Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Fitness Effects of Beneficial Mutations

Award Number: R35GM131824
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2029

Group Awards By:

View Award Description

Fitness Effects of Beneficial Mutations - Project Summary/Abstract The progression of cancer and infectious disease is an evolutionary process. Pathogens engage in an arms race with their hosts, and while antibiotics/antivirals have enabled us to skew the outcome of these contests, these bulwarks against contagion are being steadily eroded. Mutation and natural selection, coupled with rapid generation times and immense pathogen population sizes, provide pathogens a decisive advantage. To regain the upper hand, we must better understand the evolutionary process, to aid in the development of novel classes of antimicrobials and devise therapeutic strategies that take into account how these weapons work and how pathogens evade them. Until recently, efforts to gain a deep understanding of the adaptive process were stymied, because adaptive mutations are rare and identifying them is challenging. To solve this, we developed a system to track the evolutionary process, isolate thousands of adaptive lineages, remeasure the fitness of those lineages across many environments, and cheaply whole genome sequence hundreds to thousands of such mutants. I propose a new phase in my ambitious, integrated research program that takes full advantage of this lineage tracking system, and our discovery of Pareto fronts, which are indicative of trade-offs. We will pursue two major goals. First, we will expand our understanding of evolution in the face of abiotic selection pressures, especially those that produce adaptive trade-offs. Specifically, we will determine the role of historical contingency as it pertains to trade-offs in adaptation, the potential for trade-offs to force canalization (e.g., trapping lineages into extreme specialization), the influence that epistasis exerts on the geometry of trait space, and the extent to which adaptive constraints underlie negative and diminishing returns epistasis. Second, we will expand to contrast these findings with evolutionary outcomes under biotic selection pressures, using two new systems. To model genetic conflict and arms race dynamics within species we will use the killer yeast system. Killer yeast secrete a toxin that destroys sensitive yeast, while retaining an intracellular antitoxin. Toxin and antitoxin are both encoded by a vertically inherited virus, which itself parasitizes a second virus. We will co-evolve killer and sensitive cells and determine whether, as theory predicts, there are recurrent periods of selection and whether coevolved solutions show greater trade-offs than typically observed from abiotic selection pressures. To experimentally model arms race dynamics between species we will use crAssphage, one of the most prevalent bacteriophages associated with the human gut microbiome. The aim of these evolution experiments will be to evaluate the dynamics of phage and its bacterial host co-adaptation over trials of short- and medium-term duration. Overall, this integrated, multi-level research strategy will yield fundamental new insights into how the adaptive process is constrained under alternative forms of selection. Armed with this deeper understanding of adaptation, we will better be able to predict the likelihood of different evolutionary futures given knowledge of a genomic present and thereby gain the upper hand in our battle against human disease.


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 = $457,450 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	8	4/27/2026	NON-COMPETING CONTINUATION	$457,450
														Subtotal = $457,450

Issue Date FY: 2025 ( Subtotal = $457,450 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	7	5/1/2025	NON-COMPETING CONTINUATION	$457,450
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	6	11/21/2024	COMPETING CONTINUATION	$0
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	5	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $457,450

Issue Date FY: 2024 ( Subtotal = $541,108 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	6	9/4/2024	SUPPLEMENT FOR EXPANSION	$83,658
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	6	3/19/2024	COMPETING CONTINUATION	$457,450
														Subtotal = $541,108

Issue Date FY: 2023 ( Subtotal = $429,787 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	4/14/2023	NON-COMPETING CONTINUATION	$429,787
														Subtotal = $429,787

Issue Date FY: 2022 ( Subtotal = $429,205 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	4/22/2022	NON-COMPETING CONTINUATION	$429,205
														Subtotal = $429,205

Issue Date FY: 2021 ( Subtotal = $428,640 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	4/12/2021	NON-COMPETING CONTINUATION	$428,640
														Subtotal = $428,640

Issue Date FY: 2020 ( Subtotal = $428,092 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	4/6/2020	NON-COMPETING CONTINUATION	$428,092
														Subtotal = $428,092

Issue Date FY: 2019 ( Subtotal = $427,560 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	4/11/2019	NEW	$427,560
														Subtotal = $427,560

Grand Total All Awards = $3,599,292

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Fitness Effects of Beneficial Mutations

Award Number: R35GM131824

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer