Codon usage influences fitness through RNA toxicity

Pragya Mittal, James Brindle, Julie Stephen, Joshua B Plotkin, Grzegorz Kudla

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Many organisms are subject to selective pressure that gives rise to unequal usage of synonymous codons, known as codon bias. To experimentally dissect the mechanisms of selection on synonymous sites, we expressed several hundred synonymous variants of the GFP gene in Escherichia coli, and used quantitative growth and viability assays to estimate bacterial fitness. Unexpectedly, we found many synonymous variants whose expression was toxic to E. coli. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We identified RNA sequence determinants of toxicity and evolved suppressor strains that can tolerate the expression of toxic GFP variants. Genome sequencing of these suppressor strains revealed a cluster of promoter mutations that prevented toxicity by reducing mRNA levels. We conclude that translation-independent RNA toxicity is a previously unrecognized obstacle in bacterial gene expression.

Original languageEnglish
Pages (from-to)8639-8644
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Volume115
Issue number34
Early online date6 Aug 2018
DOIs
Publication statusPublished - 21 Aug 2018

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