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Empirical and Theoretical Studies of Adaptive Mutations in Microbes and Their Evolutionary Consequences

Award Number: R35GM153242
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: 03/13/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Empirical and Theoretical Studies of Adaptive Mutations in Microbes and Their Evolutionary Consequences - Project Summary Mutations are the ultimate source of genetic diversity upon which other evolutionary forces—natural se- lection, genetic drift, recombination—act. As such, mutations impose fundamental constraints on what phenotypes can evolve, but we lack a theory for understanding these constraints. Two overarching goals of my lab’s research are to (i) develop a theory for predicting the phenotypic and fitness effects of new mutations across genotypes and environments and (ii) understand how evolution proceeds on the emerging “fitness landscapes”. We take three complementary approaches to achieve these goals. Our first approach is theoretical. Even the simplest unicellular organisms are complex biochemical machines, but it is unclear how this biochemical architecture constrains the structure of the resulting fitness landscapes and the rules by which mutations “move” the organism on this landscape. We are developing mathematical theory for understanding these constraints, focusing initially on fitness landscapes that emerge in complex metabolic networks. Our second approach is empirical. While we construct the theory from first principles, we will also use tractable experimental systems, such as the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli to directly measure the effects of mutations on some cellular phenotypes that are im- portant for microbial fitness, e.g., the transcriptome. Our goal here is to identify broad and hopefully general statistical patterns in how the effects of mutations vary across genetic backgrounds and environ- ments that will help us narrow down and parameterize our theory. One practically important outcome of this work that we hope to achieve is the ability to predict the evolution of collateral antibiotic resistance. Our third approach is exploratory. If our theoretical and empirical efforts mentioned above are successful, they will give us a handle on predicting evolutionary trajectories and outcomes in controlled laboratory conditions. However, by necessity, these conditions lack many of the complexities of natural environ- ments. We would like to understand how the evolutionary process in such more complex environments differs from what we can observe and potentially predict in simple controlled laboratory conditions. To this end, we will apply some of the cutting-edge experimental tools, such as whole-genome time-course sequencing, to observe evolutionary dynamics in microbial systems of intermediate complexity, in partic- ular, in a two-species microbial community that we already developed and in a semi-natural marine mi- crobial system that we plan to develop with our collaborators.


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 = $348,522 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	12/31/2025	NON-COMPETING CONTINUATION	$348,522
														Subtotal = $348,522

Issue Date FY: 2025 ( Subtotal = $387,247 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	12/11/2024	NON-COMPETING CONTINUATION	$348,522
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	2	8/20/2025	NON-COMPETING CONTINUATION	$38,725
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	11/14/2024	NEW	$0
														Subtotal = $387,247

Issue Date FY: 2024 ( Subtotal = $404,889 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	3/13/2024	NEW	$404,889
														Subtotal = $404,889

Grand Total All Awards = $1,140,658

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Empirical and Theoretical Studies of Adaptive Mutations in Microbes and Their Evolutionary Consequences

Award Number: R35GM153242

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: 03/13/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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