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Predicting and controlling polygenic health traits using probabilistic models and evolution-inspired gene editing

Award Number: DP5OD029506
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Predicting and controlling polygenic health traits using probabilistic models and evolution-inspired gene editing - Predicting and controlling polygenic health traits using probabilistic models and evolution-inspired gene editing PROJECT SUMMARY: New mutations are a source of adaptive evolutionary novelty but can also cause genetic diseases and cancer. While we can now correct detrimental mutations using CRISPR/Cas9 technologies, DNA modifications can have unintended consequences through seemingly unpredictable epistatic and environmental interactions, as could well be the case for the presumed HIV-resistance mutations in CCR5 recently CRISPRed into humans. In higher eukaryotes, fitness or health traits such as adaptability or disease susceptibility appear to be controlled by numerous mutations acting in concert – they are so-called polygenic or complex traits. Such mutations might even manifest detrimental in some environments while beneficial in others, therefore also called antagonistic pleiotropic. The main goal of the proposed work is to use the versatile model plant Arabidopsis thaliana to enhance the predictability and control of the polygenic and antagonistic fitness effects of mutations. Results from this project will provide universal principles to deepen our understanding of complex human genetic disease and inform the safe correction or avoidance of harmful mutations in the future. Specifically, I will pursue the following aims: 1) predicting polygenic fitness effects across environments, 2) improving fitness by controlling deleterious and beneficial mutations using multiplexed genome editing and mutator alleles. Arabidopsis thaliana is an ideal model to tease apart the fitness effects of mutations in complex environments due to its high malleability to engineered mutations, and its extensive community and resources. The 1001 Arabidopsis Genome Project and a genome-wide Knock-Out (KO) collection allow for quantifying fitness of thousands of publicly available natural and artificial mutations across environments. Building a global network of Arabidopsis researchers, we have started an experiment with the same natural strains in 45 locations, which I will use to quantify environment-associated mutation effects. Integrating this with information of relevant KO lines, I will build on my previous predictive models to understand the effects of mutations on fitness across environments, and the features that make them deleterious. Such a deep understanding of mutation effects will ultimately allow us to alter fitness in predictable ways. I will test this in two ways: First, using multiplexed CRISPR base-edits, I will substitute detrimental for beneficial mutations. Second, to study how accumulating mutations impact fitness and to learn how to correct this, I will engineer plants with known mutator and anti-mutator alleles. These alleles, associated with the DNA repair machinery and cancer susceptibility, can increase or decrease the mutation rate in A. thaliana, helping us explore mutation accumulations up to lethal levels in many mammals. Overall, my research will provide fundamental insights into the genetic control of complex fitness traits, ultimately paving the way to improving personalized genomic disease risk predictions and safely probing the limits of poly-gene therapies.


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 = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	002	5	2/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$570,786
2025	2023	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	001	4	2/21/2025	NON-COMPETING CONTINUATION	-$403,825
2025	2022	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	3	2/21/2025	NON-COMPETING CONTINUATION	-$166,961
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $401,250 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Trans-NIH Research Support	001	5	9/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$401,250
2024	2023	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	4	9/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,250

Issue Date FY: 2023 ( Subtotal = $403,825 )
2023	2023	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	4	8/23/2023	NON-COMPETING CONTINUATION	$403,825
														Subtotal = $403,825

Issue Date FY: 2022 ( Subtotal = $403,825 )
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	3	8/30/2022	NON-COMPETING CONTINUATION	$403,825
														Subtotal = $403,825

Issue Date FY: 2021 ( Subtotal = $403,825 )
2021	2021	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	001	2	8/30/2021	NON-COMPETING CONTINUATION	$403,825
2021	2020	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	1	12/11/2020	NEW	$0
														Subtotal = $403,825

Issue Date FY: 2020 ( Subtotal = $403,825 )
2020	2020	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Trans-NIH Research Support	000	1	9/10/2020	NEW	$403,825
														Subtotal = $403,825

Grand Total All Awards = $2,016,550

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Predicting and controlling polygenic health traits using probabilistic models and evolution-inspired gene editing

Award Number: DP5OD029506

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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