Developmental GTEx Laboratory, Data Analysis and Coordination Center

摘要 了解控制细胞身份和功能的转录程序是许多杰出的 生物学和生物医学中的问题。大多数与常见疾病和特征相关的变异存在于非 基因组的编码和调控区域，为了解释它们的功能，我们需要识别它们影响的基因 以及这些基因如何在个体体内组织的不同细胞中表达，并量化它们的表达方式 因人而异。在人类发展过程中，这些机制是如何被调控的仍然很差。 到目前为止，大多数研究都依赖于人类细胞系或模式生物作为替代品。GTEx做到了 而不是人类出生后发育阶段的组织。调控元件和基因网络是 高度特异的细胞类型，可能只在精确的发育阶段活跃，在此期间它们可能 也会增加疾病的易感性。因此，迫切需要测量转录和 人类发育过程中组织和细胞类型的调控格局。 我们将作为开发GTEx(DGTEx)资源创建的LDACC。(1)我们会 与BPC合作，建立一个生物库，其中包括120名人类死后捐赠者每人的30个组织， 同意广泛的研究用途和数据共享。(2)我们将选出4个常见的重要组织 疾病，在发育过程中有组织重塑--大脑、肠道、肺和心脏。我们将为您介绍 这些组织进行了多种单细胞检测，包括SnRNA-seq、多组RNA/atac和空间分析。 转录学，以创建深入的分子图谱，以确定变异的特征。(3)我们将执行基线 所有样本的基因组序列和批量转录组的分子图谱，并将资源与 GTEX。我们将使用这些收集的数据来识别e/sQTL；创建跨元素-基因关系的图谱 组织；组织内和跨年龄范围的分化等级图；指定细胞类型 细胞、细胞程序和组织之间的细胞和空间关系 功能。 该项目汇集了一支在人类遗传学、生产科学(GTEx， 编码)、计算生物学、单细胞技术和常见疾病遗传学。我们将创建一个数据 以及为科学界提供的生物样品资源，这将为了解细胞和组织的研究奠定基础 人类发育、基因组调控和常见疾病变异解释过程中的变化。

ABSTRACT Understanding the transcriptional programs governing cell identity and function is key to many outstanding questions in biology and biomedicine. Most variants associated with common diseases and traits lie in non- coding, regulatory regions of the genome, and to interpret their function, we need to identify the genes they affect and how those are expressed in the different cells of a tissue within individuals, and quantify how their expression varies across individuals. How these mechanisms are regulated during human development remains poorly understood, and most studies to date have relied on human cell lines or model organisms as proxies. GTEx did not profile tissues from postnatal stages of human development. Regulatory elements and gene networks are highly cell type–specific, and may only be active during precise developmental stages, during which they may also contribute to disease susceptibility. Thus, there is a critical need for measuring the transcriptional and regulatory landscape of tissues and cell types during human development. We will serve as the LDACC for the creation of the developmental GTEx (dGTEx) resource. (1) We will work with the BPC to establish a biobank of 30 tissues from each of 120 human postnatal postmortem donors, consented for broad research use and data sharing. (2) We will select 4 tissues of importance for common diseases, and in which there is tissue remodelling during development - brain, gut, lung and heart. We will profile these tissues with multiple single cell assays including snRNA-seq, multiomic RNA/ATAC, and spatial transcriptomics to create deep molecular maps for variant characterization. (3) We will perform baseline molecular profiling of genome sequence and bulk transcriptome for all samples, and integrate the resource with GTEx. We will use these collective data to identify e/sQTLs; create maps of element-gene relationships across tissues; chart differentiation hierarchies within tissues and across age ranges; nominate cell types in which a set of variants manifest; and map cellular and spatial relationships among cells, cellular programs, and tissue features. This project brings together a team with expertise in human genetics, production science (GTEx, ENCODE), computational biology, single cell technologies, and common disease genetics. We will create a data and biospecimen resource for the scientific community that will underpin studies to understand cellular and tissue changes during human development, genome regulation, and common disease variant interpretation.