Causes and Effects of N-Terminal Codon Bias in Bacterial Genes

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Science  25 Oct 2013:
Vol. 342, Issue 6157, pp. 475-479
DOI: 10.1126/science.1241934

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Exploiting Redundancy

The genetic code is redundant—multiple codons can code for the same amino acid. So-called synonymous codon changes within genes can nonetheless have substantial affects on protein expression, which have been attributed to changes in the structure of 5′ messenger RNAs, among other factors. Goodman et al. (p. 475, published online 26 September) built and measured the expression of a synthetic library of 14,000 variant N-terminal sequences of 137 Escherichia coli genes to show that, unexpectedly, rare codons had a bigger effect on increasing protein expression than more common codons. Increased RNA structure downstream of translation initiation appeared to represent the major determinant of expression differences owing to codon usage.


Most amino acids are encoded by multiple codons, and codon choice has strong effects on protein expression. Rare codons are enriched at the N terminus of genes in most organisms, although the causes and effects of this bias are unclear. Here, we measure expression from >14,000 synthetic reporters in Escherichia coli and show that using N-terminal rare codons instead of common ones increases expression by ~14-fold (median 4-fold). We quantify how individual N-terminal codons affect expression and show that these effects shape the sequence of natural genes. Finally, we demonstrate that reduced RNA structure and not codon rarity itself is responsible for expression increases. Our observations resolve controversies over the roles of N-terminal codon bias and suggest a straightforward method for optimizing heterologous gene expression in bacteria.

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