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High-throughput experimental determination and computational prediction of variant effects in yeast

Award Number: R01GM102308
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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High-throughput experimental determination and computational prediction of variant effects in yeast - Project Summary/Abstract The broad objective of the proposed research is to achieve comprehensive understanding of the effects of DNA sequence variants on complex and quantitative traits in the yeast S. cerevisiae, arguably the most powerful eukaryotic model system due to its small genome, ease of genetic manipulation, and the ability to generate very large sample sizes. Evolutionary conservation has also ensured that many yeast traits have direct parallels to biomedically important human phenotypes. We seek to comprehensively identify the DNA loci and the candidate sequence variants within them that underlie genetic variation in fitness and expression traits, experimentally engineer and test the effects of variants on a massive scale, and build rules for predicting the functional effects of variants of unknown significance. Success in answering these questions will provide critical guidance for the design of genotype-phenotype studies in humans and other organisms of medical, biological, and agricultural interest, and enable improved diagnostic accuracy based on genome sequencing of patients. Specifically, we will leverage single-cell sequencing to massively scale up genetic mapping in order to increase statistical power and resolution of rare and common variant discovery. We will generate a mapping population of millions of genetically diverse yeast by using CRISPR/Cas9 and other strain engineering tools to facilitate crossing, selection of haploids, and incorporation of DNA barcodes. The mapping population will be genotyped and phenotyped for both genome-wide transcript abundance and multiple fitness traits, to provide a much richer sampling of the regulatory and other functional effects of natural yeast genetic variants, particularly rare genetic variants. We will then employ a CRISPR/Cas9-based strategy to engineer variants in parallel on a large scale and assess their effects in yeast through phenotypic assays. This approach involves designing libraries of edit-directing plasmids that incorporate a specific variant at the target location. The phenotypic assays rely on DNA barcoding and ultra-high-throughput sequencing. We will use statistical approaches to analyze the data and control for errors and false discoveries. We also plan to validate the efficiency of the system and improve the experimental design by evaluating the effects of various parameters. Finally, we will build improved predictive models of variant effects in yeast, using large data sets generated here in conjunction with existing yeast functional information. The focus will be on predicting the effects of coding and non-coding variants on fitness traits, with machine learning and artificial intelligence models that incorporate local sequence context, eQTL effects, and variant features such as allele frequency, functional scores, and evolutionary conservation. The performance of the predictive model will be evaluated on newly engineered variants, and the models will be improved through iterative cycles of feature selection, training, and experimental testing.


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 = $320,557 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	11	6/18/2025	NON-COMPETING CONTINUATION	$320,557
2025	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	9	2/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,557

Issue Date FY: 2024 ( Subtotal = $320,557 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	10	7/31/2024	COMPETING CONTINUATION	$320,557
														Subtotal = $320,557

Issue Date FY: 2022 ( Subtotal = $297,030 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	9	8/1/2022	NON-COMPETING CONTINUATION	$29,703
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	9	4/14/2022	NON-COMPETING CONTINUATION	$267,327
														Subtotal = $297,030

Issue Date FY: 2021 ( Subtotal = $297,030 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	4/14/2021	NON-COMPETING CONTINUATION	$297,030
														Subtotal = $297,030

Issue Date FY: 2020 ( Subtotal = $293,688 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	4/9/2020	NON-COMPETING CONTINUATION	$293,688
														Subtotal = $293,688

Issue Date FY: 2019 ( Subtotal = $293,688 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	7/12/2019	COMPETING CONTINUATION	$293,688
														Subtotal = $293,688

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	9/16/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	5/15/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $292,600 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	5/14/2015	NON-COMPETING CONTINUATION	$292,600
														Subtotal = $292,600

Issue Date FY: 2014 ( Subtotal = $282,144 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	002	4	6/19/2014	NON-COMPETING CONTINUATION	$292,600
2014	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	4/1/2014	NON-COMPETING CONTINUATION	-$240,464
2014	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	4/1/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$230,008
														Subtotal = $282,144

Issue Date FY: 2013 ( Subtotal = $278,100 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	4/1/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$230,008
2013	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	2	4/1/2014	NON-COMPETING CONTINUATION	-$240,464
2013	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	5/20/2013	NON-COMPETING CONTINUATION	$288,556
														Subtotal = $278,100

Issue Date FY: 2012 ( Subtotal = $299,286 )
2012	2012	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	8/24/2012	NEW	$299,286
														Subtotal = $299,286

Grand Total All Awards = $2,974,680

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High-throughput experimental determination and computational prediction of variant effects in yeast

Award Number: R01GM102308

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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