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Investigating the co-transcriptional impact of genetic variation on gene regulation and disease

研究遗传变异对基因调控和疾病的共转录影响

基本信息

批准号：
9918917
负责人：
Yang Li
金额：
$ 46.98万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918917
关键词：
ATAC-seq Affect Atrial Fibrillation Automobile Driving Belief Cardiac Cardiac Myocytes Cells ChIP-seq Collaborations Complex Complex Genetic Trait DNA Polymerase II DNA Sequence Data Disease Enhancers Etiology Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype-Tissue Expression Project Goals Grant Heart Human Genome Individual International Introns Link Maps Measures Messenger RNA Methods Molecular Names Phenotype Play Polyadenylation Promoter Regions Protein Isoforms Quantitative Trait Loci RNA RNA Splicing Regulation Regulator Genes Role Series Signal Transduction Spliced Genes Testing Transcript Transcription Elongation Transcription Initiation Transcriptional Regulation Untranslated RNA Variant Work cell type computer studies epigenome genetic element genetic variant genome wide association study induced pluripotent stem cell insight lymphoblastoid cell line mRNA Expression novel promoter trait transcriptome sequencing

项目摘要

Abstract Regulatory variation plays a central role in the genetics of complex traits; however, it remains challenging to determine which genes and regulatory mechanisms are affected. While large international collaborations have prioritized understanding how enhancer and promoter regions control gene expression, there remains a gap in our understanding of how genetic elements outside enhancers and promoters impact gene regulation. We propose to use a panel of 70 unrelated HapMap Yoruba lymphoblastoid cell lines (LCLs) to study the mechanisms by which genetic variation impact gene regulation independent of enhancers and promoters. We will further use the iPSCs (induced pluripotent stem cells) and derived cardiomyocytes that we have recently established from these 70 lines to study the effects of the same variants in multiple different cell-types. Recently, we found a class of expression quantitative trait loci (QTLs) variants that affect gene expression as measured by RNA-seq, but that do not show any signal of affecting enhancer or promoter function. We named these variants post-transcription initiation expression QTLs (piQTLs), reflecting our belief that piQTLs function independently of enhancers and promoters. Our data suggest that piQTLs may contribute up to 1/3 of all eQTLs, implying that they explain a considerable fraction of the genetic effects on gene expression levels. Our data also imply that the vast majority of genetic variants that affect RNA splicing (sQTLs) function independently of enhancers and promoters. Because sQTLs are a major link between genetic variation and complex traits, we propose that genetic variants outside enhancers and promoters may contribute substantially to complex traits and disease. In the project, we propose four distinct co-transcriptional mechanisms that may drive piQTLs and/or sQTLs, and we propose a series of analyses to quantify the relative contributions of these mechanisms. We will evaluate the role of each of these proposed mechanisms in LCLs, iPSCs and cardiomyocytes. We will use genome-wide association study (GWAS) data to quantify the contribution of these mechanisms to complex traits and disease. We will focus on cardiac traits for which our data in cardiomyocytes can help us tease putative causal molecular mechanisms apart. At the conclusion of this project we will have thoroughly characterized a class of variants that contribute to the genetic of complex traits independently of enhancers and promoters.

抽象的调控变异在复杂性状的遗传学中发挥着核心作用。然而，它仍然确定哪些基因和调控机制受到影响具有挑战性。虽然大国际合作优先考虑增强子和启动子区域如何尽管我们对外部遗传元件如何控制基因表达的理解仍然存在差距增强子和启动子影响基因调控。我们建议使用 70 个不相关的 HapMap 组成的面板约鲁巴淋巴母细胞系 (LCL) 用于研究遗传变异影响基因的机制调节独立于增强子和启动子。我们将进一步使用 iPSC（诱导多能干细胞）我们最近从这 70 个细胞系中建立了干细胞）和衍生心肌细胞来研究相同变体对多种不同细胞类型的影响。最近，我们发现了一类影响基因表达的表达数量性状位点（QTL）变异：通过 RNA-seq 测量，但没有显示任何影响增强子或启动子功能的信号。我们命名为这些变体转录后起始表达QTL（piQTL），反映了我们的信念：piQTL 功能独立于增强子和启动子。我们的数据表明 piQTL 可能贡献高达 1/3 所有 eQTL，这意味着它们解释了基因表达水平的遗传效应的相当一部分。我们的数据还表明，影响 RNA 剪接 (sQTL) 功能的绝大多数遗传变异独立于增强子和启动子。因为 sQTL 是遗传变异和复杂的性状，我们认为增强子和启动子之外的遗传变异可能会做出重大贡献复杂的特征和疾病。在该项目中，我们提出了四种可能驱动 piQTL 和/或 sQTL 的不同共转录机制，我们提出了一系列分析来量化这些机制的相对贡献。我们将评估每个提出的机制在 LCL、iPSC 和心肌细胞中的作用。我们将使用全基因组关联研究（GWAS）数据来量化这些机制对复杂的贡献 traits and disease.我们将重点关注心脏特征，我们的心肌细胞数据可以帮助我们梳理这些特征假定的因果分子机制分开。在这个项目结束时，我们将彻底表征一类有助于独立于增强子和启动子的复杂性状的遗传。