattcaacca actgcagatc aaaaatcttc80701taaaaaaaca aactggccgg gcgcgatggc tcacgcctgt aatcccacca ctttgggagg80761ctgagcgggc agatcacaag gtcaggagat caagacggcc tgagtggtga aaccctgtct80821ctactaaaaa tacaaaaatt agctgggcat ggtggcacgt gcctgtaatc ccagctactt80881gggaggctga ggcaggagaa ctatttgaac cagggagtcg gaggttgcag tgagcagaga80941tcgcaccaca gcactccagc ctgggcaaca gagcaagatt ccgtcccaaa acaaacaaac81001aaaaaactgt attgaacatg tacagaattt ttttcttgtc attattccct aaacaataca81061gtataccaaa atttagcatt tacattgtat taggtatcgt aagtaatcta gagatgattt81121aaagtatata ggaggatgtg tataggttat agggaactac tacgccattt tacatcaggg81181acttgagcat ccatggattt tgggtatcct cagggagttc tggaaccact ctcccatgtt81241taccaaggga catctgcata tacgtcctgc aacctccgcc tcctgggttc aagcgattct81301cctgcctcag gctcctgagg agctgggatt acaggtgtgc accactacac caagctaatt81361tttgtatttt tagttgagac ggggtttcac cacaatggcc aggctggtct tgaactcctg81421acctcaggtg atccacccac ctcggcctcc caaagtactg agattacagg cgtaagccac81481catgcctggc ctacacatgt gtcttctggg gaatggccca agcattcatc agcttctgag81541gacccaagac tcaaaacagt ttaaggaacc acagctttag ctatttcaga aagtcccaaa81601ctagtacagt atgtaagaaa taaagcacac cgtgggccag atagttgact ctttctctct81661agtctatctg gaatactcct accaaagaca ttgcctttgt tacaccaatt ccactcccaa81721ggacctgcag tgttacccta ctgcagacgg cactgggccc agctcccctg ctgggcatct81781aaggccctac agccgcaggt cccatccaca gcagcatcca gttgggctcc ccactttacc81841ctgcctgaac ccacacacac caggtctggt gtctctgcat gtgtcctctc tgtgtcctct81901ctgcctctgc aagttctgct catccttccc accctgtcca cggctcagct cctccagcag81961cctcccggaa acagttatgg gaatcacagg acaKcagagc tacagggagc ctcagagatc82021aggccgggaa accaagctat ggggaggagg aacttgccca aagttgccct gtaagtcagt82081ggcagaggta taacgagaac tgaggtttcc tgactcgcca tccagtgctc tgctgcactg82141acctcccact tctctgaact ctggaggaat ggcaatgact ataaccMcaa cttggcattc82201cctgaacacc tgtgtaatgg cgtcagtgtg ccgcattcta acaagaggaa atgctgctgt82261ttcaactctg catccattcc cccactgcct ctttccacaa aggagctgag gtggcagatg82321ctgctctatt taaggctcat gcgatgcttc ccatgcctgc gacttctcca gactacaagc82381ttcagagcac agggaggctg tgttgtcttg gctcaagtgg ctcagcagag acaggcacac82441tgtagagcta atgaggaact tactacgtca gttaaagtta tcggtccaaa gtcagagtga82501aacactttct gagcagggga tcttgcctcc atggccagca tctcagagcc ctcagggaca82561gaacaggaca aggggacaga aggttccagg cgacagaaca taaagagcct ttccaatact82621cagagctgcc tgaggcagtg gtgagcctct caacactgaa ggcatgctag ttagccagac82681agccacctga gggggccYtg cactgggcac tgacaggtac atggggcaac cagtgaacac82741aagcatattt gtcagccaaa cctttgtgaa gggaggcagc agggatcaat atatcagtga82801agggctagag cacctattgc tcgcataaca acaattaaag Raaaaaactt aaaagtggga82861aggaagggag aatggagaag gtagaaattt aagtcgttta aagaatcttc cagacttttc82921acaatggttc ttcaataagt ctgccatttt aagaaagaac agaaggagat atagttagga82981aaaaggcagc cagtgttgta aggtgtggaa tgaggatgct gggcagacgc tccagagctg83041tacgagagac agagagagag agagagagag agagagagag agagagagag agagagagag83101tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgcg cgcgcgcgcg cgcatgcgtg83161taagtggaaa gttgaacctc cttcctgtgt gctccaagag tctgcacaaa gagYaaatca83221cctgtcttac agggccctgg gccttcctaa cccttctttc tcccccgggg ttggaagccc83281acagacccaa agggctgagt catagtgtgc ggaggtgcct ggcccctggc agaaggcaac83341agggctggca aagagcccag gctttcacaa cggtcgggtg cccgtgtgct ccaagtcggg83401gaagtcacta gcccaggaat ttgcatatgt gagcgagaag caccctttgc tcctgcccct83461cgtgtatccc caagtgactc caggRtacct aasggatctg aacaggttct gtgcctctca83521catggtagca agtgacagga cacaaagagg gcagcaggtc aagcccgggg tcctgcccgt83581ccactcacca tcgcattggc atggctgctg ctctctggtg aattctgctc ctcaggagtg83641accacttcaa attcagagga ggtgccctgt gcagaaagga agttaggtgc tgcccgagag83701aaaaacagct cacccctcct ctgcggccct gtggctgaga gcagcaaggg ggacaaaatc83761tcttcccatt ttgagtacac agggaccgtt acatatcatc tcacatRaga tcacaaagca83821ggattctcga caagcctgtc atagccctct gcataatgtg aggtcatatc ccctcgatgg83881ccaatcctct tttgtagaag ggagatRtgg gactagctga ccttgaacca gcagcactgt83941aggattgcat tttttaaggc cgtgtacttt ttaaatgctt tcatgagctc cattatttct84001cagggtgacc catggagtgg gtcagaaggt tatatcctct ttggaaagat gaggaaacta84061cagtatacag ttggttaatg caaaagcagg gattgaaccc aagactgcag atccagcatt84121cctgccacgg ccccagagct gtctcttagg cccagacgtc tctgatcggt ttcccagaac84181acagatggca gctgttacgg ccaccaccaa gcatgYcctg tgctggcctt cccaagccag84241tcctggagat cccagaggag tgaactgatc tgagaaaagt cccagagatg attcaccaaa84301tttggagact atttcaggat tcaaccaaat ccacggtggc caagaaatcc cagatttttt84361cacatctttc cgtcattcct agtagaatta ctggtcattc aaccaaccaa gaagccaatg84421gcccacctga accagccatt agctctggga tctgggattt ccatgtcccg ttaaacctgg84481tctgcagcct cccttcatcc cagaaagggg caggatagat gagaggagtc agtgctcagc84541ttccagctga ccctcatggc caccaagaac tcacctctgg ctcttggccc tgccctagaa84601agtctccctc ctccatctac attttcccca ttacccgtgt aacctcagaa caggtYcttc84661tttccctgca cctgatctgt aggataagga tgctgaacta tgcaatccct tgtaggatac84721caagcaaaac ttctccagcc aaatctgtag attttttttt ttttttatga gagggtctga84781ctctgtcacc caggctggag tgtggtggca tcaacatggc tcactgcagc cttgacctcc84841tgggctcaag cgacccttct gcctcagcca gcctcccaag tagctggaac cacagacata84901caccatcaca cctgactact ttttttctta gagagatgga gtctcactat cctgcccagg84961ctggtctcaa actcctgggt tcaagcaatc ctcctgcctc agcctcccca agtgctggga85021ttataggcat gagccactgc gcccagcctg tagaagatag tttctgagcc ctctttgaga85081atgtgagctc catgtcacat ctgtctgttt tcctagcact gtgcacactc agtgatactt85141aacagtatac aacttagtaa gtgagaagaa ttccttgtac ataccagggt cttcctggta85201agttttaact atgaccttca tttcaaaatg gggaggctga ggccccagag agtttgcgat85261ggacttgccc aatatcaccc agcgagacgg aacacagttt cttgacctca accctctttc85321ttcatgttct tgtatctgtc agtaggactt gaggtccatc caggcaacct ccacccatga85381ctccaaataa aacttacact ggatggaggc ttctggactg gtgctggctt gtcactgggg85441catgcagRgg ctgtgggaga tgctgtgaca tttgagtcct ttcctggaga atcaagaaag85501cacagatgaa ctgactggga aggggagaag cccaggtacc accctctcaa ggacagccct85561tgacaaaagg gttctcagac aggattcccc actcgagtgt gggagaatgg gaggtggtct85621catcagggcc aggtagtctg agaaaatggc ctgccctgga gtgacggggc agagcctgag85681cagagagacc atgctccctg ggcttactgg gaaaatccca agttggctgc tgctccttgc85741tgccctgaac aggcctcaat gataaagaca atgatttaca atttgaaaag tctttatgta85801tctattatcc cagccattct cataaaagcc ccatatcccc attttaaagg tcaggacact85861gaggcttggg aaggtcatca Mcttgcccac agccacatag ccagcaactg caaactcagg85921actgagactt ggccctccct ccctgacttc ctgcagtcct tgctgcaggg agctccttga85981aggtagcttc atttctcact ctgagagtgg acctggcacc aatcaggaac tcaggaacat86041tgctgaatag acaagcagag gctggaaatg cccactgact gcagcacagt ggactctgag86101accatcactt tcctccattt gtccattcag caaatgcaac caccagccaa tagaaggctg86161tcacattggc ctgggccaga taccatacag tagagctgca gcaggaggca tctgagtcca86221gctgaggtgc ggatcatttc catcctggtc ccagacctta ccctggactt ggagacatgc86281cagagtaatg cacactctgt acgcatggtg atgcctctac catacatggg acttcaaccc86341cgagccacag tcaccctgtc ctttaatggg cagcacacgt aaccttacat ctgaaatacg86401ctgcagcagg ctaacaggca agcccagctt cttccctggg cctcagcttc cctaattgta86461aaatggacgc gcagggcacg accagggagc ttccaactca tatgccagct ccaagtgaca86521gggagtagct gcttggagYg cgatgcctgg cacacagtag ctgctcatta aatattaaat86581atgctgataa agaccccaag gccacaggac tgcaatgtag tcaactgttg tatctattac86641tcatgtctgc tggggcctca ggagtgctga gtcactggct atttttaaca agattgtttt86701gaagtccctt ccaaatctga ccttctgggg gatgtggcag ccaaaacatg aatggaaggg86761tagcctgtga cctaaggata aacgagagaa tgtggRtttt ggcataagaa gggagttcac86821tgtgaaggat ttgggcagtt tggggtacag ggagagtcag aggtacccag actcctctta86881tacctgtgag ctcagccagg gggtcgaagg agcccaagga gggagaaggt ggtgggagca86941gctcgttgtc cttcactagc tcctctgcct tctgccggag cctggtcgct tccatctggg87001actcttccaa aagctcccct agagttattg gggaagagga agcaaaagca tttactYggc87061tcagtgtgct gcttctcccc gtcccaggcc cctaaccgtg ctgccgcctg gcttctgagg87121ctccaggccc tggacttcac tcccaccgtt gctctgtggg ccaagtggga caaactccat87181gctggtccac cataagaaac aggctagagc aaggacgagg gcccagcaat cgggggacac87241aggagcggaa ggaatctatg agaaactcct cggctccccc aacccccagc attctctttc87301tgccccactc ccttcacacc cagccagggc actccacaga aagccagggg ctcccccacc87361ctacgggcta cccacagcct gagccaccag ggcaaagggc tgcctgcagg gcggagacct87421tggataattc caaccagccc tctaggcctc cattttcctt ctcctacaag tggagatggg87481gaaaccactc ctccctcccc agtcggccat cccaagcaag gatctgccaa gcaaggagaa87541agcattttaa aaatcagggg gctatgctcc cctctaaaac atgagactag agaagggcac87601ggcaaggcaa aggaagagtt tcaggagtgt ggaagaaaga gagccccctc tggatgggga87661aatcaatgaa agccttgtct ggaggagaag ggggcacagc aactgggtgc tgatgcacag87721ggcccgtcgg tcgtgtggag ggaggtgggg ttgttctaaa gtggggatgg cttgagcaag87781agccaggaga agagaactga gggacctacc acctccttgc ttcaagccaa gctctgctcc87841ctgctccaac acctaggaac gcgtgcccca gttgcctggt catgctggct ctccccatct87901ctcgtgcccc agaaagagga gRccactcta gttccatggc cattaactgg gccttccagc87961cccctttccc ttagcccacg cctccctctt ggacctgagt cctgtcatcc tggtttccgg88021gtgctgagga atcagggttg ggaatactgt caccatgcta catggtgcat agagacagct88081gtgaggcagg agccagcRct gggccaggag ggacagggga tgacttgggc agaggcatat88141gccagcttca ttctccactg ctagtagagg gactggcatc acagtctgca gggaggggcg88201ctcgcaggga ggggacaggg tctgctttac ctaacatctt tatcccttgc attttttcct88261tcagccggga attctccttc actaggcgct caaaagctgc ggatgcctct cctgagggca88321cgctgccccc agggtcgtag atccggtacg gtcctctccc ttccatgagg gtagctcagc88381ccctgccgtg gtgcccgcct ggctgtaagg acaacagcag catatcagca ggctggccag88441gccatggggg catcctttgc agagaagctc tagtctgtca atgccccaga aggcagtccc88501ccactttaag ctggtctgac catattatag taaagcagga cagtcacctc cttttatctg88561gacgctctgc ctctattaat acaaccttag aatggcatta gtttctctta gcagcctcaa88621tgcactgttg gcttgtttgg aacaggagtc caaataaaca gtagggtgca atgtgggata88681caagaaagaa cctggacttg gaaaaaaaaa aatctgagtt catgtcctgt ctgtgaggtc88741cagaagaaca ggaatcccat atgttttacc catcattgca tcctcagagc ctaccacagt88801attagctatg aattttgccc aataaacact tactcaatta atggtctagg cattaattta88861ctatgggatt atgggcagtc ccttcccctc tctgagggag ggaaatgaaa gtcttaagtt88921aatttagtaa tctttaaagt gaaatgcttg taccctaagg gataagcaag tcaacccagt88981ccaaagttcc atttatatgt gtatcatctt ctttaaaaaa agaaaagaaa aaaacaccct89041gactaatatt taatacactg tcaccctcct ccgtgagtct catatcatat atggtctgtc89101ccttgcagtt ctaaggaaca gaagaatttt tcatcaaacc actgtctatt tgagcaccaa89161ggtttttttt tagtaatctg ttcagtttca tctgctttat gtcactgaaa ccagttggaa89221aggtgatttt agaatcctaa ctctgtggct tagtagagaa gctctctgtc cattcactca89281tccattcaac aattacttat tgagcatcga ctccgtgcKa ggcaccagtc tgggtgctga89341ggaattatca gcaaataaaa cagacaaaaa tccttcatgg agcttatagt ctaggggtga89401aagcagagga ggatggtggg gaacacaata tttcaggtaa tcaaaaagtc tatgcacaaa89461aggccccaag cataaggagc tattttagcc aagacctgaa agaggtgagg gaactagcca89521tgaagacatc tgaaggaaga acattctttg cagagagaac agtaagggca gaggccctaa89581ggctgaaaca ccgagccagc ctccagccct ccaaatagct ctccagcatg aaagggccaa89641ggccttcact ggggacctca gaagggtttg ggggctcRgc accttcctcc caaggtcacc89701acccccaaga caaaaactgt ttcatcagga atcctcaaag accctcccaa gtccacacac89761catgctccgt gggtccttgg cgctgccagg tgactacgac cataccaccc tgctcccaga89821atgtaaatga aagatcagag tgagaaagga ttaacagcaa caccaccatg cttgaatcgc89881ctccttgtca ggcactgcat taaatgtttc agatatacaa tcttggagga gctgcacagt89941aactctaaca tgcatactaa tctcatctgc attttacaag ggagaaactg aggctcaggg90001cggttaagta actcagccac gatgaMccgg ccRcaataag agccaagatg caaagtcagc90061cctgcctgct gtgactctga cccccaccat actcacacag ccaggacaca gagScagagg90121ggcagacagg gagttcaaat ctctttgtag ggcagcacca tgctatcagg tcacctctgg90181gcagtttccc ttgccctgca gcataagaac caataaggac ttgtccaaga gcgtccatag90241gatggaatgg gccagaaaga aaaacaaagt tctgatgaga aggacccctt ctcccaaaga90301ctgacagata caagatgaat acaccRtgtg ggaggcaccc acgccctgct gagcctgcga90361ggcaaaggac agctacccac actcccatca caagtcatca cccggcttag gggtgacttg90421tttttaacct gaaaggtcag tgttctacag catagcacaa agYgcagatg tttccaccga90481actaagaaac agtgtggggg ctgcacttag cactggaact ggcacatagt aaagtactca90541aaaatgtYgg cagacattgg gggtccttcc cctctgcttg cctctgtcct cacgaggctt90601gccacctggt acagcatgtg tctgactggt gcgggcattg cccatctggc tgggaacttc90661ctgaggcagg agcgtacttt gcacatcttt gtattcctgt cgggagcaca ggagggtggg90721ccttccttga gagctgcttg gagttcaaga acagtgaaac agagggctac aaggggcctg90781gagccacctt gcatgacaaR ggcagcagtg tcctggttct tgtccaccat tatgcatKca90841ccctaaatgg aactcacagt caacaccaca tgaaggcatg gggaatttct tactcaatgt90901ctgccttgtc ctgtagatta gaggctgcat gaggacaggg agcaagtcca tcctgtgtgc90961cagggtatct tcagagtggc ccagagtagg gcctcggtaa accttgaatt cagagaagtc91021agactgaagg gaacaagccc ttgaccccga ccccgcctcc tgcaaggcca tgtccaacat91081cccagagaaa gcctaaccct gacccactga ccagacgcac ttggacgccc agacacttct91141agaatccagg ctgggccagc catgctccct cagagaggcc cagatgtaag gcgaagggac91201aaagcaggat gcaggatgtg ggaactgaaa cccaccccac gtcctccaaa acacgcaaca91261ctcagtttct cttggcgctg gggagtcaac gggaaagggg ttcatgggaa acaaaaagtg91321ggcagacaga gctatgctcc cctactttag cctcaggggg cagagcttgg ggagaaagaa91381aggcagtggg cagaggagaS gcaggagaaa tatcctattg tgggaaaacc ctctctggag91441atcagaggag ccacccctgg agggcctgga cttctggagg aaagaaagac aaagagggaa91501acagggaatt tccaagttct gctgacctca tgcccagatg gtcagcggca gtccctggat91561gaccactggg cagacgggaa ctctccctct gatcaatgag gtttttataa cttctcccag91621agagaggact cattctcagg atgacagagc tggaggggac tctccaaggg caatgaggcg91681aatcctgcat tatcaggtgg gagagagatg cacccagaaa cactcaatgg atgaggggct91741gcattcgaac atgacgatgg catgcactcc cctctgctgt ccacaaacca cgaggatgtt91801ttcaaagggg aaaaggaagc actgaccact cccctccatg tggcagtatc tggagttcag91861agcccaggag tcctcgggca tgagctcatc tgattctcac tcacggcaca ggcagtgcag91921caaggcaagg ccctgagcag ggaaggccaa ggtcacaaag gagtcaggat ggagctggga91981ccagaagatc cctgctctcc ctccaggctg cccacagccc atcctccatt tcccttcctg92041cccagcaatc ccatggcaca ccacaggccc ccaccacatc ttctcRgagt ctctttccac92101ctggcctggt tccacaaact acaaatcagc aggtgctcca ccagcagtgg gactccagcc92161ccgcttgccc aaaccagaaa cagctggtgg tatagaagca gccagcgcag actttcttcc92221aaaacaagac ctcagccagc ggggcctcca cagcctgccc cagaggggcc ctggggctgc92281ccgctggaac cagaaaggcc cagtttgggg gcagaaaggg gcccagacag acggcaggtc92341aggcaacaac cacagaccgt gaagatggaa gtgatgctgc tgaaaccgaa ggagccaccc92401actagcaggc aagcacttgt gggtggcagg gaggcagtag tccccagggc tcaactctca92461gccttacccc agaaagagag gggtatgata aagactacat tcagaattaa atttacattc92521tagcttttgc tctgaaatgc tttggtctgt cagattatct tcccattagc agtgttctgg92581tggctgggta ggggggtggt cccagacccc ccaaatgata ttcacttgca tagccactaa92641catttgcaaa atacttcata gtgtcccaag cattgttttt ccatctgatt atcacaacag92701ccctgggaag aaggcagggc tgatacctgc ctgatggata aggaaactga agtccagctt92761ggggacttaa tcagcccaat ttaatgcctt tggtcactgg ctgcatcctg gggccagcta92821tccctgcaac cctggagcag gtgatgccct ccctggccca gagggaaaag tgtaagcaaa92881tctctggtac agggaggtgg aaggtcatcg aggccaacat ctacctcccc agcagaggtg92941agggctgcca gggatgctgg caggtgggct ggcagagggg gtatagggaa ggggtctcca93001ggaaagacgg cacagaacag aacgtcagag aggtctattc tagtgtctac tctgctgtgt93061atggaaccat gggctcattc cctcacatgc aaggggagga gcatgggcca cacagaaacc93121gggtgatggc taaagctggc ctcaggatca agaagaccca agtctcagga gctagcagca93181agctgaggaa agagagagag ccagcaccat ggaaacatcg ctgccttgga ggcaggaaga93241aaggtccaca cagggaaagt gctcaaggcc aaccttgcga acacgaggcc tgagaggggg93301cctcacctgc actagcctca gctctgtcca ccctgtgggc tgtgaaaccc tggagcagcc93361actcaccttt cctgagcctc aggtgcctca tctgtaaagc aggagtaata atagaaccta93421cctgatagaa gatcaaagaa attaaatgaa acaatatgtg tatagttgga agggaattct93481cactttctac tttaggcaat acttcctgat tatctgattt aacaagaaac acatctttgt93541tttataataa gatttccaaa ataataagag tatacagtaa ctagctcagc atttgacaca93601cagcaggtgc ttaataaaag gctgaggcaa ccccacaact gtgcccagct tatctaaggg93661ccaaggcttt ccccatttgt tctctccttt aatgggattt taggctcttc cgtcagctca93721gtaagctagg ttctggcctc cacttattct ctagtgacct gcatatcacc atttaactgt93781ggttaagcag ggtgcctgga cacaccatag ctagtgaaca tgtagctata agaagccctt93841gaaccacgat gccacactca ccaacaactg ggaatctgag cctcatttcc tctgctgtaa93901agggcaatat cctgcaattc cacccaagga tgaaaggaag tgagaYgcca tgatatcaca93961ttgcagacat aaacaaaaaa ctgtccacat atttgtgtta tgatgacctc cagtcctccc94021caaccaattt ccaggctggg gaaactgcag cctcaggtcc atccatcaaa ggccgggttg94081gatttttcag gcagtgaaac tactctgttc aatactgtaa tggtggacac ctgccattcc94141acatttgtcc aaacccatag aacatacacc accaagaggg aacactgatg taaaccatgg94201actccgggtg acagtggtgt caatgtagat tcatcaactg taaaaaatct accactctgg94261tggaggatgt tgataatggg ggaagctatg cctgttaggg gtgggggggg cgcagtatat94321gtaaaatctc tgtaccttct tctcaatttt gctgtgaacc taaaactgct ctataaaaaa94381taaggtcttt aatttaaaag agaaaaggac caggctgggc tctcctgatg gctgtcaggt94441tcacacatga gtgaggacac agcacatact tgagacagtg tgtattcaag gaccgcaccc94501tggcatcctc accaacaagg agcccagact taactcctcc atccttgcaa tcaactgagc94561aacaatgagg ctgcagacac agagtctcat atagtaacag ctggggcgcc agaactgtgg94621gatctagtca aggtacacta gggcgaacat cttaaccctc actaggcctc agttacctaa94681aaagagggag ctgcaaaaat agtaataaca tggggggttg tgcgggataa tcattaaggc94741cccttccagt tctaacattt caggatctga aatttattag cactactttc tttaaccttc94801taaccttaag aaggctccaa tccccagctc caatcccttc taaggcccag gtggatttcc94861ctaacccatc agtcctccca taagagcttt cataggtgct atcccctccc cgagggcagt94921cagagaccct cagctgacat ccgcagccct gtgccaggtc ctcccctcct gcctaacttg94981taccaggctc tggccaagcc tgatctgtgt tcctcaacat ggcacacatc ttcccatgtc95041cttcatcctc ccctcccgag tcacccacaa agaaggcccc actgtctcca ctcagcctcc95101gaggcccaga ttacacacca cccgctaaac acctgagcca gaattcacac tgcaaaagag95161gactggagag cacctaacta agctggagag agggtgacag ttcgttaggc gctaccgtat95221gccaggtgct gggccgcatc atgacgcaca tgacctcatt ttcttcttgc cacacagata95281tggaaattat catccacact ttccagcaag gaaaccagtc gacgcagcta catggatgag95341gaagcagact cagagaagtY aagtcatttg cctgagaata cacagctggt tagtggtaga95401acaaataatg cagcctcaat ctgtcagatt ccaacatcag tgccctttcc actgctctac95461actgcctgga gaggcggcag gctgaagctc agaggtggga aaccagacct actttccagt95521tctccagaac gtgccccaag ttcctagccc ctgcctttat atgtctctag ctttatatgc95581aaccaggtgg caatctgccc cacatcacct gcagtcaaca gggtttagaa tctcaggctg95641gaagggagct cagaggacat tccatcctgt gcttacccag tcctctgagg agcccaggga95701ctccagctgg ccaactttag caatccagat ctcaccaact tcctccccaa aacaattcct95761ggggcagcca gcactggcta cagttaggct gctcccagtt ctgtttccac tggcccttct95821ctcccctctg tggtcccctg gaataaggaa caagatgccc atcttcagca tgacagccag95881ccctgaggac atttggaacc tgcagccttc tctatactgt tccacatagg gactgccccc95941cctccagtcc cccaccaacc ctctacccca cactatctct agttggttct agcactggac96001ccaacattcc aggcatggtt tgcctgacca aatgcaggct ttcacctcca cccttttagg96061tagtatattc ctattgaggg agcctgggta tacatttgct tttcttacag ctgagtcacc96121tactgaagaa tgtcctttct caatgacaac aacctgcatg tatgcctaac tggtgagaac96181aaagttctca tgtagaaacg tgtgcttgag ggctgggtgc ggtggctcat gcctgtaatt96241ccagcacttt gggaggccga ggtgggcgga tcacctgagg tcaggagttc gagatcagcc96301tggccaacat ggcaaaaccc agtctctact aaaaatacaa aaattagcca ggtgtggtgg96361cgggtgcctg tagtcccagc tactggggag gctgaggtag gagaatcgct tgaacttggg96421aggtggagat tgcagtaagc cgagatcacg ccacagcact ccagcctggg agacagagtg96481ggactccatc tcaaaagaaa aaaaaaaaaa aaaaggggtg tttgaggagg tgtgagttac96541ctaagggggc agaagtaact gattgattca gtaatMccct atctaggaat ctagagatct96601ttgcatcagt acacagaagc tggacaaaaa tatgcactgc cacatgcttt gtaatagaca96661tttttgctat tcttgaatgt ccatcaagaa gggactggtt aaacaaacca ccattcattc96721Ratggaatac tatacagcca tcaaaaagaa tggggtagat tgcttggcaa tgatacagaa96781agatgcccat aaaatacaaa gcaaagtgca gatttatatg tgtaacagga tgctattttt96841ttcaaaaaca cattgtgtgt gtgtgtgtat acatacggaa tcttaaatgt gcatagaaaa96901aggcctggaa gcccagtgct ttgggaggcc aaggtgggag gattgcttga ggccaggggt96961tcaagaccag cctgggcaaa aagcaagaat agattctcta ttaaaaaaaa acttttttac97021attagcagag catggtggca catgcctgga gtcccagcta ctcggaaagt tgaggtggga97081ggatcacttg agcccagcag ttcaggctac agtgagctat gatcatgcca ctgaactcca97141gcctgagtga cagactaata ctctgtctct taaaaaaaag aaaagaagaa aagaaaaaag97201tctcaaagga tacataccaa actgctacta gtagactgct ctacagaagg acctcggtaa97261ggaactaaaa ccaaaagaaa cttttatttt acctatgcta ttttaactct ttacatggga97321aatctagtcc tgttcttata caattataaa attagttttt aaatacagta gggacagagg97381aaggggaaag gaaggagaga gaagacaact gtcatttttt acattatatc ttttgtactg97441cttgagtttt ggggggtttt tccccaataa tcatgtgcta tttggtaatt ttttttaaag97501ggaaatttta aaatattttt ctaaaaaatt taagtgagct gagtgcagtg gtgcatgcct97561gtagtcccag ctactccaga gacagacgca ggaggatggc ctgaaaccag agtttatcta97621accctgtaac tcccctgcct ccaagaggta agatgccaat tttggggaat tcctcttata97681caaaatatgg tggaaagagg gtttcacaga ttcaaatcct ggctatgatc ccttctcgaa97741tgaccctggg taggcctcac tttccugtt tctccctatg gaaatgttat gaggaccaag97801taggaaccat agagttctct gtaaacctta aaatgctacc cagacaggag cagtaatggc97861tgccaaggag ctaggaagga aaaggggctg gacaggggct gaggtactca gatgaaagcc97921aaagatgcct tgtgttaaca acaaaaagct gaaagctacc taaaatgaag agaaaaatga97981ataaatacat tgtggcaatt tcctatcagg aaatactata cagcagtgaa aaaagaatga98041gccacagctg gagatacgaa catgaatgaa tctgggtctc actctgttgc ccaggctgga98101gtgcagtggc atgatctcag ttcactgcaa cttccacctc ccagcccaag tcatcctccc98161acctLagcct ctcaagtagc tggaactaca ggcatgcgcc accacaccca gctaattttt98221gtattgtttg cagagatggg ttttggccat gttgcccaag ctggtctcaa actcctgggc98281tcaagagatc cacctgcctg ctctgcctcc caaagWgcca gtaaggcatg agtcaccacg98341ctcagcctaa ataacatttt taaacataaa aaaatactat gtattattta gggatgcaca98401cattaaaaaa aaaactttaa agaaatgcaa gaaaaaaacc ccactaaatt cagaacactt98461gtttcttgtt ggtggctgat gaaggagaaa tttcaaStga ttggaaatgt gttatttctt98521aaaccagatg agtgagcatg taggtgcctg cgtgttaccc tcggtatctg agagactcct98581tcaatttttc ttttttcttt ttactgtatt gtttgctttt tttctgcttc aacttttatt98641ttagattcgg ggggtacatg tgcaggtttg ctacctgggt atactgcgtg atttgggtag98701gggtgatccc atcacctggg tactgagcat agttcccaac agtttttcaa ctctgcctcc98761ctccctcccc actctagcag tccccagtgt ctactgttgc catctttatg tccatgagga98821cctgatattt agctccactt ataagtgaga aaatgcagca tttggttttc tgttcctgtg98881ttaatgtgct taggacaata ttttctaaaa gtctatgttg ccagtttcct gaggaccaga98941tcacgcagga gttgcacctg cagagacaga agtgggctgg agagggacca gggctcctaa99001gtctgctgct gaagctgact atagcgaagg caaaggacaa gtggcctgaa ggccaacaga99061gagcctggcc aatgctctgc ccagtgggtg gagactgagc caaaggccct tgactcatag99121ggcagtccca tacctgccct ggcctctcag catgactcct tggtgacaca actcccacag99181cacccacaca cctacaccca cctaccccac acacacaccc ctgcctgggc tgcccggttt99241gtccactgtg taggtgctca aggacgcaga gctcctgcct ctcaaggaac agcctcaggg99301tgaggtccct gggagagaag agttcagctc tgcccagagc agccctcaga caaacagcca99361gctgctgctc accagtcatc cRttccaatc tgaagagtga ctgtcctggg ccagtcatgg99421gaaaatcatc aagaacttcc cRcaatggtc atggtggccg ccaaggtctt tctctggggg99481ttgggagctg tgctccccca caaaacaagg ggacccagct gccctgtgcc ttcctgtggc99541aactctctgg aggatgcctg gataccctcc ctacagacgg ccagggatag gaggggcagg99601cactgcaggc atgtgggggc atagcagcaa gaatctagga gggcaggcac agcaaggcct99661ggcccagagg gaaaccagga gctgccagag ccaaagagag ggtgacccaa tcattggttg99721ttatagagtt tttaagactt ggaagagaat gccctgagat gccaNagagt gaaacatttt99781cattctaaag ctgggaaacc aaagtcggca aaggcgaaca gacgtgccca cagccacatg99841ggacagcagt ggcacagaag aaatgcacac ctcgtcctct ggtggccact gtgcactctc99901ttaccacacc atgctactgc tcaacctctc cccctccctc acagtggtca ggtaagcaat99961gagggaaaat gatggaggtg agaaaggaag aacccgggct


Following is a CETP coding nucleotide sequence (cDNA, SEQ ID NO: 6). >gi|4557442|ref|NM000078.1| Homo sapiens cholesteryl ester transfer protein, plasma (CETP), mRNA.

1gtgaatctct ggggccagga agaccctgct gcccggaagagcctcatgtt ccgtgggggc61tgggcggaca tacatatacg ggctccaggc tgaacggctcgggccactta cacaccactg121cctgataacc atgctggctg ccacagtcct gaccctggccctgctgggca atgcccatgc181ctgctccaaa ggcacctcgc acgaggcagg catcgtgtgccgcatcacca agcctgccct241cctggtgttg aaccacgaga ctgccaaggt gatccagaccgccttccagc gagccagcta301cccagatatc acgggcgaga aggccatgat gctccttggccaagtcaagt atgggttgca361caacatccag atcagccact tgtccatcgc cagcagccaggtggagctgg tggaagccaa421gtccattgat gtctccattc agaacgtgtc tgtggtcttcaaggggaccc tgaagtatgg481ctacaccact gcctggtggc tgggtattga tcagtccattgacttcgaga tcgactctgc541cattgacctc cagatcaaca cacagctgac ctgtgactctggtagagtgc ggaccgatgc601ccctgactgc tacctgtctt tccataagct gctcctgcatctccaagggg agcgagagcc661tgggtggatc aagcagctgt tcacaaattt catctccttcaccctgaagc tggtcctgaa721gggacagatc tgcaaagaga tcaacgtcat ctctaacatcatggccgatt ttgtccagac781aagggctgcc agcatccttt cagatggaga cattggggtggacatttccc tgacaggtga841tcccgtcatc acagcctcct acctggagtc ccatcacaagggtcatttca tctacaagaa901tgtctcagag gacctccccc tccccacctt ctcgcccacactgctggggg actcccgcat961gctgtacttc tggttctctg agcgagtctt ccactcgctggccaaggtag ctttccagga1021tggccgcctc atgctcagcc tgatgggaga cgagttcaaggcagtgctgg agacctgggg1081cttcaacacc aaccaggaaa tcttccaaga ggttgtcggcggcttcccca gccaggccca1141agtcaccgtc cactgcctca agatgcccaa gatctcctgccaaaacaagg gagtcgtggt1201caattcttca gtgatggtga aattcctctt tccacgcccagaccagcaac attctgtagc1261ttacacattt gaagaggata tcgtgactac cgtccaggcctcctattcta agaaaaagct1321cttcttaagc ctcttggatt tccagattac accaaagactgtttccaact tgactgagag1381cagctccgag tccatccaga gcttcctgca gtcaatgatcaccgctgtgg gcatccctga1441ggtcatgtct cggctcgagg tagtgtttac agccctcatgaacagcaaag gcgtgagcct1501cttcgacatc atcaaccctg agattatcac tcgagatggcttcctgctgc tgcagatgga1561ctttggcttc cctgagcacc tgctggtgga tttcctccagagcttgagct agaagtctcc1621aaggaggtcg ggatggggct tgtagcagaa ggcaagcaccaggctcacag ctggaaccct1681ggtgtctcct ccagcgtggt ggaagttggg ttaggagtacggagatggag attggctccc1741aactcctccc tatcctaaag gcccactggc attaaagtgctgtatccaagCDS: 131-1612 base pairsSignal peptide: 131-181 base pairsMature peptide: 182-1609 base pairsPolyA signal: 1771-1776 base pairs


Following is a second PROL4 cDNA sequence (SEQ ID NO:7). >gi|6005801|ref|NM007244.1| Homo sapiens proline rich 4 (lacrimal) (PRR4), mRNA

1cagagcctcc ttcaagatgc tgctggtcct gctctcagtgtccttctgg ctctgagctc61agctcagagc acagataatg atgtgaacta tgaagactttactttcacca taccagatgt121agaggactca agtcagagac cagatcaggg accccagagacctcctcctg aaggactcct181acctagaccc cctggtgata gtggtaacca agatgatggtcctcagcaga gaccaccaaa241accaggaggc catcaccgcc atcctccccc acctccttttcaaaatcagc aacgaccacc301ccaacgagga caccgtcaac tctctctacc ccgatttccttctgtcagcc tgcaggaagc361atcatcattc ttccggaggg acagaccagc aagacatccccaggagcaac cactctggta421atctagaatt cagtggcaga aaataaataa gaagataacttcattcagaa agccatgaca481ttgaaataat gtggtcataa ctctttcCDS: 17 . . . 421 base pairsPolyA signal: 442 . . . 447 base pairs


Following is a GRID2 cDNA sequence (SEQ ID NO: 8). >gi|4557632|ref|NM001510.1| Homo sapiens glutamate receptor, ionotropic, delta 2 (GRID2), mRNA.

1atggaagttt tccccttgct cttggttttg tccgtctggtggtctcgaac ctgggactcg61gcgaatgcgg attcgatcat tcacatcgga gcaatttttgatgaatctgc caaaaaggat121gatgaggtat ttcgcactgc ggttggtgac cttaaccagaatgaagagat cttacagact181gagaaaatca cattttcagt gacgtttgtt gatggcaacaaccctttcca agcagttcaa241gaagcctgtg aacttatgaa tcaaggcatc ttggccctggtcagctccat tggctgcacg301tcagcaggat ccctccagtc tttggcagac gccatgcatatcccccacct cttcattcag361cgctcaacag ctgggacccc aaggagtggc tgtggactcacccggagcaa caggaatgat421gactacactc tctcagttcg cccacctgtc tacttgcatgatgttatcct aagagtggtc481acagagtatg cctggcagaa attcattata ttctatgatagtgaatacga tatccgtgga541atacaggagt tcttggacaa agtctctcag cagggaatggatgttgcact tcagaaggta601gaaaacaaca tcaataaaat gattaccact ctctttgacaccatgagaat agaagaactg661aatcgctatc gagacactct taggcgagcg atccttgttatgaatcctgc tacagccaaa721tccttcatta ctgaggttgt ggagactaat ttggttgcttttgactgtca ctggatcatt781ataaatgagg aaataaacga tgtggacgta caggaacttgtaagaaggtc aattggaagg841ttaacgatta ttcggcagac atttccaatt ccccagaacataagtcagcg gtgtttccgt901ggcaaccatc gaatatcttc aacattgtgt gatccaaaggatccatttgc tcagaatatg961gagatttcca acctttacat atatgacacg gtgcttctgcttgctaatgc ttttcataag1021aagctggagg accgaaagtg gcacagcatg gcaagtctgtcatgtatcag aaagaactca1081aagccctggc agggtgggcg ctccatgttg gagaccatcaagaagggtgg agttagtggg1141ttgactggag agctagaatt tggagaaaat ggaggcaatcccaatgtcca ctttgaaatc1201cttggaacca actatggaga agagcttggc agaggtgttcgaaaacttgg gtgctggaat1261cctgtcacag gtctgaatgg gtcactgact gacaagaaattggagaataa catgcgtgga1321gtggttctac gtgtagtaac tgttctggaa gaaccttttgtgatggtctc tgaaaatgtc1381ttgtgtaagc cgaagaaata ccagggcttc tccattgatgttttggatgc cttatctaac1441tacctgggtt ttaactacga aatttacgta gcaccggatcacaaatacgg aagcccacaa1501gaagatggga catggaatgg cttggtagga gaacttgtctttaagagagc cgacataggg1561atttctgctt taaccatcac tccagatcgt gaaaatgtggtggactttac gacacgttac1621atggactact cagtgggggt actacttcga agggctgaaaagacagtgga tatgtttgcc1681tgtcttgcac catttgatct ctctctatgg gcttgcattgctggcacagt ccttctggtg1741ggtctactgg tctacctctt gaactggctt aatcccccacgattacaaat gggatcaatg1801acgtctacta ctctctacaa ctccatgtgg tttgtgtatggatcttttgt acaacaaggc1861ggggaagtcc cgtacacgac tctggctacc cgaatgatgatgggggcttg gtggctattt1921gctttgattg ttatctcatc ttacacggca aacctcgctgctttcctcac tattacacgc1981attgaaagtt ccatccagtc tctccaggac ctttccaagcaaacagaaat cccttatggc2041acagtcctag actctgcggt atatgagcat gtccgcatgaaaggactgaa tccttttgag2101agggacagca tgtattccca aatgtggcgg atgatcaaccgaagcaatgg atcggagaac2161aatgttctgg agtcccaggc aggcattcaa aaggtaaaatatggaaatta tgctttcgta2221tgggatgcag ctgtattgga atatgtggct atctatgacccagattgttc cttttacacc2281attggaaata ctgttgctga tcggggatat ggaattgcattacaacatgg cagtccttac2341cgagatgttt tttcacaaag gatcctggag cttcagcagaatggtgacat ggacatcctg2401aagcacaaat ggtggcctaa gaatggccag tgtgacctgtactcgtcagt ggacacaaag2461cagaaaggag gcgccctgga cataaagagc tttgcaggggtcttttgtat cctggctgct2521ggaattgtcc tctcctgctt catagccatg ctggagacgtggtggaacaa gaggaaaggc2581tcccgggttc catcaaaaga ggatgacaag gaaattgacctggagcacct ccatagacgt2641gtaaatagct tgtgcacaga tgacgacagc ccccataaacagttttccac ctcgtcaatt2701gatttgaccc ctctggacat tgacactttg ccaacacgacaagcactgga gcaaatcagt2761gatttcagga acactcatat taccacaaca acctttatcccagagcagat ccagactctt2821agccgcacac tgtcagctaa agctgcttct ggtttcacttttggcaacgt gcctgagcac2881cgaactggcc cttttaggca cagggcacct aatgggggctttttcaggag tcctataaaa2941acaatgtcat ctattcctta tcaaccaact cctaccctggggctcaatct gggtaatgat3001ccagaccgag gcacctccat atga


Following is a PDE4D cDNA sequence (SEQ ID NO: 9). >gi|4636198|ref|006203.3| Homo sapiens phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) (PDE4D), mRNA.

1ggaattcatc tgtaaaaatc actacatgta acgtaggagacaagaaaaat attaatgaca61gaagatctgc gaacatgatg cacgtgaata attttccctttagaaggcat tcctggatat121gttttgatgt ggacaatggc acatctgcgg gacggagtcccttggatccc atgaccagcc181caggatccgg gctaattctc caagcaaatt ttgtccacagtcaacgacgg gagtccttcc241tgtatcgatc cgacagcgat tatgacctct ctccaaagtctatgtcccgg aactcctcca301ttgccagtga tatacacgga gatgacttga ttgtgactccatttgctcag gtcttggcca361gtctgcgaac tgtacgaaac aactttgctg cattaactaatttgcaagat cgagcaccta421gcaaaagatc acccatgtgc aaccaaccat ccatcaacaaagccaccata acagaggagg481cctaccagaa actggccagc gagaccctgg aggagctggactggtgtctg gaccagctag541agaccctaca gaccaggcac tccgtcagtg agatggcctccaacaagttt aaaaggatgc601ttaatcggga gctcacccat ctctctgaaa tgagtcggtctggaaatcaa gtgtcagagt661ttatatcaaa cacattctta gataagcaac atgaagtggaaattccttct ccaactcaga721aggaaaagga gaaaaagaaa agaccaatgt ctcagatcagtggagtcaag aaattgatgc781acagctctag tctgactaat tcaagtatcc caaggtttggagttaaaact gaacaagaag841atgtccttgc caaggaacta gaagatgtga acaaatggggtcttcatgtt ttcagaatag901cagagttgtc tggtaaccgg cccttgactg ttatcatgcacaccattttt caggaacggg961atttattaaa aacatttaaa attccagtag atactttaattacatatctt atgactctcg1021aagaccatta ccatgctgat gtggcctatc acaacaatatccatgctgca gatgttgtcc1081agtctactca tgtgctatta tctacacctg ctttggaggctgtgtttaca gatttggaga1141ttcttgcagc aatttttgcc agtgcaatac atgatgtagatcatcctggt gtgtccaatc1201aatttctgat caatacaaac tctgaacttg ccttgatgtacaatgattcc tcagtcttag1261agaaccatca tttggctgtg ggctttaaat tgcttcaggaagaaaactgt gacattttcc1321agaatttgac caaaaaacaa agacaatctt taaggaaaatggtcattgac atcgtacttg1381caacagatat gtcaaaacac atgaatctac tggctgatttgaagactatg gttgaaacta1441agaaagtgac aagctctgga gttcttcttc ttgataattattccgatagg attcaggttc1501ttcagaatat ggtgcactgt gcagatctga gcaacccaacaaagcctctc cagctgtacc1561gccagtggac ggaccggata atggaggagt tcttccgccaaggagaccga gagagggaac1621gtggcatgga gataagcccc atgtgtgaca agcacaatgcttccgtggaa aaatcacagg1681tgggcttcat agactatatt gttcatcccc tctgggagacatgggcagac ctcgtccacc1741ctgacgccca ggatattttg gacactttgg aggacaatcgtgaatggtac cagagcacaa1801tccctcagag cccctctcct gcacctgatg acccagaggagggccggcag ggtcaaactg1861agaaattcca gtttgaacta actttagagg aagatggtgagtcagacacg gaaaaggaca1921gtggcagtca agtggaagaa gacactagct gcagtgactccaagactctt tgtactcaag1981actcagagtc tactgaaatt ccccttgatg aacaggttgaagaggaggca gtaggggaag2041aagaggaaag ccagcctgaa gcctgtgtca tagatgatcgttctcctgac acgtaacagt2101gcaaaaactt tcatgccttt ttttttttta agtagaaaaattgtttccaa agtgcatgtc2161acatgccaca accacggtca cacctcactg tcatctgccaggacgtttgt tgaacaaaac2221tgaccttgac tactcagtcc agcgctcagg aatatcgtaaccagtttttt cacctccatg2281tcatccgagc aaggtggaca tcttcacgaa cagcgtttttaacaagattt cagcttggta2341gagctgacaa agcagataaa atctactcca aattattttcaagagagtgt gactcatcag2401gcagcccaaa agtttattgg acttggggtt tctattcctttttatttgtt tgcaatattt2461tcagaagaaa ggcattgcac agagtgaact taatggacgaagcaacaaat atgtcaagaa2521caggacatag cacgaatctg ttaccagtag gaggaggatgagccacagaa attgcataat2581tttctaattt caagtcttcc tgatacatga ctgaatagtgtggttcagtg agctgcactg2641acctctacat tttgtatgat atgtaaaaca gattttttgtagagcttact tttattatta2701aatgtattga ggtattatat ttaaaaaaaa ctatgttcagaacttcatct gccactggtt2761atttttttct aaggagtaac ttgcaagttt tcagtacaaatctgtgctac actggataaa2821aatctaattt atgaatttta cttgcacctt atagttcatagcaattaact gatttgtagt2881gattcattgt ttgttttata taccaatgac ttccatattttaaaagagaa aaacaacttt2941atgttgcagg aaaccctttt tgtaagtctt tattatttactttgcatttt gtttcactct3001ttccagataa gcagagttgc tcttcaccag tgtttttcttcatgtgcaaa gtgactattt3061gttctataat acttttatgt gtgttatatc aaatgtgtcttaagcttcat gcaaactcag3121tcatcagttc gtgttgtctg aagcaagtgg gaaatatataaatacccagt agctaaaatg3181gtcagtcttt tttagatgtt ttcctactta gtatctcctaataacgtttt gctgtgtcac3241tagatgttca tttcacaagt gcatgtcttt ctaataatccacacatttca tgctctaata3301atccacacat ttcatgctca tttttattgt ttttacagccagttatagca agaaaaaggt3361ttttcccctt gtgctgcttt ataatttagc gtgtgtctgaaccttatcca tgtttgctag3421atgaggtctt gtcaaatata tcactaccat tgtcaccggtgaaaagaaac aggtagttaa3481gttagggtta acattcattt caaccacgag gttgtatatcatgactagct tttactcttg3541gtttacagag aaaagttaaa caaccaacta ggcagtttttaagaatatta acaatatatt3601aacaaacacc aatacaacta atcctatttg gttttaatgatttcaccatg ggattaagaa3661ctatatcagg aacatccctg agaaacggct ttaagtgtagcaactactct tccttaatgg3721acagccacat aacgtgtagg aagtccttta tcacttatcctcgatccata agcatatctt3781gcagagggga actacttctt taaacacatg gagggaaagaagatgatgcc actggcacca3841gagggttagt actgtgatgc atcctaaaat atttattatattggtaaaaa ttctggttaa3901ataaaaaatt agagatcact cttggctgat ttcagcaccaggaactgtat tacagtttta3961gagattaatt cctagtgttt acctgattat agcagttggcatcatggggc atttaattct4021gactttatcc ccacgtcagc cttaataaag tcttctttaccttctctatg aagactttaa4081agcccaaata atcatttttc acattgatat tcaagaattgagatagatag aagccaaagt4141gggtatctga caagtggaaa atcaaacgtt taagaagaattacaactctg aaaagcattt4201atatgtggaa cttctcaagg agcctcctgg ggactggaaagtaagtcatc agccaggcaa4261atgactcatg ctgaagagag tccccatttc agtcccctgagatctagctg atgcttagat4321cctttgaaat aaaaattatg tctttataac tctgatcttttacataaagc agaagaggaa4381tcaactagtt aattgcaagg tttctactct gtttcctctgtaaagatcag atggtaatct4441ttcaaataag aaaaaaataa agacgtatgt ttgaccaagtagtttcacaa gaatatttgg4501gaacttgttt cttttaattt tatttgtccc tgagtgaagtctagaaagaa aggtaaagag4561tctagagttt attcctcttt ccaaaacatt ctcattcctctcctccctac acttagtatt4621tcccccacag agtgcctaga atcttaataa tgaataaaataaaaagcagc aatatgtcat4681taacaaatcc agacctgaaa gggtaaaggg tttataactgcactaataaa gagaggctct4741ttttttttct tccagtttgt tggtttttaa tggtaccgtgttgtaaagat acccactaat4801ggacaatcaa attgcagaaa aggctcaata tccaagagacagggactaat gcactgtaca4861atctgcttat ccttgccctt ctctcttgcc aaagtgtgcttcagaaatat atactgcttt4921aaaaaagaat aaaagaatat ccttttacaa gtggctttacatttcctaaa atgccataag4981aaaatgcaat atctgggtac tgtatgggga aaaaaatgtccaagtttgtg taaaaccagt5041gcatttcagc ttgcaagtta ctgaacacaa taatgctgttttaattttgt tttatatcag5101ttaaaattca caataatgta gatagaacaa attacagacaaggaaagaaa aaacttgaat5161gaaatggatt ttacagaaag ctttatgata atttttgaatgcattattta ttttttgtgc5221catgcatttt ttttctcacc aaatgacctt acctgtaatacagtcttgtt tgtctgttta5281caaccatgta tttattgcaa tgtacatact gtaatgttaattgtaaatta tctgttctta5341ttaaaacatc atcccatgat ggggtggtgt tgatatatttggaaactctt ggtgagagaa5401tgaatggtgt gtatacatac tctgtacatt tttcttttctcctgtaatat agtcttgtca5461ccttagagct tgtttatgga agattcaaga aaactataaaatacttaaag atatataaat5521ttaaaaaaac atagctgcag gtctttggtc ccagggctgtgccttaactt taaccaatat5581tttcttctgt tttgctgcat ttgaaaggta acagtggagctagggctggg cattttacat5641ccaggctttt aattgattag aattctgcca ataggtggattttacaaaac cacagacaac5701ctctgaaaga ttctgagacc cttttgagac agaagctcttaagtacttct tgccagggag5761cagcactgca tgtgtgatgg ttgtttgcca tctgttgatcaggaactact tcagctactt5821gcatttgatt atttcctttt tttttttttt taactcggaaacacaactgg gggaat


Following is a GPX3 cDNA sequence (SEQ ID NO: 10). >gi|6006000|ref|NM002084.2| Homo sapiens glutathione peroxidase 3 (plasma) (GPX3), mRNA.

1agccaaaaga ggaagggacc ggcctcccac gtccacagggacctgacttc cacctctctg61cccagatttg cttatgtcac tgtcgccccg ggacggggaggtggggagct gagggcaagt121cgcgcccgcc cctgaaatcc cagccgccta gcgattggctgcaagggtct cggcttggcc181gcggattaat cacacccgag ggcttgaaag gtggctgggagcgccggaca cctcagacgg241acggtggcca gggatcaggc agcggctcag gcgaccctgagtgtgccccc accccgccat301ggcccggctg ctgcaggcgt cctgcctgct ttccctgctcctggccggct tcgtctcgca361gagccgggga caagagaagt cgaagatgga ctgccatggtggcataagtg gcaccattta421cgagtacgga gccctcacca ttgatgggga ggagtacatccccttcaagc agtatgctgg481caaatacgtc ctctttgtca acgtggccag ctactgaggcctgacgggcc agtacattga541actgaatgca ctacaggaag agcttgcacc attcggtctggtcattctgg gctttccctg601caaccaattt ggaaaacagg aaccaggaga gaactcagagatccttccta ccctcaagta661tgtccgacca ggtggaggct ttgtccctaa tttccagctctttgagaaag gggatgtcaa721tggagagaaa gagcagaaat tctacacttt cctaaagaactcctgtcctc ccacctcgga781gctcctgggt acatctgacc gcctcttctg ggaacccatgaaggttcacg acatccgctg841gaactttgag aagttcctgg tggggccaga tggtatacccatcatgcgct ggcaccaccg901gaccacggtc agcaacgtca agatggacat cctgtcctacatgaggcggc aggcagccct961gggggtcaag aggaagtaac tgaaggccgt ctcatcccatgtccaccatg taggggaggg1021actttgttca ggaagaaatc cgtgtctcca accacactatctacccatca cagacccctt1081tcctatcact caaggcccca gcctggcaca aatggatgcatacagttctg tgtactgcca1141ggcatgtggg tgtgggtgca atgtgggtgt ttacacacatgcctacaggt atgcgtgatt1201gtgtgtgtgt gcatgggtgt acagccacgt gtctacctatgtgtctttct gggaatgtgt1261accatctgtg tgcctgcagc tgtgtagtgc tggacagtgacaaccctttc tctccagttc1321tccactccaa tgataatagt tcacttatac ctaaacccaaaggaaaaacc agctctaggt1381ccaattgttc tgctctaact gatacctcaa ccttggggccagcatctccc actgcctcca1441aatattagta actatgactg acgtccccag aagtttctgggtctaccaca ctccccaacc1501ccccactcct acttcctgaa gggccctccc aaggctacatccccacccca cagttctccc1561tgagagagat caacctccct gagatcaacc aaggcagatgtgacagcaag ggccacggac1621cccatggcag gggtggcgtc ttcatgaggg aggggcccaaagcccttgtg ggcggacctc1681ccctgagcct gtctgagggg ccagccctta gtgcattcaggctaaggccc ctgggcaggg1741atgccacccc tgctccttcg gaggacgtgc cctcacccctcactggtcca ctggcttgag1801actcaccccg tctgcccagt aaaagccttt ctgcagcaaaaaaaaaaaaa aaaaaaCDS: 299-979 base pairsSignal peptide: 299-358 base pairsMature peptide: 359-976 base pairsPolyA signal: 1838 base pairs


Following is a CETP amino acid sequence (SEQ ID NO: 11). >gi|4557443|ref_NP900069.1| cholesteryl ester transfer protein, plasma precursor [Homo sapiens]

MLAATVLTLALLGNAHACSKGTSHEAGIVCRITKPALLVLNHETAKVIQTAFQRASYPDITGEKAMMLLGQVKYGLHNIQISHLSIASSQVELVEAKSIDVSIQNVSVVFKGTLKYGYTTAWWLGIDQSIDFEIDSAIDLQINTQLTCDSGRVRTDAPDCYLSFHKLLLHLQGEREPGWIKQLFTNFISFTLKLVLKGQICKEINVISNIMADFVQTRAASILSDGDIGVDISLTGDPVITASYLESHHKGHFIYKNVSEDLPLPTFSPTLLGDSRMLYFWFSERVFHSLAKVAFQDGRLMLSLMGDEFKAVLETWGFNTNQEIFQEVVGGFPSQAQVTVHCLKMPKISCQNKGVVVNSSVMVKFLFPRPDQQHSVAYTFEEDIVTTVQASYSKKKLFLSLLDFQITPKTVSNLTESSSESIQSFLQSMITAVGIPEVMSRLEVVFTALMNSKGVSLFDIINPEIITRDGFLLLQMDFGFPEHLLVDFLQSLSProtein: 1 . . . 493 amino acidsSignal peptide: 1-17 amino acidsMature peptide: 18-493 amino acids


Following is a second PROL4 amino acid sequence (SEQ ID NO: 12). >gi|6005802|ref|NP009175.1| proline rich 4 (lacrimal) [Homo sapiens].

MLLVLLSVVLLAISSAQSTDNDVNYEDFTFTIPDVEDSSQRPDQGPQRPPPEGLLPRPPGDSGNQDDGPQQRPPKPGGHHRHPPPPPFQNQQRPPQRGHRQLSLPRFPSVSLQEASSFFRRDRPARHPQEQPLWProtein: 1 . . . 134 amino acidsSignal peptide: 1-16 amino acidsMature peptide: 17-134 amino acids


Following is a GRID2 amino acid sequence (SEQ ID NO: 13). >gi|4557633|ref|NP001501.1| glutamate receptor, ionotropic, delta 2 [Homo sapiens].

MEVFPLLLVLSVWWSRTWDSANADSIIHIGAIFDESAKKDDEVFRTAVGDLNQNEEILQTEKITFSVTFVDGNNPFQAVQEACELMNQGILALVSSIGCTSAGSLQSLADAMHIPHLFIQRSTAGTPRSGCGLTRSNRNDDYTLSVRPPVYLHDVILRVVTEYAWQKFIIFYDSEYDIRGIQEFLDKVSQQGMDVALQKVENNINKMITTLFDTMRIEELNRYRDTLRRAILVMNPATAKSFITEVVETNLVAFDCHWIIINEEINDVDVQELVRRSIGRLTIIRQTFPIPQNISQRCFRGNHRISSTLCDPKDPFAQNMEISNLYIYDTVLLLANAFHKKLEDRKWHSMASLSCIRKNSKPWQGGRSMLETIKKGGVSGLTGELEFGENGGNPNVHFEILGTNYGEELGRGVRKLGCWNPVTGLNGSLTDKKLENNMRGVVLRVVTVLEEPFVMVSENVLCKPKKYQGFSIDVLDALSNYLGFNYEIYVAPDHKYGSPQEDGTWNGLVGELVFKRADIGISALTITPDRENVVDFTTRYMDYSVGVLLRRAEKTVDMFACLAPFDLSLWACIAGTVLLVGLLVYLLNWLNPPRLQMGSMTSTTLYNSMWFVYGSFVQQGGEVPYTTLATRMMMGAWWLFALIVISSYTANLAAFLTITRIESSIQSLQDLSKQTEIPYGTVLDSAVYEHVRMKGLNPFERDSMYSQMWRMINRSNGSENNVLESQAGIQKVKYGNYAFVWDAAVLEYVAIYDPDCSFYTIGNTVADRGYGIALQHGSPYRDVFSQRILELQQNGDMDILKHKWWPKNGQCDLYSSVDTKQKGGALDIKSFAGVFCILAAGIVLSCFIAMIETWWNKRKGSRVPSKEDDKEIDLEHLHRRVNSLCTDDDSPHKQFSTSSIDLTPLDIDTLPTRQALEQISDFRNTHITTTTFIPEQIQTLSRTLSAKAASGFTFGNVPEHRTGPFRHRAPNGGFFRSPIKTMSSIPYQPTPTLGLNLGNDPDRGTSI


Following is a PDE4D amino acid sequence (SEQ ID NO: 14). >gi|32306513|ref|NP006194.2| cAMP-specific phosphodiesterase 4D [Homo sapiens]

MMHVNNFPFRRHSWICFDVDNGTSAGRSPLDPMTSPGSGLILQANFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNFAALTNLQDRAPSKRSPMCNQPSINKATITEEAYQKLASETLEELDWCLDQLETLQTRHSVSEMASNKFKRMLNRELTHLSEMSRSGNQVSEFISNTFLDKQHEVEIPSPTQKEKEKKKRPMSQISGVKKLMHSSSLTNSSIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSGNRPLTVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYHADVAYHNNIHAADVVQSTHVLLSTPALEAVFTDLEILAAIFASAIHDVDHPGVSNQFLINTNSELALMYNDSSVLENHHLAVGFKLLQEENCDIFQNLTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSGVLLLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERGMEISPMCDKHNASVEKSQVGFIDYIVHPLWETWADLVHPDAQDILDTLEDNREWYQSTIPQSPSPAPDDPEEGRQGQTEKFQFELTLEEDGESDTEKDSGSQVEEDTSCSDSKTLCTQDSESTEIPLDEQVEEEAVGEEEESQPEACVIDDRSPDT


Following is a GPX3 amino acid sequence (SEQ ID NO: IS). >gi|6006001|ref|NP002075.2| plasma glutathione peroxidase 3 precursor [Homo sapiens]

MARLLQASCLLSLLLAGFVSQSRGQEKSKMDCHGGISGTIYEYGALTIDGEEYIPFKQYAGKYVLFVNVASYUGLTGQYIELNALQEELAPFGLVILGFPCNQFGKQEPGENSEILPTLKYVRPGGGFVPNFQLFEKGDVNGEKEQKFYTFLKNSCPPTSELLGTSDRLFWEPMKVHDIRWNFEKFLVGPDGIPIMRWHHRTTVSNVKMDILSYMRRQAALGVKRK


Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, yet these modifications and improvements are within the scope and spirit of the invention, as set forth in the claims which follow. Also, citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. The content of each patent, patent application and other publication and document referenced is incorporated herein by reference in its entirety, including drawings, tables and cited documents.

Claims
  • 1. A method for identifying a subject at risk of low bone mineral density (BMD), which comprises detecting the presence or absence of one or more polymorphic variations associated with low BMD in a nucleic acid sample from a subject, wherein the one or more polymorphic variations are detected in a nucleotide sequence in SEQ ID NOs:1-5, a substantially identical sequence thereof or a fragment of the foregoing; whereby the presence of the polymorphic variation is indicative of the subject being at risk of low BMD.
  • 2. The method of claim 1, which further comprises obtaining the nucleic acid sample from the subject.
  • 3. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs7500979, rs2217332, rs8044804, rs2270835, rs2133783, rs247609, rs952440, rs881598, rs2291955, rs2518054, rs866038, rs1436425, rs173537, rs247611, rs166017, rs173538, rs193694, rs7205692, rs8048746, rs247618, rs183130, rs6499863, rs4783961, rs3816117, rs711752, rs708272, rs1864163, rs4369653, rs1864165, rs891141, rs891143, rs7205804, rs5885, rs1532625, rs1532624, rs289712, rs7499892, rs5883, rs289714, rs158480, rs289717, rs4344729, rs289718, rs289719, rs2033254, rs4784744, rs291044, rs8053613, rs5881, rs5880, rs7198026, rs5882, rs8045701, rs289741, rs1801706, rs289742, rs289743, rs289746, rs172337, rs289747, rs1566439, rs7205459, rs289749, rs289751, rs8059220, rs8058353, rs289735, rs289737, rs291042, rs1875236, rs821466, rs821465, rs4275846, rs289707, rs821463, rs289706, rs1167741, rs2052880, rs1167742, rs1183256, rs1651665, rs1651666, rs4784751, rs1651667, rs8052091, rs1684574, rs1684575, rs1672865, rs821470, rs1549669, rs291040 and rs289754.
  • 4. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs166017, rs193694, rs7205804, rs1801706, rs7205459 and rs821465.
  • 5. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 14,328 to 68,805 in SEQ ID NO: 1.
  • 6. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs523051, rs693620, rs2588349, rs2588350, rs619381, rs3759252, rs3759251, rs2418107, rs7303054, rs1838345, rs620878, rs2537817, rs1548803, rs667123, rs1838346, rs2159903, rs3944035, rs3741845, rs2110096, rs759055, rs589377, rs7960194, rs7978242, rs601051, rs4262797, rs2215714, rs1373434, rs2215715, rs612456, rs612808, rs689118, rs597468, rs592864, rs640372, rs7966559, rs654834, rs4763216, rs668521, rs669503, rs3906864, rs3906863, rs7957888, rs9300230, rs7306214, rs763839, rs2418105, rs666841, rs3851578, rs7138797, rs7295252, rs2418106, rs7299578, rs621112, rs3863320, rs1373432, rs1047699, rs1063193, rs2232959, rs2227296, rs1548804, rs2232958, rs2232957, rs2232956, rs1972571, rs3759250, rs3759249, rs1541525, rs2098248, rs2900550, rs7302130, rs4763583, rs4360778, rs1607695, rs1607694, rs2192139, rs7978300, rs7397871, rs4763217, rs2159900, rs10772370, rs7398682, rs2900551, rs2900552, rs2418214, rs2418215, rs965243, rs1117548, rs1520225, rs1520226, rs1520227, rs971919, rs2159901, rs2159902, rs2110099, rs7314847, rs7296003, rs4281556, rs4763219, rs3851579, rs3851580, rs1049119, rs2298866, rs2298865, rs2298864, rs2298863, rs3180393, rs2070837, rs7956204, rs2418216, rs3741844, rs4262798, rs2418217, rs2418218, rs7137492, rs2110100, rs1013312, rs4579993, rs1013313, rs7397106, rs2215716, rs2192140, rs4763589, rs1468697, rs2070837, rs3180393 and rs2298865.
  • 7. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs2588350, rs619381, rs620878, rs759055, rs4262797, rs612808, rs3906863, rs7957888, rs763839, rs2418105, rs666841, rs3851578, rs7299578, rs621112, rs1047699, rs1548804, rs2232956, rs1520227 and rs2215716.
  • 8. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 2,424 to 93,715 in SEQ ID NO: 2.
  • 9. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs1433661, rs1485009, rs7681947, rs1816432, rs1485018, rs1485017, rs7438397, rs6834311, rs1368717, rs1017391, rs2870701, rs7679839, rs1385404, rs1368716, rs4693316, rs1905707, rs1905708, rs1905709, rs3912442, rs2082553, rs6831638, rs5860329, rs2870702, rs2870703, rs1948016, rs6835836, rs1994253, rs1905710, rs1485019, rs978191, rs1385405, rs7694361, rs1905711, rs1905734, rs1485012, rs1485013, rs4692981, rs7670552, rs7670932, rs7688091, rs7440540, rs2171000, rs2870704, rs7655758, rs7661436, rs7662289, rs7667044, rs7691929, rs5860330, rs901013, rs901012, rs901011, rs1948018, rs2870705, rs1948017, rs1905733, rs1385408, rs1385409, rs1385410, rs1485026, rs1485027, rs2904483, rs1385406, rs1905732, rs2046418, rs2200377, rs1905731, rs1905730, rs975713, rs6820985, rs7670441, rs6810794, rs7676623, rs1154861, rs1032125, rs1485022, rs1485024, rs3913651, rs4693319, rs1872383, rs2200376, rs7668090, rs7692930, rs967096, rs6822249, rs6532405, rs1017897, rs7672674, rs7694568, rs2904484, rs7340830, rs1485033, rs2870706, rs1905729, rs4693320, rs6848749, rs6532406, rs6532407, rs1905728, rs6819866, rs1905727, rs7674069, rs1905724, rs1905723, rs1485020 and rs6814101.
  • 10. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs1433661, rs7679839, rs1368716, rs1905707, rs1905708, rs1994253, rs1485019, rs1905734, rs1485012, rs7670552, rs7691929, rs1948018, rs1948017, rs1485024, rs7694568, rs4693320, rs6848749, rs6532406, rs6532407 and rs6819866.
  • 11. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 206 to 90,969 in SEQ ID NO: 3.
  • 12. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs6886495, rs6450498, rs1472456, rs4700315, rs4700316, rs7714708, rs7710479, rs2968013, rs2968014, rs2968015, rs1391648, rs2055297, rs2055296, rs3989138, rs4700317, rs2036220, rs7727206, rs7723432, rs1546221, rs4479801, rs4395595, rs4395596, rs4699932, rs2936201, rs7356672, rs2936200, rs1909296, rs7703131, rs7445308, rs3087748, rs4321723, rs2968016, rs5868151, rs1874858, rs1874857, rs7712922, rs4631140, rs4469166, rs1078369, rs1078368, rs2968006, rs2968005, rs2936190, rs2409613, rs4415048, rs2968004, rs2968003, rs2968002, rs2936191, rs1498610, rs6874662, rs3060393, rs7729722, rs7733884, rs7714489, rs7735570, rs2936193, rs2291851, rs2291852, rs1498602, rs1995166, rs1498603, rs1498604, rs1498605, rs1948651, rs4699934, rs4700319, rs2279737, rs7720361, rs7706419, rs1006431, rs1353747, rs1498606, rs1353748, rs1553113, rs2968012, rs2968011, rs1498608, rs2936189, rs1498609, rs2968019, rs6891238, rs2968010, rs2968009, rs2936203, rs1498601, rs1498600, rs1498599, rs2936202, rs7730070, rs6450501, rs6450502, rs6889456, rs6894618, rs7706044, rs7707541, rs7712076, rs6892860, rs6867053, rs7737269, rs6864156, rs950447, rs2936196, rs7719347, rs1391649, rs1391650, rs1391651, rs1353749, rs10682149, rs5868153, rs1363882, rs2409626, rs2968018, rs954740, rs986067, rs6869400, and rs5010782.
  • 13. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs7714708, rs1498602, rs4699934, rs1006431, rs1353747, rs1498608, rs1498609, rs2968010, rs2936202 and rs1391649.
  • 14. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 1,599 to 82,591 in SEQ ID NO: 4.
  • 15. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs1478398, rs1478397, rs1160114, rs1160113, rs1382323, rs1160112, rs7709870, rs7710643, rs7730467, rs6579829, rs6579830, rs6579831, rs6896232, rs1351131, rs1038074, rs1478396, rs6880512, rs4958858, rs4958431, rs4958432, rs6898463, rs4958859, rs4130064, rs4130065, rs4133119, rs4958860, rs4958861, rs4437356, rs4958868, rs1478400, rs6889375, rs1600159, rs6875892, rs4608909, rs2345000, rs4516840, rs2054440, rs707141, rs707142, rs841236, rs707143, rs707144, rs6869405, rs707145, rs707146, rs707148, rs707150, rs5872184, rs3763015, rs2042235, rs3763013, rs2042236, rs1946234, rs1946235, rs1946236, rs8177402, rs8177403, rs8177404, rs8177405, rs8177406, rs8177407, rs8177408, rs8177409, rs6888961, rs8177410, rs8177411, rs8177412, rs8177413, rs870407, rs870406, rs6873202, rs8177414, rs8177415, rs3805435, rs8177416, rs3792799, rs3792798, rs3828599, rs8177417, rs3792797, rs8177418, rs8177419, rs8177420, rs8177421, rs4958872, rs3792796, rs8177422, rs8177423, rs4958434, rs8177424, rs8177425, rs8177426, rs8177427, rs8177429, rs6889737, rs3792795, rs8177430, rs8177431, rs4958873, rs8177432, rs8177433, rs8177434, rs8177435, rs3763011, rs8177436, rs8177437, rs4958874, rs8177439, rs8177440, rs8177441, rs8177442, rs8177443, rs869975, rs869976, rs8177444, rs8177445, rs7721469, rs8177446, rs7704191, rs8177447, rs11548, rs2230303, rs7722386, rs8177448, rs8177449, rs2070593, rs8177450, rs8177451, rs8177452, rs8177453, rs8177454, rs3763010, rs8177455, rs8177456, rs736775, rs2277940, rs8177458, rs8177834, rs3924, rs2233312, rs2233311, rs2233310, rs2233309, rs4958875, rs2233308, rs2233307, rs2233306, rs2233305, rs2233304, rs2233303, rs2233302, rs2287719, rs2287720, rs7727034, rs7727250, rs7709800, rs3840312, rs2287721, rs6875293, rs3805434, rs2080982, rs2080983, rs2287722, rs2233301, rs2233300, rs4958876, rs2233299, rs2233298, rs2287723, rs2161359, rs7734456, rs4292439, rs4958878, rs6862024, rs3834819, rs2233297, rs2233296, rs2233295, rs2233294, rs7713028, rs7713223, rs7713567, rs888989, rs2233293, rs3749657, rs2233292, rs2112635, rs871269, rs3792794, rs6579837, rs3805433, rs5872186, rs2233291, rs2233290, rs2233289, rs4958435, rs4958880, rs1422673, rs2042234, rs3805432, rs3805431, rs2233288, rs2233287, rs3815720, rs3792792, rs3792791, rs2303018, rs3792790, rs4958436, rs2233286, rs2233285, rs7732451, rs2233284, rs1422674, rs3792789, rs4562032, rs6865077, rs1559126, rs3792788, rs1559127, rs3792786, rs6880110, rs6861227, rs3805430, rs1862364, rs4958881, rs3792785, rs6869605, rs6870205, rs4246047, rs4958882, rs3792784, rs3792783 and rs5872188.
  • 16. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions selected from the group consisting of rs1478398, rs1160114, rs1160113, rs1160112, rs4958858, rs4958431, rs6898463, rs4958859, rs4958860, rs4608909, rs707144, rs2042235, rs3763013, rs2042236, rs8177404, rs8177426, rs8177427, rs8177429, rs3792795, rs4958873, rs8177437, rs869975, rs8177447, rs11548, rs2277940, rs8177834, rs2233311, rs2233302, rs7727034, rs7727250, rs3805434, rs7734456, rs7713028, rs7713223, rs888989, rs3792794, rs4958880, rs1422673, rs3805432 and rs4958436.
  • 17. The method of claim 1, wherein the one or more polymorphic variations are detected in a region spanning positions 231 to 86,539 in SEQ ID NO: 5.
  • 18. The method of claim 1, wherein the one or more polymorphic variations are detected at one or more positions in linkage disequilibrium with one or more positions selected from the grout consisting of rs7500979, rs2217332, rs8044804, rs2270835, rs2133783, rs247609, rs952440, rs881598, rs2291955, rs2518054, rs866038, rs1436425, rs173537, rs247611, rs166017, rs173538, rs193694, rs7205692, rs8048746, rs247618, rs183130, rs6499863, rs4783961, rs3816117, rs711752, rs708272, rs1864163, rs4369653, rs1864165, rs891141, rs891143, rs7205804, rs5885, rs1532625, rs1532624, rs289712, rs7499892, rs5883, rs289714, rs158480, rs289717, rs4344729, rs289718, rs289719, rs2033254, rs4784744, rs291044, rs8053613, rs5881, rs5880, rs7198026, rs5882, rs8045701, rs289741, rs1801706, rs289742, rs289743, rs289746, rs172337, rs289747, rs1566439, rs7205459, rs289749, rs289751, rs8059220, rs8058353, rs289735, rs289737, rs291042, rs1875236, rs821466, rs821465, rs4275846, rs289707, rs821463, rs289706, rs1167741, rs2052880, rs1167742, rs1183256, rs1651665, rs1651666, rs4784751, rs1651667, rs8052091, rs1684574, rs1684575, rs1672865, rs821470, rs1549669, rs291040 and rs289754.
  • 19. The method of claim 1, wherein detecting the presence or absence of the one or more polymorphic variations comprises: hybridizing an oligonucleotide to the nucleic acid sample, wherein the oligonucleotide is complementary to a nucleotide sequence in the nucleic acid and hybridizes to a region adjacent to the polymorphic variation; extending the oligonucleotide in the presence of one or more nucleotides, yielding extension products; and detecting the presence or absence of a polymorphic variation in the extension products.
  • 20. The method of claim 1, wherein the subject is a human.
  • 21-55. (canceled)
RELATED APPLICATIONS

This patent application claims the benefit of U.S. Provisional Patent Application No. 60/640,966 filed on 31 Dec. 2004, entitled “Methods For Identifying Risk Of Low BMD And Treatments Thereof,” naming Steven Mah et al. as inventors, and designated by attorney docket no. SEQ-4095-PV. This patent application is related to U.S. Provisional Patent Application Nos. 60/640,967 and 60/640,796, each filed on 31 Dec. 2004, entitled “Methods For Identifying Risk Of Low BMD And Treatments Thereof,” naming Steven Mah et al. as inventors, and designated by attorney docket nos. SEQ-4094-PV and SEQ-4096-PV, respectively. The content and subject matter of each of these patent applications is hereby incorporated by reference in its entirety, including all text and drawings, in jurisdictions providing for such incorporation.

PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/US05/47411 12/29/2005 WO 6/27/2007
Provisional Applications (1)
Number Date Country
60640966 Dec 2004 US