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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：
10473897
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/10473897
关键词：
3-Dimensional Address Adult Affect Alleles Binding Proteins Cardiac Cardiac Myocytes Catalogs Cell Line Cells Chromatin Loop Clone Cells 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 Human Human Development Human Genetics Image Knowledge Link Mass Spectrum Analysis Measures Molecular Morphology Mosaicism 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 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/文摘