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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 theEscherichia coli TEM-1β-lactamase antibiotic resistance gene using growth competition experiments in the absence of antibiotic. At least 42% of missense mutations inTEM-1were 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 inTEM-1than 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.
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This content will become publicly available on April 22, 2026
The evolution of robustness and fragility during long-term bacterial adaptation
Theory predicts that well-adapted populations may evolve mechanisms to counteract the inevitable influx of deleterious mutations. While mutational robustness can be directly selected in the laboratory, evidence for its spontaneous evolution during general adaptation is mixed. Moreover, whether robustness evolves to include pleiotropic effects remains largely unexplored. Here, we studied the effects of point mutations in the RNA polymerase ofEscherichia coliover a 15,000-generation adaptive trajectory. Fitness effects of both beneficial and deleterious mutations were attenuated in fitter backgrounds. In contrast, pleiotropic effects became more severe and widespread with greater adaptation. These results show that trade-offs between robustness and fragility can evolve in regulatory networks, regardless of whether driven by adaptive or nonadaptive processes. More broadly, they illustrate how adaptation can generate hidden variability, with unpredictable evolutionary consequences in new environments.
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- Award ID(s):
- 1951307
- PAR ID:
- 10637800
- Publisher / Repository:
- Proceedings of the National Academy of Sciences, USA
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 122
- Issue:
- 16
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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