Resources for Teleost Gene Duplicates and Human Disease

项目概要/摘要：全基因组关联研究（GWAS）已经检测到数千个 单核苷酸多态性（SNP）与许多人类疾病相关的数百个基因座。 了解GWAS基因座可以帮助破译复杂疾病的机制，并在不同人群中个性化治疗。 许多国家卫生研究院。问题是GWAS疾病基因座占据了连锁不平衡区， 几个或没有基因，只是连接到尚未未知的病原体，通常驻留在难以确定的， 研究非编码区域，这些区域可能是调节性的，并且通常在长距离上起作用。通常的假设是， 最接近前导SNP的基因是致病的，但这一想法必须得到验证。进步的障碍在于， 顺式调节模块可以在远处发挥作用，其作用靶点和作用方式通常不清楚。比较 医学可以帮助提供一条前进的道路。硬骨鱼，包括斑马鱼，有着相同的生理，行为， 发展，和人类的直系遗传途径，但拥有进化的基因组差异，我们可以 利用它来理解GWAS轨迹函数。先前的支持发现了硬骨鱼基因组复制（TGD） 并表明，斑点雀鳝代表了TGD之前最近分化的谱系，其基因组 将硬骨鱼医学模型与人类生物学联系起来。这些特征有助于将GWAS基因座与靶基因相关联 因为这两种硬骨鱼复制品通常保留不同的祖先组织特异性调节元件， 蛋白质结构域（亚功能化）;在不同硬骨鱼中不同地解析为单拷贝的重复基因; 与人类相比，硬骨鱼有许多染色体重排。我们利用这些特性， 在GWAS基因座上区分靶基因和旁观者基因。我们的广泛目标是开发资源， 非编码遗传元件的功能，包括GWAS基因座，用于人类疾病。目标1是开发一个 通过绘制人类保守的非编码元件将硬骨鱼基因组与人类生物学联系起来的资源 （CNEs）到硬骨鱼基因组;通过分析保守的同线性来解决GWAS疾病基因座的假设 目标;并通过在交互式基因组浏览器中提供结果。目的2是通过作图确定调控基因座 活跃转录基因，开放染色质区域，以及关键的染色质构象结构域， 在四种鳍鱼中标准化的发育阶段和组织;并通过在UCSC中公开结果 浏览器和ZFIN。目的3是通过建立GWAS基因座，研究GWAS基因座在骨密度（BMD）疾病中的作用。 和表征人GWAS BMD基因座的斑马鱼直系同源物的功能丧失等位基因的表型， 通过检测这些基因座的增强子活性预期成果包括用于排除潜在目标的资源 GWAS基因座;人类硬骨鱼直系同源基因表达和表观遗传标志的全基因组相关性 GWAS基因座，以及更好地理解GWAS基因座改变人类骨矿物质的机制 密度的意义：这些研究提供了资源，以改善硬骨鱼模型，了解的作用， 人类非编码功能元件，包括GWAS基因座，在健康和疾病。

PROJECT SUMMARY/ABSTRACT: Genome-wide association studies (GWAS) have detected thousands of single nucleotide polymorphisms (SNPs) at hundreds of loci associated with numerous human diseases. Understanding GWAS loci can help decipher mechanisms of complex diseases and personalize therapies across many NIH institutes. The problem is that GWAS disease loci occupy blocks of linkage disequilibrium containing several or no genes, are merely linked to the as yet unknown causative agents, and usually reside in difficult-to- study noncoding regions that are likely regulatory and often act at long range. The usual hypothesis is that the gene nearest the lead SNP is causative, but this idea must be tested. A barrier to progress is that, because cis-regulatory modules can act at a distance, their targets and modes of action are usually unclear. Comparative medicine can help provide a way forward. Teleost fish, including zebrafish, share physiology, behavior, development, and orthologous genetic pathways with humans, but possess evolved genomic differences we can exploit to understand GWAS locus functions. Prior support uncovered the Teleost Genome Duplication (TGD) and showed that spotted gar represents the most recently diverging lineage before the TGD with a genome that bridges teleost medical models to human biology. These features help associate GWAS loci with target genes because the two teleost duplicates often retained different ancestral tissue-specific regulatory elements or protein domains (subfunctionalization); duplicated genes resolved to single copy differently in different teleosts; and teleosts have many chromosome rearrangements compared to human. We exploit these features to distinguish targets from bystander genes at GWAS loci. Our broad goal is to develop resources to help annotate functions of non-coding genetic elements, including GWAS loci, for human disease. Aim1 is to develop a resource that connects teleost genomes to human biology by mapping human conserved non-coding elements (CNEs) to teleost genomes; by analyzing conserved syntenies to address hypotheses for GWAS disease locus targets; and by providing results in an interactive genome browser. Aim2 is to identify regulatory loci by mapping actively transcribing genes, regions of open chromatin, and chromatin conformation domains in key developmental stages and tissues standardized across four ray-fin fish; and by making results public in a UCSC browser and ZFIN. Aim3 is to find functions of GWAS loci for bone mineral density (BMD) diseases by making and characterizing phenotypes of loss-of-function alleles of zebrafish orthologs of human GWAS BMD loci and by testing these loci for enhancer activity. Expected outcomes include a resource for ruling out potential targets of GWAS loci; a genome-wide correlation of expression and epigenetic landmarks for teleost orthologs of human GWAS loci, and a better understanding of the mechanisms by which GWAS loci alter human bone mineral density. Significance: these studies provide resources to improve teleost models for understanding the roles of human non-coding functional elements, including GWAS loci, in health and disease.