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Genetic and Nongenetic Variation in Complex Traits

Award Number: R35GM148344
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: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Genetic and Nongenetic Variation in Complex Traits - PROJECT SUMMARY/ABSTRACT The long-term goal of this research program is to understand the mechanistic and evolutionary causes of variation in complex traits. The primary experimental approach is to perform large-scale analyses of single-cell traits of the budding yeast, Saccharomyces cerevisiae, and follows two major lines of work. One line of work aims to understand how interaction between genes (epistasis) contributes to natural trait variation. Understanding the sources of variation in complex traits is a major goal in biomedical research because this knowledge impinges directly on the prospect of personalized medicine, for example the prediction of disease risk from an individual’s genotype. If not taken into account, epistasis can confound such predictions. Epistasis is also important because it can constrain evolutionary adaptation to follow particular paths, making adaptation more predictable. This predictability could be valuable in the treatment of diseases that have a strong evolutionary component, such as microbial infections and cancer. Although epistasis has been well studied using lab- derived mutations, as well as in some cases of viruses or microbes under strong pressures to evolve, its role in determining how traits vary in natural populations is poorly understood. Key goals of this research program are to perform experiments with dramatically increased power to detect interactions, and to expand the range of traits that are studied to include cell shape and size, which are important in many disease processes. These studies will leverage recent progress in using high-throughput, microscopy-based methods to quantify many independent cellular features, and they will create and use strains of S. cerevisiae that make searching for epistasis much more powerful. The other line of work aims to understand molecular mechanisms that allow clonal cell populations to generate heterogeneity that might be beneficial in the face of environmental uncertainty. Such heterogeneity is seen in the responses of pathogenic microbes and tumor cells to drugs, and therefore has major clinical implications, yet there is very little known about how heterogeneity is regulated and how it can be altered. Recent work has shown that clonal populations of S. cerevisiae contain fast-growing cells that are susceptible to acute stress and slow-growing cells that are tolerant of acute stress, and that these differences are mediated by variable activity of the conserved Ras/cyclic AMP/protein kinase A pathway. The role of this kinase in tuning growth rates and stress tolerances will be probed using chemical-genetic manipulation. The goal is to better understand the mechanistic basis of adaptive heterogeneity in this model system, and ultimately to advance treatment of persistent pathogens and cancers.


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: 2026 ( Subtotal = $354,465 )
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	4	1/2/2026	NON-COMPETING CONTINUATION	$354,465
														Subtotal = $354,465

Issue Date FY: 2025 ( Subtotal = $400,018 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	3	1/15/2025	NON-COMPETING CONTINUATION	$360,016
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	3	8/13/2025	NON-COMPETING CONTINUATION	$40,002
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	11/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $400,018

Issue Date FY: 2024 ( Subtotal = $395,236 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	12/8/2023	NON-COMPETING CONTINUATION	$355,712
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	2	6/21/2024	NON-COMPETING CONTINUATION	$39,524
														Subtotal = $395,236

Issue Date FY: 2023 ( Subtotal = $496,909 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	12/29/2022	NEW	$496,909
														Subtotal = $496,909

Grand Total All Awards = $1,646,628

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Genetic and Nongenetic Variation in Complex Traits

Award Number: R35GM148344

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: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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