Codon usage of highly expressed genes affects proteome-wide translation efficiency

Although the genetic code is redundant, synonymous codons forthe same amino acid are not used with equal frequencies ingenomes, a phenomenon termed “codon usage bias.” Previousstudies have demonstrated that synonymous changes in a codingsequence can exert significant cis effects on the gene’s expressionlevel. However, whether the codon composition of a gene can alsoaffect the translation efficiency of other genes has not been thoroughlyexplored. To study how codon usage bias influences thecellular economy of translation, we massively converted abundantcodons to their rare synonymous counterpart in several highlyexpressed genes in Escherichia coli. This perturbation reduces boththe cellular fitness and the translation efficiency of genes thathave high initiation rates and are naturally enriched with the manipulatedcodon, in agreement with theoretical predictions. Interestingly,we could alleviate the observed phenotypes by increasingthe supply of the tRNA for the highly demanded codon, thus demonstratingthat the codon usage of highly expressed genes was selectedin evolution to maintain the efficiency of global protein translation.