High-resolution mapping of DNaseI hypersensitive regulatory DNA in GTEx samples

将遗传变异与基因表达和其他表型联系起来是基因组科学的一个主要目标。 基因表达模式在不同细胞和组织类型之间差异很大，在一个区域内也是如此。 组织。因此，基因变异对基因表达模式的影响预计会有很大不同。 在纸巾之间。基因类型组织表达(GTEx)正在建立资源数据库，以使 组织基因表达谱的综合分析及其与个体基因型别的关系。 大多数与人类基因表达的个体差异有关的变异位于 基因组；在这些基因中，有一部分预计会通过干扰 DNA调控区域。系统地理解遗传变异对基因表达的影响 因此，既需要全面描述调控DNA，也需要了解 各个监管区域的驱动因素在人口层面上有所不同。 在这项提议中，我们的目标是增强GTEx的核心目标--将基因与基因联系起来 表达模式--通过全面描绘高度调控的DNA，对不同的人体组织进行表达 解决，并系统地识别影响其功能的遗传变异，通过废除 调节因子结合和局部染色质结构的扰动。我们将应用高分辨率 基因组规模的DNaseI超敏部位作图，以全面描绘 GTEx项目收集的多种族人口的组织样本。我们还将应用基因组学 DNaseI在基因组规模上的足迹，并以有针对性的方式绘制转录因子在 核苷酸分辨率的调节性DNA。

Connecting genetic variation with gene expression and other phenotypes is a major goal of genomic science. Gene expression patterns vary widely among different cell and tissue types, and also regionally within a tissue. The impact of genetic variation on gene expression patterns is thus expected to differ substantially between tissues. The Genotype-Tissue Expression (GTEx) is establishing resource databases to enable comprehensive analysis of tissue gene expression profiles and their connection with individual genotypes. Most variants linked to individual variation in human gene expression lie in non-coding regions of the genome; of these, a proportion is expected to directly impact gene regulation through perturbation of regulatory DNA regions. Systematic understanding of the impact of genetic variation on gene expression will thus require both comprehensive delineation of regulatory DNA, and an understanding of the degree to which actuation of individual regulatory regions varies at the population level. In this proposal we aim to empower the central goal of GTEx -- connecting genotype to gene expression patterns -- for diverse human tissues by comprehensively delineating regulatory DNA at very high resolution, and systematically identifying genetic variants that impact its function through abrogation of regulatory factor binding and perturbation of local chromatin architecture. We will apply high-resolution genome-scale mapping of DNaseI hypersensitive sites to comprehensively delineate regulatory DNA within tissue samples from a multi-ethnic population accrued by the GTEx project. We will also apply genomic DNaseI footprinting at genome-scale and in a targeted fashion to map transcription factor occupancy within regulatory DNA at nucleotide resolution.