UM1HG011996

Multiscale Functional Characterization of Genomic Variation in Human Developmental Disorders - 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 for 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.
(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.

The University Of Texas Southwestern Medical Center

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Dallas, Texas 753907208 United States

Single Zip Code

Systematic Characterization of Genomic Variation on Genomic Function and Phenotype (UM1 Clinical Trial Not Allowed) (RFA-HG-20-043)

Amendment Since initial award the total obligations have increased 793% from $978,087 to $8,736,987.