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Using genomic perturbations to understand trait-associated human genetic variation

Award Number: R35HG011315
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/19/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Using genomic perturbations to understand trait-associated human genetic variation - PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with metabolic, cardiovascular, autoimmune and other diseases. These variants have the potential to reveal molecular mechanisms that underpin human diseases, but their interpretation is extremely challenging, because most are within non-coding genomic regions with unknown function. The long-term goal of the proposed research is to elucidate the molecular basis of complex diseases by assembling comprehensive catalogs of regulatory sequences and illuminating how non-coding genetic variants affect gene regulation. This proposal will leverage the power of high-throughput genomic perturbations and computational analyses to discover regulatory sequences, interpret non-coding genetic variants, and connect disease-associated variants to the genes they regulate. Research Focus 1 will systematically discover novel regulatory sequences using CRISPR-directed tiling deletion screens, which can discover regulatory sequences that are invisible to other approaches. These screens will be performed in primary T cells and applied to megabase-scale regions surrounding T cell differentiation genes, which are rich in uncharacterized GWAS hits. To determine how frequently GWAS hits affect novel regulatory sequences lacking canonical enhancer marks, fine-mapped GWAS variants will be intersected with regulatory sequences discovered by the screens. The function of novel regulatory sequences will be determined with deletions followed by experiments to measure 3D chromatin contacts, gene expression, and cellular proliferation. Research Focus 2 will utilize single-cell genome perturbations to connect thousands of variants associated with human diseases to the genes they regulate across multiple cell types. Sequences containing potentially causal GWAS variants will be targeted with CRISPR interference and gene expression will be measured with single-cell RNA-seq in a mixture of disease-relevant immune cells. Using the single-cell data, perturbed sequences will be connected to changes in gene expression in specific cell types. Variants predicted to regulate gene expression will be validated by modifying alleles with genome editing. The expected outcomes of this project are (i) systematic catalogs of regulatory sequences for genes involved in T cell differentiation, (ii) molecular characterization of novel unmarked regulatory sequences that contain GWAS hits and (iii) connections between sequences containing GWAS hits and genes that they regulate in specific cell types. This proposal will establish genomic perturbations as a new strategy to interpret non-coding variants, uncover important new regulatory biology, and accelerate mechanistic understanding of disease-associated variants.


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 = $570,000 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Human Genome Research	001	4	9/16/2024	NON-COMPETING CONTINUATION	$11,400
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Human Genome Research	000	4	9/9/2024	NON-COMPETING CONTINUATION	$558,600
														Subtotal = $570,000

Issue Date FY: 2023 ( Subtotal = $570,000 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Human Genome Research	000	3	6/6/2023	NON-COMPETING CONTINUATION	$570,000
														Subtotal = $570,000

Issue Date FY: 2022 ( Subtotal = $570,000 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Human Genome Research	000	2	6/1/2022	NON-COMPETING CONTINUATION	$570,000
														Subtotal = $570,000

Issue Date FY: 2021 ( Subtotal = $570,000 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Human Genome Research	000	1	8/19/2021	NEW	$570,000
														Subtotal = $570,000

Grand Total All Awards = $2,280,000

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Using genomic perturbations to understand trait-associated human genetic variation

Award Number: R35HG011315

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/19/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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