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Multiplexed Locus-Specific Hypermutation for Functional Characterization of the Coding and Noncoding Genome

Award Number: R01HG013336
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/08/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Multiplexed Locus-Specific Hypermutation for Functional Characterization of the Coding and Noncoding Genome - SUMMARY While laboratory directed evolution has become a workhorse for generating novel therapeutics and synthetic biomolecules, few tools exist for directly evolving the endogenous mammalian genome. Most tools have extremely broad or narrow targeting windows (e.g., alkylators that introduce mutations genome-wide2 or CRISPR base-editors that target narrow windows of 4-10 nts3,4). To systematically evolve entire gene regulatory networks and query gene functions with base-level resolution, we must develop targeted long-range approaches that can quickly introduce variants in gene sets and in multiple regulatory elements that contribute to gene expressions. Here, we will develop a novel platform for performing multiplexed locus-specific hypermutation within the mammalian genome called helicase-assisted continuous evolution (HACE). HACE utilizes a nick-directed helicase fused to a deaminase domain to perform continuous mutagenesis in a large (>1000nt) genomic target. This helicase-deaminase fusion can be directed to specific genomic regions of interest using a Cas9 nickase (nCas9) with loci-specific sgRNAs. We will apply HACE to functionally characterize both non-coding regulatory elements, as well as enable multiplexed probing of the MEK signaling pathway for small molecule resistance.


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 = $724,969 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	001	1	4/23/2025	NEW	$74,344
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Human Genome Research	000	1	1/8/2025	NEW	$650,625
														Subtotal = $724,969

Grand Total All Awards = $724,969

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Multiplexed Locus-Specific Hypermutation for Functional Characterization of the Coding and Noncoding Genome

Award Number: R01HG013336

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/08/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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