Collateral fitness effects of mutations

Abstract

<jats:title>Abstract</jats:title><jats:p>The distribution of fitness effects (DFE) 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 <jats:italic>E. coli TEM-1</jats:italic> β-lactamase antibiotic resistance gene using growth competition experiments in the <jats:italic>absence</jats:italic> of antibiotic. At least 42% of missense mutations in <jats:italic>TEM-1</jats:italic> were deleterious, indicating that for some proteins, collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper post-translational 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 <jats:italic>TEM-1</jats:italic> 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 mutations with deleterious effects on protein activity and protein abundance.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>Mutations provide the source of genetic variability upon which evolution acts. Deleterious protein mutations are commonly thought of in terms of how they compromise the protein’s ability to perform its physiological function. However, mutations might also be deleterious if they cause negative effects on one of the countless other cellular processes. The frequency and magnitude of such collateral fitness effects is unknown. Our systematic study of mutations in a bacterial protein finds widespread collateral fitness effects that were associated with protein aggregation, improper protein processing, incomplete protein transport across membranes, incorrect disulfide-bond formation, induction of stress-response pathways, and unexpected changes in cell properties. Our results suggest that deleterious collateral fitness effects may be an important constraint on protein evolution.</jats:p></jats:sec>

Fitness variation across subtle environmental perturbations reveals local modularity and global pleiotropy of adaptation

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Development of antibiotic resistance reveals diverse evolutionary pathways to face the complex and dynamic environment of a long-term treated patient

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