Fitness Effects of Phenotypic Mutations at Proteome-Scale Reveal Optimality of Translation Machinery

Mol Biol Evol. 2024 Mar 1;41(3):msae048. doi: 10.1093/molbev/msae048.


Errors in protein translation can lead to non-genetic, phenotypic mutations, including amino acid misincorporations. While phenotypic mutations can increase protein diversity, the systematic characterization of their proteome-wide frequencies and their evolutionary impact has been lacking. Here, we developed a mechanistic model of translation errors to investigate how selection acts on protein populations produced by amino acid misincorporations. We fitted the model to empirical observations of misincorporations obtained from over a hundred mass spectrometry datasets of E. coli and S. cerevisiae. We found that on average 20% to 23% of proteins synthesized in the cell are expected to harbor at least one amino acid misincorporation, and that deleterious misincorporations are less likely to occur. Combining misincorporation probabilities and the estimated fitness effects of amino acid substitutions in a population genetics framework, we found 74% of mistranslation events in E. coli and 94% in S. cerevisiae to be neutral. We further show that the set of available synonymous tRNAs is subject to evolutionary pressure, as the presence of missing tRNAs would increase codon-anticodon cross-reactivity and misincorporation error rates. Overall, we find that the translation machinery is likely optimal in E. coli and S. cerevisiae and that both local solutions at the level of codons and a global solution such as the tRNA pool can mitigate the impact of translation errors. We provide a framework to study the evolutionary impact of codon-specific translation errors and a method for their proteome-wide detection across organisms and conditions.

Keywords: amino acid misincorporation; mass spectrometry; population genetics; translation error landscape; translation fidelity.

MeSH terms

  • Amino Acids / genetics
  • Codon / metabolism
  • Escherichia coli / genetics
  • Mutation
  • Protein Biosynthesis
  • Proteome* / genetics
  • RNA, Transfer / metabolism
  • Saccharomyces cerevisiae* / genetics


  • Proteome
  • Amino Acids
  • RNA, Transfer
  • Codon

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