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Exploration of cis-regulatory diversity underlying phenotypic innovation

Award Number: K99GM144742
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Exploration of cis-regulatory diversity underlying phenotypic innovation - Project Summary The falling costs of DNA sequencing has resulted in a proliferation of genome-wide association studies (GWAS) seeking to identify causal variants associated with disease and other important phenotypes. However, a striking 93% of phenotype-associated variants fall within non-coding regions, often several hundreds of kilobases away from the nearest gene. Recent studies have demonstrated that such variants are enriched within cis-regulatory elements (CREs) and can affect transcriptional outcomes. CREs are composed of clusters of 4-30 bp DNA motifs recognized by sequence-specific transcription factors (TFs) that cooperatively establish patterns of transcription in a development and cell type-specific manner. However, it remains unclear how genetic variants within CREs mechanistically perturb patterns of transcription and contribute towards phenotypic diversity at the scale of individual cells, tissues and whole organisms. The aim of this proposal is to determine the molecular relationships among genetic variants, CREs, and gene transcription across diverse cell types and genetic backgrounds, and their concerted effects on cellular and organismal phenotypes. Zea mays (maize) is characterized by extensive intraspecies phenotypic and genetic variation comparable to the levels observed among primates. The genetic framework of this proposal, the 282 maize diversity panel, was specifically constructed from geographically dispersed individuals to represent the full spectrum of extant variation within the species. The rate of linkage-disequilibrium decay in the 282 maize diversity panel is 10-40X that of human and mouse genomes, affording significantly smaller population sizes with equivalent resolution. The rationale for this study is that the abundance of genetic variation, genomic resources, reduced population size requirements and recent expansion of reference-quality genomes (~35) present an ideal model to investigate the mechanistic basis of phenotypic diversity stemming from regulatory variation. The proposed research is innovative in that cutting edge genomic approaches, including scATAC-seq and snRNA-seq, will be utilized in parallel with microscopy-based imaging across 200 maize genotypes to test the central hypothesis that CRE variation underlies distinct spatiotemporal patterns of gene transcription that collectively manifest in phenotypic diversity at cellular and organismal levels. Realization of the proposed aims will usher a new understanding of the determinants of cell type-specificity and the phenotypic consequences of evolving gene regulatory landscapes. Successful completion the proposed work will lay the foundation for future interrogation of the mechanistic role of genetic variants towards human disease, relevant to the missions of the NIH. This application was specifically designed to enhance the applicants career development through associated training activities in mentorship, grant writing, and scientific communication. Accomplishment of the career training plan will facilitate the successful transition of the applicant from a post-doctoral position to a faculty position at a research-intensive institution.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	2	11/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $41,667 )
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	2	3/6/2023	NON-COMPETING CONTINUATION	$41,667
														Subtotal = $41,667

Issue Date FY: 2022 ( Subtotal = $100,000 )
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	1	3/1/2022	NEW	$100,000
														Subtotal = $100,000

Grand Total All Awards = $141,667

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Exploration of cis-regulatory diversity underlying phenotypic innovation

Award Number: K99GM144742

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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