Tuesday, October 21, 2025 10/21/2025

Multi-scale functional dissection and modeling of regulatory variation associated with human traits

Award Number: R01HG012872
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/16/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Multi-scale functional dissection and modeling of regulatory variation associated with human traits - Our ability to identify genetic sequence variation in humans has thus far outstripped the field’s ability to interpret these mutations. Genome-wide association studies have identified hundreds of thousands of genomic loci associated with disease risk and human phenotypic traits, yet in few instances do we know the identity of the exact causal mutation, nor the molecular mechanism behind its function. Much of this limitation is due to a large portion of this variation residing in cis-regulatory regions (CREs), where our inability to identify a variants’ regulatory impacts or target gene(s) presents a major hurdle. Better understanding of this regulatory grammar - the complex logic of how sequence content in CREs controls transcription – is a crucial next step for genomics, but requires a vast expansion of well characterized regulatory mutations. To achieve this goal, we will employ a multi-pronged approach to build a large-scale, regulatory variant functional catalog. We will focus on CREs harboring genetically fine-mapped, likely causal variants from global populations for a variety of metabolic traits and disease (Aim 1). We will first identify CRE-gene interactions using highly-sensitive and scalable endogenous CRISPR approaches. This large-scale mapping effort will inform our understanding of the CRE-gene targeting logic of regulatory grammar. We will use this data to map the transcriptional architecture of metabolic complex traits. We then propose to interrogate sequence determinants of regulatory grammar for hundreds of trait-associated CREs at their endogenous location in the genome (Aim 2). We will first develop an endogenous saturation mutagenesis system to generate hundreds of thousands of nucleotide changes in these CREs. We will then assay the regulatory architecture of these changes using multiplexed amplicon ChIP-sequencing to identify epigenetic changes, and HCR-FlowFISH to detect transcriptional changes. In addition to identifying causal variants for a variety of metabolic diseases, this proposal will generate a repertoire of 300,000+ functionally characterized regulatory variants. This variant impact catalog will serve as an ideal training set to model regulatory grammar with our powerful machine learning approaches. We will incorporate endogenous saturation mutagenesis data into our variant effect prediction models (VEPs). Importantly, such models will find utility across global populations as they will explain a universal regulatory code of the human genome and thus enable interpretation of population-specific variation. We will then deploy these VEPs to understudied variation and in understudied populations. Overall, this proposal is structured to generate a functional characterization catalog at multiple levels: first providing molecular mechanisms and gene targets for thousands of causal variants, secondly building comprehensive genomic etiological understanding for phenotypically related complex traits, and lastly providing the scale of endogenous data necessary to improve VEPs. Our approach combines our group’s unique expertise spanning functional genomics, CRISPR screens, statistical genetics, and machine learning.


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 = $757,328 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	001	3	4/28/2025	NON-COMPETING CONTINUATION	$75,733
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	3	3/14/2025	NON-COMPETING CONTINUATION	$681,595
														Subtotal = $757,328

Issue Date FY: 2024 ( Subtotal = $770,996 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	2	3/4/2024	NON-COMPETING CONTINUATION	$693,897
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	001	2	5/24/2024	NON-COMPETING CONTINUATION	$77,099
														Subtotal = $770,996

Issue Date FY: 2023 ( Subtotal = $746,416 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Human Genome Research	000	1	5/16/2023	NEW	$746,416
														Subtotal = $746,416

Grand Total All Awards = $2,274,740

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Multi-scale functional dissection and modeling of regulatory variation associated with human traits

Award Number: R01HG012872

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/16/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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