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

根据 3D 基因组组织研究人类遗传变异的功能

基本信息

批准号：
10624054
负责人：
Ferhat Ay
金额：
$ 72.14万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-07-31
项目状态：
未结题

项目摘要

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.

摘要在通过以下方法鉴定的许多变体中，寻找与特定疾病相关的致病遗传变体全基因组关联研究（GWAS）已经通过通量的增加而恢复了几次活力，分辨率和广泛可用的实验技术的数量/方式。捕获的进展基因组区域之间的细胞类型特异性物理接近性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方面的重要性。这些不同技术的许多组合已被证明在确定一些因果关系方面是有用的。但是在我们创建基因型-表型的完整图谱的目标中仍然存在许多重大挑战。与复杂疾病有关。我们最近的重点是解决目前的一个重要差距，遗传变异如何影响3D基因组组织的知识，可用于分子表征的细胞状态/类型的基因表达。我们已经确定了一与读段覆盖率、特定环的强度和/或总体相关的遗传变异的数量大基因组区域的连接性。利用我们在计算分析和新的我们的实验室建立的实验组成部分，我们将解决一些问题，从我们最近的未来五年内的调查结果。我们将首先定义和描述遗传变异的作用，发现与特定的染色质环和/或含有调控基因的区域的整体连接有关。特定人类免疫细胞类型的元素。接下来，我们将进行基于长读取的测定，并开发伴随的分析方法，以解决等位基因特异性和连接方式的多途径相互作用涉及监管因素。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。和普遍性，因为它们被其他研究人员广泛使用。