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Multiscale functional characterization of genomic variation in human developmental disorders

人类发育障碍基因组变异的多尺度功能表征

基本信息

批准号：
10689051
负责人：
Gary Chung Hon
金额：
$ 195.93万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689051
关键词：
3-Dimensional Acceleration Address Adult Affect Alleles Binding Proteins Cardiac Cardiac Myocytes Catalogs Cell Line Cells Chromatin Loop Collaborations Communities Complex Coupling Data Data Set Defect Detection Development Disease Disease susceptibility Elderly Elements Enhancers Evaluation Foundations Future Gene Expression Gene Expression Regulation Gene Targeting Genetic Transcription Genetic Variation Genome Genome engineering Genomics Goals Heterozygote Human Human Development Human Genetics Image Knowledge Link Mass Spectrum Analysis Measures Molecular Morphology Neurons Outcome Pathway interactions Patients Phenotype Placenta Predisposition RNA Regulatory Element Repression Research Personnel Resources Risk Series Techniques Tissues Variant autism spectrum disorder cell type combinatorial congenital heart disorder data interoperability developmental disease disease phenotype experimental study functional genomics gene network genetic variant genome wide association study genomic variation high throughput analysis human disease human embryonic stem cell human model improved insight molecular phenotype mosaic multimodality novel pleiotropism predictive modeling recruit risk variant screening single cell technology single-cell RNA sequencing technological innovation tool trophoblast

项目摘要

Project Summary/Abstract Large-scale studies have identified thousands of genetic variants linked to developmental defects, together with the regulatory elements harboring these variants and the cell types in which these variants likely function. This diversity of variants, regulatory elements, and cell types indicates that multiple mechanisms contribute to developmental defects. One key challenge to our understanding of these mechanisms is that the molecular, cellular, and functional phenotypes of each variant remain largely uncharacterized. Until these critical gaps in knowledge are addressed, the underlying molecular and cellular determinants of developmental disease susceptibility will remain incomplete. To bridge these gaps, we propose to establish the “UT Southwestern Center for Regulatory Element Variation and Function”. The primary goal of this Center is to systematically catalog molecular and cellular phenotypes for disease-associated enhancers in human development, with a focus on gaining insights into mechanisms of non-canonical human genetics and gene regulation. To build a generalizable framework to understanding the impact of human genetic variation on function, we propose a high throughput perturbation platform with three primary goals: (1) Contribute to a variant/element/phenotype catalog with relevance to diseases of human development, focusing on elements genetically associated with congenital heart disease (cardiomyocytes), autism (neurons), and placental defects (trophoblasts); (2) Contribute to a variant/element/phenotype catalog for non-canonical human genetics, focusing on two understudied topics in human genetics: pleiotropic effects and non-cell autonomous effects; and (3) Contribute to a variant/element/phenotype catalog with relevance to mechanisms of gene regulation, focusing on enhancer RNAs. The Center will take advantage of recent technological innovations in genome engineering, single-cell genomics, and high content screening to enable the multiscale functional characterization of genomic variation in human developmental disorders. Several of these techniques have been pioneered by investigators contributing to this project, including: the development of novel tools for enhancer perturbation and the coupling of endogenous enhancer perturbations with a single-cell RNA-Seq readout (Mosaic-Seq). Impact and Significance: The efforts on this project will lead to a number of key outcomes and deliverables, including (1) greater understanding of the relationships between sequence variation and genome function, (2) an extensive variant/element/phenotype catalog for the community, (3) tools for generating predictive models for the community, and (4) resources to enable future functional genomics studies. Together, our multifaceted and combinatorial approaches will open new horizons to understanding the impact of regulatory variants on developmental disease phenotypes.

项目总结/摘要大规模的研究已经确定了数千种与发育缺陷有关的遗传变异，以及携带这些变体的调节元件和这些变体可能在其中发生的细胞类型功能变异体、调控元件和细胞类型的多样性表明，导致发育缺陷。对我们理解这些机制的一个关键挑战是，每种变异体的分子、细胞和功能表型仍基本上未被表征。直到这些关键的知识的空白得到解决，发育性疾病的潜在分子和细胞决定因素敏感性将保持不完整。为了弥合这些差距，我们建议建立“UT西南监管要素变化和功能中心。该中心的主要目标是系统地人类发育中疾病相关增强子的分子和细胞表型目录，专注于深入了解非经典人类遗传学和基因调控的机制。为了建立一个可推广的框架来理解人类遗传变异对功能的影响，我们提出了一个高吞吐量扰动平台，其主要目标有三个：（1）有助于与人类发育疾病相关的变异/元件/表型目录，重点是元件与先天性心脏病（心肌细胞）、自闭症（神经元）和胎盘缺陷有遗传相关性（滋养层）;（2）有助于非规范人类遗传学的变体/元件/表型目录，专注于人类遗传学中两个未充分研究的主题：多效性效应和非细胞自主效应; (3)有助于与基因调控机制相关的变体/元件/表型目录，重点是增强子RNA该中心将利用基因组工程方面的最新技术创新，单细胞基因组学和高含量筛选，以实现基因组的多尺度功能表征人类发育障碍的变异。这些技术中有几种是由调查人员开创的为该项目做出贡献，包括：开发用于增强子扰动和耦合的新工具内源性增强子扰动与单细胞RNA-Seq读数（Mosaic-Seq）。影响和意义：该项目的努力将产生一些关键成果，可交付成果，包括（1）更好地理解序列变异和基因组之间的关系功能，（2）社区的广泛变体/元件/表型目录，（3）生成社区的预测模型，和（4）资源，使未来的功能基因组学研究。我们一起努力，我们的多方面和组合的方法将打开新的视野，了解监管的影响，发育疾病表型的变异。