Collateral fitness effects of mutations

• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1918680117

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.