Investigating the role of transcription factors in the context variability of genetic variant effects

项目摘要 基因型组织表达（GTEx）联盟已经确定了数千个表达定量 在人类群体中影响多个组织中基因表达的性状基因座（eQTL）。这些监管 变异体富含顺式调控元件，并与GWAS位点共定位，这意味着许多eQTL作用于 通过非编码机制影响人类表型并可能导致疾病。目前的研究工作 表明非编码eQTL对基因表达的影响主要是通过改变转录因子介导的 (TF)结合亲和力长期目标：鉴于组织在疾病表型中的生物学相关性以及 环境效应对细胞状态对疾病易感性的影响，了解 eQTL对于揭示其对复杂性状和疾病的遗传贡献至关重要。中心假设： 由于TF活性水平在细胞类型和个体之间存在差异，我假设观察到的环境 许多eQTL的变异性可以通过不同的TF水平来解释。研究设计和方法：我建议使用 组织间和个体间TF活性的自然变异，以阐明eQTL的作用机制 调控变异和理解eQTL效应的背景特异性。然后我将利用这些机制， 了解GWAS效应的组织变异性和基因与环境的相互作用。为此，我将使用数据 来自GTEx联盟v8版本，其中包括838个个体的全基因组序列及其RNA- 来自49种组织的总共15，201个样品的SEQ数据。具体目标：在目标1中，我将描述组织的特征- eQTLs的变异机制及其在人类疾病中的应用，将发现上游反式作用 调节子的eQTL的子集，并提出因果机制和GWAS基因座的反式调节。目的2 侧重于eQTL个体之间的差异和eQTL效应的环境修饰因子，我将使用 通过这些分析来确定常见疾病和复杂性状的基因与环境的相互作用。我 拟议的研究将阐明特定eQTL和GWAS基因座的作用机制和反式调节因子， 它将发现影响疾病发病率的基因与环境的相互作用。它承诺了一个更深的 了解基因调控以及遗传和环境对复杂性状和疾病的影响。 奖学金培训计划：我提出的研究培训计划使我能够利用我的优势， 以前的经验，它将提高我的技能，在统计和计算基因组数据分析，以及 如研究设计、批判性思维、沟通、指导、领导力和专业发展。 环境：在我的培训计划中，我能够从多个研究社区中受益，包括我的 赞助人（Tuuli Lappalainen博士）的实验室，我的共同赞助人（Harmen Bussemaker博士）的实验室，纽约基因组 中心，哥伦比亚综合博士课程，和哥伦比亚系统生物学系。

PROJECT SUMMARY The Genotype Tissue Expression (GTEx) Consortium has identified thousands of expression quantitative trait loci (eQTLs) in the human population that affect gene expression in multiple tissues. These regulatory variants are enriched in cis-regulatory elements and co-localize with GWAS loci, implying that many eQTLs act via non-coding mechanisms to impact human phenotype and possibly cause disease. Current research efforts suggest that noncoding eQTLs’ effects on gene expression are primarily mediated by altered transcription factor (TF) binding affinity. Long-term objective: Given the biological relevance of tissue in disease phenotypes and the impact of environmental effects on cell state on disease penetrance, understanding the context variability of eQTLs is crucial for unraveling their genetic contributions to complex traits and disease. Central hypothesis: Since TF activity levels vary among cell types and between individuals, I hypothesize that the observed context variability of many eQTLs is explained by varying TF levels. Research design and methods: I propose to use the natural variation of TF activity among tissues and between individuals to elucidate mechanisms of action of eQTL regulatory variants and understand context specificity of eQTL effects. I will then exploit these mechanisms to understand tissue variability and gene-by-environment interactions of GWAS effects. To do so, I will use data from the GTEx Consortium v8 release, which includes 838 individuals’ whole genome sequences and their RNA- seq data from a total of 15,201 samples across 49 tissues. Specific aims: In Aim 1, I will characterize tissue- variable mechanisms of eQTLs and their application to human disease, which will discover upstream trans-acting regulators of a subset of eQTLs and will propose causal mechanisms and trans-regulators of GWAS loci. Aim 2 focuses on eQTL differences between individuals and environmental modifiers of eQTL effects, and I will use these analyses to identify gene-by-environment interactions of common diseases and complex traits. My proposed research will elucidate mechanisms of actions and trans-regulators of specific eQTLs and GWAS loci, and it will discover gene-by-environment interactions that affect disease penetrance. It promises a deeper understanding of gene regulation and of genetic and environmental contributions to complex traits and disease. Fellowship training plan: My proposed research training plan allows me to capitalize on my strengths and previous experiences, and it will improve my skills in statistics and computational genomic data analysis, as well as in study design, critical thinking, communication, mentorship, leadership, and professional development. Environment: During my training plan, I am able to benefit from multiple research communities, including my sponsor’s (Dr. Tuuli Lappalainen), lab, my cosponsor’s (Dr. Harmen Bussemaker) lab, the New York Genome Center, the Columbia Integrated PhD Program, and the Columbia Department of Systems Biology.