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

项目总结/摘要 基因组的三维（3D）构象在调节基因表达中起着不可或缺的作用。 基因组折叠成兆碱基长的拓扑关联结构域（TADs），这些区域可以自我相互作用， 很少接触域外区域。TADs通过限制以下物质的相互作用来调节基因调控： 调节元件，如增强子，到它们的靶基因。绝缘边界的破坏 大规模罕见变异引起的TADs可导致严重的发育表型。然而， 在不同的基因组中，常见表型的遗传基础和3D基因组结构之间存在差异， 细胞类型不被理解。常见的小规模（例如SNP）变异可能会改变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 相关性研究（GWAS）变得更加普遍，疾病相关性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 在不同的细胞类型的背景下，量化它们的进化约束和共同的贡献 表型我假设，在边界的遗传变异有助于更多的负担， 常见病多于变异。此外，我推测，细胞类型特异性转录因子的破坏， 边界导致相关细胞类型的疾病。一、37种跨细胞型和4种跨物种3D 将整合基因组图谱以测量3D元件功能保守性。比较不同的3D 跨细胞类型和物种的上下文（即TADs和边界）将为整合3D 基因组图谱来解释疾病相关的变异。二、3D之间的关系 28个常见复杂性状的遗传结构和遗传结构将通过分区映射 遗传力分析这将揭示，如果不同的边界有更大的遗传贡献， 疾病比TADs第三，将评估细胞类型特异性3D元件的细胞类型特异性功能性差异。 通过对现有功能注释和生物库数据的丰富分析，这项工作将使 细胞类型特异性和3D结构感知的变体解释，通过量化细胞类型之间的关系， 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，将提供与专家进行跨学科合作的机会 并掌握了人类遗传学的多种技术，使我成为一名医生兼科学家 遗传学的领导者。

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.