Thursday, July 3, 2025 7/3/2025

Genetic and biophysical causes of historical protein evolution

Award Number: R35GM145336
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Genetic and biophysical causes of historical protein evolution - My lab develops and applies new approaches at the interface of molecular evolution and protein biochemistry . We have played a lead role in developing ancestral protein reconstruction (APR) with molecular experiments as a powerful strategy to decisively identify the genetic, biophysical, and evolutionary mechanisms by which extant proteins evolved new functions. We recently expanded this approach by conducting the first studies to use deep mutational scanning of massive protein libraries to characterize the distribution of functions in the sequence space around ancestral proteins; this allows us to compare the trajectories taken during history to the vast number of alternative paths that could have been taken, thus providing insight into the roles of functional optimization, neutral chance, epistasis, and historical contingency in shaping the trajectories and outcomes of protein evolution. In the next 5 years, we will further develop these approaches and apply them to two major problem areas: 1) Evolution of complex protein features. Many proteins assemble into specific multimeric complexes and are functionally regulated by binding to allosteric effectors. These features usually many interacting residues, so it has been difficult to identify the evolutionary genetic and biochemical mechanisms by which they originate during evolution. We will use APR and vertebrate hemoglobin as an ideal model system to dissect the particular historical mutations and consequent changes in physical properties that cause this essential protein to acquire multimerization and allostery from a simpler precursor. 2) Comprehensive assessment of the functional, fitness, and epistatic effects of substitutions during long-term protein evolution. Targeted experiments have shown that mutations often epistatically modify the effects of other mutations in the same protein; theory and case studies suggest these dependencies can make evolutionary paths and outcomes contingent on chance events. There have been no comprehensive studies, however, to characterize the extent of epistasis among the full set of substitutions that occurred during history, their effects on evolutionary processes, or the temporal dynamics by which these effects emerge. We will use high-throughput protein library assays on ancestral proteins to measure the functional and fitness effects and epistatic interactions of all substitution that occurred across long, well-resolved historical trajectories, determine how shifts in these effects over time affected evolutionary processes, and analyze how underlying biophysical mechanisms mediated these effects. As in our past work, we expect these new strategies to generate strongly supported new knowledge concerning the mechanisms and forces that drive protein evolution, and that our approaches will be adopted by other groups to deepen our evolutionary and biochemical understanding of other protein families.


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 = $576,339 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	4	6/24/2025	NON-COMPETING CONTINUATION	$576,339
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	3	12/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $576,339

Issue Date FY: 2024 ( Subtotal = $512,326 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	3	6/10/2024	NON-COMPETING CONTINUATION	$512,326
														Subtotal = $512,326

Issue Date FY: 2023 ( Subtotal = $490,990 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	2	6/8/2023	NON-COMPETING CONTINUATION	$490,990
														Subtotal = $490,990

Issue Date FY: 2022 ( Subtotal = $434,790 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	1	6/30/2022	NEW	$434,790
														Subtotal = $434,790

Grand Total All Awards = $2,014,445

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Genetic and biophysical causes of historical protein evolution

Award Number: R35GM145336

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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