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Regulatory modifiers of coding variant penetrance via haplotype epistasis in human populations and diseases

Award Number: R01GM122924
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT ABSTRACT Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among individuals who carry it. We propose to study a specific type of modified penetrance caused by genetic interaction or epistasis in humans, where a regulatory variant in cis modifies the penetrance of coding variants of the target gene. We call this phenomenon haplotype epistasis. We will study this phenomenon using genetic data of the general human population and of diseases with different genetic architectures. First, we will study signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant epistatic effects. This will shed light on the modes and prevalence of haplotype epistasis, and the role of epistatic selection in shaping the spectrum of genetic variation in humans. Second, haplotype epistasis has been shown to affect genetic disease risk in some specific examples, but this mechanism is rarely considered in genetic studies that typically analyze genetic variants one-by-one. We aim to characterize haplotype epistasis as a potentially important phenomenon in rare variants contributing to autism risk, common variants predisposing to diverse traits mapped by genome-wide association studies, and germline modifiers of somatic cancer driver mutations. Furthermore, we will validate 5-10 examples of epistasis by genome editing of human cell lines, followed by cellular phenotyping. In summary, our study integrates many domains in human genetics that are usually studied in isolation. It is the first systematic characterization of haplotype epistasis and has potential to bring forward an important paradigm of epistatic functional effects of genetic 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 = $0 )
2024	2021	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	5	2/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $347,458 )
2021	2021	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	5	4/28/2021	NON-COMPETING CONTINUATION	$347,458
														Subtotal = $347,458

Issue Date FY: 2020 ( Subtotal = $373,604 )
2020	2020	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	4	4/13/2020	NON-COMPETING CONTINUATION	$373,604
														Subtotal = $373,604

Issue Date FY: 2019 ( Subtotal = $369,166 )
2019	2019	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	3	5/7/2019	NON-COMPETING CONTINUATION	$369,166
														Subtotal = $369,166

Issue Date FY: 2018 ( Subtotal = $326,671 )
2018	2018	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	2	4/27/2018	NON-COMPETING CONTINUATION	$326,671
														Subtotal = $326,671

Issue Date FY: 2017 ( Subtotal = $274,117 )
2017	2017	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Biomedical Research and Research Training	000	1	4/28/2017	NEW	$274,117
														Subtotal = $274,117

Grand Total All Awards = $1,691,016

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Regulatory modifiers of coding variant penetrance via haplotype epistasis in human populations and diseases

Award Number: R01GM122924

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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