Collateral fitness effects of mutations

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 c...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 21; pp. 11597 - 11607
Main Authors:	Mehlhoff, Jacob D., Stearns, Frank W., Rohm, Dahlia, Wang, Buheng, Tsou, Erh-Yeh, Dutta, Nisita, Hsiao, Meng-Hsuan, Gonzalez, Courtney E., Rubin, Alan F., Ostermei, Marc
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-05-2020
Subjects:	Abundance Antibiotic resistance Antibiotics beta-Lactamases - chemistry beta-Lactamases - genetics beta-Lactamases - metabolism Biological Sciences Constraining Drug resistance E coli Environmental effects Escherichia coli - enzymology Escherichia coli - genetics Escherichia coli - physiology Escherichia coli Proteins - chemistry Escherichia coli Proteins - genetics Escherichia coli Proteins - metabolism Evolution Evolution, Molecular Fitness Gene expression Genetic Fitness - genetics Low concentrations Missense mutation Mutation Mutation, Missense - genetics Mutation, Missense - physiology Phenotypes Physiological effects Physiology Protein interaction Proteins Reproductive fitness fitness landscape beta-lactamase stress response protein evolution protein aggregation
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Summary:	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 β-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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: J.D.M., F.W.S., and M.O. designed research; J.D.M., F.W.S., D.R., B.W., E.-Y.T., N.D., and M.-H.H. performed research; J.D.M., F.W.S., D.R., B.W., E.-Y.T., N.D., M.-H.H., C.E.G., A.F.R., and M.O. analyzed data; J.D.M. and M.O. wrote the paper; and J.D.M., F.W.S., D.R., A.F.R., and M.O. edited the paper. Edited by Dan Weinreich, Brown University, Providence, RI, and accepted by Editorial Board Member Daniel L. Hartl April 8, 2020 (received for review October 29, 2019)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1918680117