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

项目摘要/摘要 基因组的三维构象在基因表达调控中起着不可或缺的作用。 基因组折叠成百万碱基长的拓扑相关结构域(TADS)，这些区域自我作用，但 很少联系域外的区域。TADS通过限制相互作用来调节基因调控 调节元件，如增强剂，它们的目标基因。破坏两地之间的绝缘边界 由大规模罕见变异引起的TADS可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不同类型的3D基因组结构之间的关系 不了解细胞类型。常见的小规模(如SNP)变异可能改变3D基因组结构 细胞类型特有的方式，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)变得更加常见，对疾病相关的特定细胞类型的解释 变异体对于机械地理解疾病是必不可少的。这项工作将检查不同3D中的变化 不同细胞类型的背景，量化它们的进化限制和对共同 表型。我假设TAD边界上的遗传变异更多地造成了 常见疾病多于TADS的变异。此外，我假设特定细胞类型的TAD的中断 边界导致相关细胞类型的疾病。第一，37个跨细胞类型和4个跨物种3D 基因组图谱将被整合，以衡量3D元件的功能保守。比较不同的3D 跨细胞类型和物种的环境(即TADS和边界)将提供集成3D的框架 基因组映射到对疾病相关变异的解释。第二，3D与互联网的关系 28个常见复杂性状的结构和遗传结构将通过分区映射 遗传力分析。这将揭示TAD界限是否对不同的共同基因有更大的贡献 疾病多于TADS。第三，将评估特定于细胞类型的3D元素的特定于细胞类型的功能 通过丰富分析现有的功能注释和生物库数据而产生的效果。这项工作将使 通过量化细胞类型特定的和3D结构感知的变体解释 疾病的遗传结构和三维基因组结构。此外，当这个项目与 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，使我有能力成为一名内科科学家 遗传学领域的领军人物。

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.