Tuesday, July 1, 2025 7/1/2025

Next generation massively multiplexed combinatorial genetic screens

Award Number: R01HG012351
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Next generation massively multiplexed combinatorial genetic screens - PROJECT SUMMARY/ABSTRACT Genes and variants often act in combination to drive cellular and organismal phenotypes. Mapping these functional interactions advances our fundamental understanding of biological systems and has broad applicability to therapeutics development. Gene-gene interactions also likely constitute a considerable component of the undiscovered genetics underlying human diseases, due to the extensive buffering encoded in genomes which makes many individual genes appear dispensable. In this regard, we and others have shown that combinatorial screens, such as those based on CRISPR-Cas systems, are powerful platforms for mapping synergistic relationships among genes and variants. However, unlike screens based on single-gene perturbations which are broadly utilized, combinatorial screens have been significantly harder to deploy. Two fundamental challenges underlying combinatorial CRISPR screens are: 1) the requirement to physically link multiple perturbagens on the same library element which, in addition to complicating library generation, prevents different classes of genome and epigenome engineering toolsets from being readily combined; and 2) analysis of the resulting combinatorial screening data is highly complex, especially in the context of multi- dimensional phenotypic assays. Furthermore, because the perturbation space scales exponentially with the number of simultaneous perturbagens, it is critical to be able to computationally infer interactions beyond those measured experimentally. To address these challenges, we propose to engineer a new screening platform, CombinX, that auto-tethers individual library elements expressed at the RNA, instead of the DNA, level to enable massively multiplexed combinatorial screens. Scalability of this platform is thus limited only by cell culture and sequencing power. We propose to develop the system for both two-way and multi-way (>2 perturbagen) combinatorial screens via application to genetic interaction mapping and cellular reprogramming respectively. Resulting screening data will be interpreted via new advanced computational methods and machine learning approaches to systematically determine genetic interactions, as well as to predict interactions well beyond those that can be covered by direct experimental screens. We anticipate this experimental and computational platform will have broad applicability in basic science and therapeutics discovery, and that it will generate widely useful reagents and data.


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 = $678,814 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	3	3/20/2025	NON-COMPETING CONTINUATION	$610,933
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	001	3	4/25/2025	NON-COMPETING CONTINUATION	$67,881
														Subtotal = $678,814

Issue Date FY: 2024 ( Subtotal = $684,387 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	2	1/19/2024	NON-COMPETING CONTINUATION	$628,518
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	001	2	8/28/2024	NON-COMPETING CONTINUATION	$55,869
														Subtotal = $684,387

Issue Date FY: 2023 ( Subtotal = $698,956 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	1	3/15/2023	NEW	$698,956
														Subtotal = $698,956

Grand Total All Awards = $2,062,157

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Next generation massively multiplexed combinatorial genetic screens

Award Number: R01HG012351

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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