Studying the function of human genetic variation in the light of 3D genome organization

摘要 在许多变异中寻找与特定疾病有关的遗传变异 全基因组关联研究(GWAS)已经由于吞吐量的增加而几次恢复活力， 分辨率和广泛可用的实验技术的数量/形式。捕获技术的研究进展 基因组区域之间特定细胞类型的物理接近也为这种搜索增加了一个新的维度 揭示了3D基因组组织在解释遗传变异在基因调控中的作用的重要性。 事实证明，这些不同技术的一些组合在确定一些原因时是有用的 变异，但在我们创建完整的基因-表型图谱的目标上仍然存在许多重大挑战 与复杂疾病的联系。我们最近的重点一直是解决当前 了解基因变异如何影响3D基因组组织，无论是否对 可用于分子表征的细胞状态/类型的基因表达。我们已经确定了一个 与读取覆盖率、特定环路的强度和/或总体相关的遗传变异的数量 大基因组区域的连通性。利用我们在计算分析方面的专业知识和新的 作为我们实验室的已建立的实验组件，我们将解决从最近的 在接下来的五年内发现。我们将首先定义和描述遗传变异的作用，我们 发现与特定染色质环和/或调控区域的整体连通性有关 特定人类免疫细胞类型中的元素。接下来，我们将执行基于长时间读取的分析并开发 伴随分析方法解决多向交互作用的等位基因特异性和连接方式 涉及监管因素。在整个项目期间，我们将继续开发计算方法 用于构象捕获数据的综合、比较和高分辨率分析。就像我们以前做过的那样， 我们的方法开发将与我们试图回答的生物学问题保持一致，但具有灵活性 以及可推广性，因为它们被其他研究人员广泛使用。

Abstract The search for causal genetic variants associated with specific diseases among many variants identified by genome-wide association studies (GWAS) has been rejuvenated several times by the increase in throughput, resolution and the number/modality of experimental techniques that are broadly available. Advances in capturing cell-type-specific physical proximity among genomic regions also added a new dimension for this search by revealing the importance of 3D genome organization in interpreting the role of genetic variants in gene regulation. A number of combinations of these different techniques have proven useful in identifying a number of causal variants but many major challenges remain in our goal towards creating complete maps of genotype-phenotype associations for complex diseases. Our recent focus has been to address an important gap in the current knowledge of how genetic variants may impact 3D genome organization with or without a measurable impact on gene expression of the cell state/type that is available for molecular characterization. We have identified a number of genetic variants that associate with read coverage, strengths of specific loops and/or overall connectivity of large genomic regions. Leveraging our expertise in computational analysis and the newly established experimental component of our lab, we will address a number of questions emerging from our recent findings within the next five years. We will first define and characterize the role of genetic variants, which we found to be associated with specific chromatin loops and/or overall connectivity of regions harboring regulatory elements in specific human immune cell types. Next, we will perform long read-based assays and develop accompanying analysis methods to resolve allele-specificity and connection modality of multi-way interactions involving regulatory elements. Throughout the project period, we will continue developing computational methods for integrative, comparative and high-resolution analysis of conformation capture data. As we have done before, our methods development will be in alignment with biological questions we are trying to answer but with flexibility and generalizability in mind for their broad utility by other researchers.