Quantifying the relationship between 3D genome structure and the genetic architecture of common complex disease

量化 3D 基因组结构与常见复杂疾病遗传结构之间的关系

基本信息

批准号：
10417135
负责人：
Evonne McArthur
金额：
$ 4.75万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-05-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417135
关键词：
3-Dimensional Address Architecture Awareness Binding Sites Cells Clinical Complex Data Development Disease Electronic Health Record Elements Enhancers Gene Expression Gene Expression Regulation Genes Genetic Genetic Diseases Genetic Variation Genome Genotype Heritability Hi-C Housekeeping Gene Human Genetics Knowledge Link Maps Measures Medical Molecular Conformation Pattern Phenotype Physicians Play Positioning Attribute Quantitative Trait Loci Regulatory Element Role Scientist Single Nucleotide Polymorphism Specificity Structure Techniques Tissues Training Translating Untranslated RNA Variant Work base biobank cell type disorder risk experience genetic architecture genetic association genetic variant genome wide association study human disease interdisciplinary collaboration phenome pressure profiles in patients rare variant trait

项目摘要

PROJECT SUMMARY/ABSTRACT The three-dimensional (3D) conformation of the genome plays an integral role in regulating gene expression. The genome folds into megabase-long topologically associating domains (TADs), regions that self-interact, but rarely contact regions outside the domain. TADs modulate gene regulation by restricting interactions of regulatory elements, like enhancers, to their target genes. Disruption of the insulating boundaries between TADs by large-scale rare variants can cause severe developmental phenotypes. However, the relationship between the genetic basis underlying common phenotypes and 3D genome architecture across different cell-types is not understood. Common small-scale (e.g. SNP) variation may change 3D genome structure in a cell-type-specific manner, leading to changes in gene expression and disease risk. As genome-wide association studies (GWAS) become more common, cell-type-specific interpretation of disease-associated variants is essential for mechanistic understanding of disease. This work will examine variation in different 3D contexts across diverse cell-types, quantifying their evolutionary constraint and contribution to common phenotypes. I hypothesize that genetic variation at TAD boundaries contributes more to the burden of common disease than variation in TADs. Furthermore, I hypothesize that disruption of cell-type-specific TAD boundaries contributes to diseases in relevant cell-types. First, 37 cross-cell-type and four cross-species 3D genome maps will be integrated to measure 3D element functional conservation. Comparing different 3D contexts (i.e. TADs and boundaries) across cell-types and species will provide a framework for integrating 3D genome maps into interpretation of disease-associated variants. Second, the relationship between 3D architecture and the genetic architecture of 28 common complex traits will be mapped through partitioned heritability analysis. This will reveal if TAD boundaries have a greater genetic contribution to different common diseases than TADs. Third, cell-type-specific 3D elements will be assessed for cell-type-specific functional effects through enrichment analyses of existing functional annotations and biobank data. This work will enable cell-type-specific and 3D structural-aware variant interpretation by quantifying the relationship between the genetic architecture of disease and 3D genome structure. Furthermore, this project, when combined with rigorous clinical and scientific training, will provide opportunity for interdisciplinary collaboration with experts and mastery of multiple techniques in human genetics, well-equipping me to become a physician-scientist leader in genetics.

项目概要/摘要基因组的三维 (3D) 构象在调节基因表达中发挥着不可或缺的作用。基因组折叠成兆碱基长的拓扑关联域（TAD），这是自我相互作用的区域，但是很少接触域外的区域。 TAD 通过限制相互作用来调节基因调控调控元件，如增强子，针对其靶基因。破坏之间的绝缘边界大规模罕见变异引起的 TAD 可能导致严重的发育表型。然而，这种关系共同表型的遗传基础和跨不同基因组的 3D 基因组结构之间细胞类型尚不清楚。常见的小规模（例如 SNP）变异可能会改变基因组中的 3D 基因组结构。细胞类型特异性的方式，导致基因表达和疾病风险的变化。作为全基因组关联研究（GWAS）变得更加普遍，对疾病相关的细胞类型特异性解释变异对于理解疾病的机制至关重要。这项工作将检查不同 3D 中的变化跨不同细胞类型的背景，量化它们的进化限制和对共同的贡献表型。我假设 TAD 边界处的遗传变异对常见疾病多于 TAD 变异。此外，我假设细胞类型特异性 TAD 的破坏边界会导致相关细胞类型的疾病。一、37个跨细胞类型和4个跨物种3D 基因组图谱将被整合以测量 3D 元素功能保护。比较不同的 3D 跨细胞类型和物种的上下文（即 TAD 和边界）将为集成 3D 提供框架基因组图谱可解释疾病相关变异。二、3D之间的关系 28个常见复杂性状的结构和遗传结构将通过分区进行映射遗传力分析。这将揭示 TAD 边界是否对不同的共同点有更大的遗传贡献疾病比 TAD 更严重。第三，将评估细胞类型特异性 3D 元素的细胞类型特异性功能通过对现有功能注释和生物样本库数据进行富集分析来确定效果。这项工作将使通过量化细胞类型特异性和 3D 结构感知变异解释疾病的遗传结构和 3D 基因组结构。此外，该项目与严格的临床和科学培训，将为与专家进行跨学科合作提供机会并掌握人类遗传学的多种技术，使我有能力成为一名医师科学家遗传学领域的领导者。