Mistranslation can enhance fitness through purging of deleterious mutations

Bratulić, Siniša; Toll-Riera, Macarena; Wagner, Andreas

doi:10.1038/ncomms15410

Cited by 33 publications

(51 citation statements)

References 62 publications

(107 reference statements)

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“…To understand how the additional mutations in the LL lines constrain adaptation, we performed a few further analyses. Because mutations G238S, E104K, and M182T were selected in the LL lines, as well as in previous studies (16,24,27,30,31), we first asked whether allele SL2 is selectively accessible from the genotype containing these three mutations, using two independent analyses. We first constructed and analyzed the resistance landscape connecting threefold mutant E104K/M182T/G238S and the genotype containing the six nonsynonymous mutations of final allele SL2 (neglecting synonymous mutation G143* obtained in round 5).…”

Section: Resultsmentioning

confidence: 99%

“…Not only could clinical patterns of molecular evolution be recapitulated in the laboratory (22,23), TEM-1 has also been used to address basic evolutionary questions. For example, recent work with TEM-1 revealed molecular details that determine its evolvability (14,(24)(25)(26)(27)(28), and showed that its fitness landscape is rugged (16,27,29,30). This causes TEM alleles selected from large mutation supplies to often follow the same trajectory involving three common mutations (16).…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme

Salverda

Koomen

Koopmanschap

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Populations with large mutation supplies adapt via the "greedy" substitution of the fittest genotype available, leading to fast and repeatable short-term responses. At longer time scales, smaller mutation supplies may in theory lead to larger improvements when distant high-fitness genotypes more readily evolve from lower-fitness intermediates. Here we test for long-term adaptive benefits from small mutation supplies using in vitro evolution of an antibiotic-degrading enzyme in the presence of a novel antibiotic. Consistent with predictions, large mutant libraries cause rapid initial adaptation via the substitution of cohorts of mutations, but show later deceleration and convergence. Smaller libraries show on average smaller initial, but also more variable, improvements, with two lines yielding alleles with exceptionally high resistance levels. These two alleles share three mutations with the large-library alleles, which are known from previous work, but also have unique mutations. Replay evolution experiments and analyses of the adaptive landscape of the enzyme suggest that the benefit resulted from a combination of avoiding mutational cohorts leading to local peaks and chance. Our results demonstrate adaptive benefits from limited mutation supplies on a rugged fitness landscape, which has implications for artificial selection protocols in biotechnology and argues for a better understanding of mutation supplies in clinical settings.

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme

Salverda

Koomen

Koopmanschap

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, compared to prior work our results are somewhat more applicable to E. coli function and evolution in natural ecosystems. For instance, the ecological relevance of genetic manipulations used in prior work (such as mutations in the ribosomal protein S4 (Fan et al 2015;Bratulic et al 2017)) is unclear. In contrast, translation -and specifically translation initiation -is reduced in response to several environmental stresses (Nagase et al 1988;Winther and Gerdes 2011;Watanabe et al 2013), creating a cellular environment analogous to that of our mistranslating mutant with reduced initiator tRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, while our experiments inform about the short-term impact of altering mistranslation, the longer-term impacts of mistranslation need to be investigated further. For instance, recent work showed that a mistranslating strain fixes distinct sets of beneficial mutations during laboratory adaptation to antibiotic stress (Bratulic et al 2017). It would be exciting if these results could be generalized across various stresses and forms of mistranslation.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Mistranslation on Phenotypic Variability and Fitness

Samhita

Raval

Stephenson

et al. 2020

Preprint

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Phenotypic variation is widespread in natural populations, and can significantly alter their ecology and evolution. Phenotypic variation often reflects underlying genetic variation, but also manifests via non-heritable mechanisms. For instance, translation errors result in about 10% of cellular proteins carrying altered sequences. Thus, proteome diversification arising from translation errors can potentially generate phenotypic variability, in turn increasing variability in the fate of cells or of populations. However, this link remains unverified. We manipulated mistranslation levels in Escherichia coli, and measured phenotypic variability between single cells (individual level variation), as well as replicate populations (population level variation). Monitoring growth and survival, we find that mistranslation indeed increases variation across E. coli cells, but does not consistently increase variability in growth parameters across replicate populations. Interestingly, although any deviation from the wild type (WT) level of mistranslation reduces fitness in an optimal environment, the increased variation is associated with a survival benefit under stress. Hence, we suggest that mistranslation-induced phenotypic variation can impact growth and survival and has the potential to alter evolutionary trajectories.

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“…It this case, mistranslation is beneficial in response to environmental stresses as it can help sustain and disseminate cellular phenotypic viability, e.g. as it may enhance pathogens survival by creating antigenic diversity in surface proteins 15 On an evolutionary time scales too, phenotypic errors might open evolutionary paths otherwise precluded by epistatic interactions 16 , and facilitate the purging of deleterious mutations 17 . A computational analysis of codon usage patterns across genomes revealed that natural selection constrains the identity of codons at evolutionarily conserved positions, suggesting that evolution favors more accurate codons at these sites 18 .…”

Section: Introductionmentioning

confidence: 99%

Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors

Mordret

Yehonadav

Barnabas

et al. 2018

Preprint

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Translation errors limit the accuracy of information transmission from DNA to proteins. Selective pressures shape the way cells produce their proteins: the translation machinery and the mRNA sequences it decodes co-evolved to ensure that translation proceeds fast and accurately in a wide range of environmental conditions. Our understanding of the causes of amino acid misincorporations and of their effect on the evolution of protein sequences is largely hindered by the lack of experimental methods to observe errors at the full proteome level. Here, we systematically detect and quantify errors in entire proteomes from mass spectrometry data. Following HPLC MS-MS data acquisition, we identify E. coli and S. cerevisiae peptides whose mass and fragment ion spectrum are consistent with that of a peptide bearing a single amino acid substitution, and verify that such spectrum cannot result from a post-translational modification. Our analyses confirm that most substitutions occur due to codon-to-anticodon mispairing within the ribosome. Patterns of errors due to mispairing were similar in bacteria and yeast, suggesting that the error spectrum is chemically constrained. Treating E. coli cells with a drug known to affect ribosomal proofreading increased the error rates due to mispairing at the wobble codon position. Starving bacteria for serine resulted in specific patterns of substitutions reflecting the amino acid deficiency. Overall, translation errors tend to occur at positions that are less evolutionarily conserved, and that minimally affect protein energetic stability, indicating that they are selected against. Genome wide ribosome density data suggest that errors occur at sites where ribosome velocity is relatively high, supporting the notion of a tradeoff between speed and accuracy as predicted by proofreading theories. Together our results reveal a mechanistic basis for ribosome errors in translation.

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Mistranslation can enhance fitness through purging of deleterious mutations

Cited by 33 publications

References 62 publications

Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme

Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme

The Impact of Mistranslation on Phenotypic Variability and Fitness

Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors

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