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Precision mapping of regulatory causal variants by expression CROPseq

Award Number: R01HG011459
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/04/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Precision mapping of regulatory causal variants by expression CROPseq - ABSTRACT Genetic differences among individuals ultimately trace to single nucleotide polymorphisms, the majority of which affect traits, including disease susceptibility, by influencing the expression of nearby genes. Over the past decade, tens of thousands of loci of this type have been mapped to what are called credible intervals, namely sets of anywhere from a handful to over one hundred polymorphisms that have similar statistical signals. The next step is to resolve the identities of the causal variant(s) within these credible intervals. Similarly, there is a parallel pressing need to validate that de novo and ultra-rare variants in the promoter of a gene thought to contribute to a congenital abnormality actually disrupt expression of the gene. This project proposes a systematic effort to fine map causal variants for hundreds of genes that influence autoimmune and other immune conditions. It utilizes a combination of genome engineering and single cell genomics, in a recently developed assay called expression CROP-seq, or eCROPseq. The idea is to knock out each of the variants in a credible interval with a pool of CRISPR-Cas9 guide RNAs, each targeting one SNP for microdeletion of mutation, and taken up by about 100 cells. The expression of the gene in those cells is then compared with the expression in all other cells that receive different guide RNAs in the same experiment. Aim 1 is to use eCROPseq to identify causal variants in up to 600 credible intervals associated with 350 immune loci, measured in both a myeloid (HL60) and lymphoid (Jurkat) cell line. Aim 2 is to perform a similar analysis of up to 500 rare variants in the promoter regions of these genes to evaluate whether new mutations can cause extreme levels of aberrant gene expression. With these results in hand, Aim 3 utilizes a more precise genome editing tool, search-and-replace CRISPR (also known as prime editing) to substitute one allele for another instead of just evaluating mutations. Then Aim 4 asks whether the effects observed in the cell lines are also seen in primary T cells from eight different people, and whether the magnitude of effect differs among people. Collectively the proposed experiments will systematically map the causal regulatory variants for hundreds of autoimmune genes, and establish a tool that should be readily adapted by even small labs to test the function of new genome-wide associations.


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: 2025 ( Subtotal = $682,310 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Human Genome Research	000	5	3/20/2025	NON-COMPETING CONTINUATION	$614,078
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Human Genome Research	001	5	4/25/2025	NON-COMPETING CONTINUATION	$68,232
														Subtotal = $682,310

Issue Date FY: 2024 ( Subtotal = $682,624 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Human Genome Research	001	4	6/6/2024	NON-COMPETING CONTINUATION	$55,725
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Human Genome Research	000	4	3/21/2024	NON-COMPETING CONTINUATION	$626,899
														Subtotal = $682,624

Issue Date FY: 2023 ( Subtotal = $696,862 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Human Genome Research	000	3	3/15/2023	NON-COMPETING CONTINUATION	$696,862
														Subtotal = $696,862

Issue Date FY: 2022 ( Subtotal = $697,161 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Human Genome Research	001	2	5/2/2022	NON-COMPETING CONTINUATION	$69,720
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Human Genome Research	000	2	1/27/2022	NON-COMPETING CONTINUATION	$627,441
														Subtotal = $697,161

Issue Date FY: 2021 ( Subtotal = $710,460 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Human Genome Research	000	1	2/4/2021	NEW	$639,414
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Human Genome Research	001	1	3/15/2021	NEW	$71,046
														Subtotal = $710,460

Grand Total All Awards = $3,469,417

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Precision mapping of regulatory causal variants by expression CROPseq

Award Number: R01HG011459

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/04/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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