Collateral fitness effects of mutations

Proc Natl Acad Sci U S A. 2020 May 26;117(21):11597-11607. doi: 10.1073/pnas.1918680117. Epub 2020 May 8.


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.

Keywords: beta-lactamase; fitness landscape; protein aggregation; protein evolution; stress response.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Escherichia coli / physiology
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism
  • Evolution, Molecular*
  • Genetic Fitness / genetics*
  • Mutation, Missense / genetics*
  • Mutation, Missense / physiology*
  • beta-Lactamases / chemistry
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism


  • Escherichia coli Proteins
  • beta-Lactamases
  • beta-lactamase TEM-1