Collateral fitness effects of mutations

Mehlhoff, JD; Stearns, FW; Rohm, D; Wang, B; Tsou, EY; Dutta, N; Hsiao, MH; Gonzalez, CE; Rubin, AF; Ostermeier, M

Author(s): Mehlhoff, JD; Stearns, FW; Rohm, D; Wang, B; Tsou, EY; Dutta, N; Hsiao, MH; Gonzalez, CE; Rubin, AF; Ostermeier, M;
Details: Publication Year 2020-05-08,Volume 117,Issue #21,Page 11597-11607
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Journal Article
Abstract: The distribution of fitness effects of mutation plays a central role in constraining protein evolution. The underlying mechanisms by which mutations lead to fitness effects are typically attributed to changes in protein specific activity or abundance. Here, we reveal the importance of a mutation's collateral fitness effects, which we define as effects that do not derive from changes in the protein's ability to perform its physiological function. We comprehensively measured the collateral fitness effects of missense mutations in the Escherichia coli TEM-1 beta-lactamase antibiotic resistance gene using growth competition experiments in the absence of antibiotic. At least 42% of missense mutations in TEM-1 were deleterious, indicating that for some proteins collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper posttranslational processing, incorrect disulfide-bond formation, protein aggregation, changes in gene expression, and pleiotropic effects on cell phenotype. Deleterious collateral fitness effects occurred more frequently in TEM-1 than deleterious effects on antibiotic resistance in environments with low concentrations of the antibiotic. The surprising prevalence of deleterious collateral fitness effects suggests they may play a role in constraining protein evolution, particularly for highly expressed proteins, for proteins under intermittent selection for their physiological function, and for proteins whose contribution to fitness is buffered against deleterious effects on protein activity and protein abundance.
Publisher: Rockefeller University Press
Research Division(s): Bioinformatics
PubMed ID: 32385156
Publisher's Version: https://doi.org/10.1073/pnas.1918680117
NHMRC Grants: NHMRC/1054618,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2020-05-18 11:14:12

Last Modified: 2020-08-26 10:52:52