Defining interaction quantitative trait loci (iQTLs) in the human genome

摘要 我的研究旨在了解染色质三维结构在基因调控中的作用。这 涉及研究基因、组蛋白修饰、转录因子结合、非编码 RNA、染色质相互作用和基因表达。为了将这种全基因组信息转化为 新的生物发现，我的实验室开发可扩展和可解释的计算方法，基于 统计学、图论和机器学习。我们最近的重点是解决当前 了解3D染色质结构在基因调控中的作用。也就是说，我们的目标是定义基因分型 变异会影响基因启动子的3D组织，进而影响它们的表达。为了在基因组上实现这一点-- 大规模是一个雄心勃勃的目标，因为它要求至少有基因、基因表达和 来自大量捐赠者的特定细胞类型的纯群体中的染色质相互作用图谱。 然而，我的实验室在进行这项研究方面是独一无二的，因为：i)我们参与了一项研究 在拉霍亚研究所(LJI-R24AI108564)，已经对大约100名捐赠者进行了基因分型和表达谱分析 超过15种不同的纯人类免疫细胞类型，我们可以获得相同的 染色质相互作用图谱的样本，ii)与LJI的其他小组合作，我们已经 发现了一个互作数量性状基因座(IQTL)的原型，它可以改变和重新连接 来自与哮喘易感性相关的特定基因启动子的相互作用，III)我们有 在实验设计和计算分析方面具有必要的专业知识和良好的记录 染色质构象捕捉分析。利用LJI的可用资源和我们在 我们将围绕iQTL这一新颖的概念建立一个独特的研究计划。新兴的三人组 我们计划在未来五年内解决的主要问题是：Q1)我们如何定义特定类型的细胞 常见基因变异的iQTL？Q2)iQTL和GWASSNP之间的重叠程度有多大？第三季度) 我们能为染色质相互作用和iQTL的细胞类型特异性建立预测模型吗？虽然我们 建议仅在两个丰富、易于访问且与疾病高度相关的免疫细胞中定义iQTL 在其他类型的细胞中，iQTL的概念在与遗传性疾病有关的其他细胞类型中同样重要 组件。因此，这项工作开发的概念验证无疑将在 研究疾病易感性变异，特别是非编码SNPs以前未被表征的作用， 来自全基因组关联研究(GWAS)中的基因调控。

Abstract My research aims to understand the role of three-dimensional (3D) chromatin structure in gene regulation. This involves studying associations among genotype, histone modifications, transcription factor binding, non-coding RNAs, chromatin interactions and gene expression. In order to transform this genome-wide information into new biological discoveries, my laboratory develops scalable and interpretable computational methods based on statistics, graph theory and machine learning. Our recent focus is to address an important gap in the current knowledge of the role of 3D chromatin structure in gene regulation. That is, we aim to define how genotypic variation affects 3D organization of gene promoters, and in turn, their expression. To achieve this at a genome- wide scale is an ambitious goal, because it requires having at a minimum, genotype, gene expression and chromatin interaction profiles in pure populations of specific cell types from a large number of donors. However, my laboratory is uniquely positioned to perform this research because: i) we are involved in a study at the La Jolla Institute (LJI-R24AI108564) that has already genotyped ~100 donors and expression-profiled more than 15 different pure populations of human immune cell types, and we have access to the same samples for chromatin interaction mapping, ii) in collaboration with other groups at LJI, we have already discovered a prototypical example of an interaction quantitative trait locus (iQTL) that alters and rewires interactions from the promoter of a specific gene that is associated with asthma susceptibility, iii) we have the necessary expertise and proven track record in experimental design and computational analyses of various chromatin conformation capture assays. Leveraging the resources available at LJI and our expertise in the field, we will build a unique research program around the novel concept of iQTLs. The emerging set of three main questions we propose to address within the next five years are: Q1) How do we define cell-type-specific iQTLs for common genetic variants? Q2) What is the extent of overlap between iQTLs and GWAS SNPs? Q3) Can we build predictive models for the cell-type specificity of chromatin interactions and iQTLs? Although we propose to define iQTLs only in two abundant, easily accessible, and highly disease-relevant immune cell types, the concept of iQTLs is equally important in other cell types implicated in diseases with a genetic component. Hence, the proof-of-concept developed by this work, without a doubt, will open up a new field in studying a previously uncharacterized role for disease-susceptibility variants, specifically non-coding SNPs, from genome-wide association studies (GWAS) in gene regulation.