Genome-wide discovery of allele-specific gene expression and chromatin states

描述（由申请人提供）：高通量测序（如“ChIP-seq”和“RNA-seq”）的应用最近已经改变了我们研究蛋白质-DNA相互作用、染色质修饰和基因表达的能力，这是通过它们在全基因组范围内精确定量这些现象实现的。虽然这些技术的应用已经产生了许多突破性的发现，但很少有人认为基因组实际上是由两个拷贝代表的，这两个拷贝在功能上往往是不同的。经受ChIP-seq或RNA-seq的生物样品中的杂合多态性（如SNP）提供了通过区分映射到一个等位基因相对于另一个等位基因的序列读段来量化等位基因特异性事件的手段，因为序列读段中等位基因的偏倚表示可以揭示受顺式作用多态性影响的位点/基因。我们的目标是创建工具，使社区能够更容易地分析他们的等位基因特异性信号数据;将这些工具应用于数十个现有数据集;并生成新的ChIP-seq和RNA-seq数据，这些数据非常适合全面表征等位基因特异性偏倚。 公共卫生相关性：阐明遗传多态性的功能后果对于理解人类疾病的遗传风险因素至关重要。这个项目将推进我们的知识顺式作用多态性，这是一个广泛的来源表型多样性，影响mRNA丰度。此外，我们的方法在人类样本中的应用有可能揭示由全基因组疾病关联研究揭示的显著关联背后的精确因果多态性，这对于例如进行靶向随访研究和功能测定以更好地理解每个多态性及其对基因表达和疾病的影响是重要的。

DESCRIPTION (provided by applicant): Applications of high-throughput sequencing (such as "ChIP-seq" and "RNA-seq") have recently transformed our ability to study protein-DNA interactions, chromatin modifications, and gene expression through their precise quantification of these phenomena genome-wide. Although numerous groundbreaking discoveries have emerged from the application of these techniques, few efforts have considered that the genome is in fact represented by two copies that often differ in functionally important ways. Heterozygous polymorphisms (such as SNPs) in a biological sample that is subject to ChIP-seq or RNA-seq provide a means to quantify allele-specific events by discriminating sequence reads that map to one allele versus the other, since biased representation of alleles among sequence reads can reveal sites/genes that are affected by cis- acting polymorphisms. It is our objective to create tools that will allow the community to more easily analyze their data for allele-specific signals; apply these tools to dozens of existing data sets; and generate new ChIP-seq and RNA-seq data that are ideally suited for the comprehensive characterization of allele-specific biases. PUBLIC HEALTH RELEVANCE: Elucidating the functional consequences of genetic polymorphisms is crucial for understanding the genetic risk factors underlying human diseases. This project will advance our knowledge of how cis-acting polymorphisms, which are a widespread source of phenotypic diversity, affect mRNA abundances. In addition, application of our methodology in human samples has the potential to uncover the precise causal polymorphisms underlying significant associations revealed by genome-wide disease association studies, which is important e.g. for performing targeted follow-up studies and functional assays to better understand each polymorphism and its effects on both gene expression and disease.