Synonymous mutations not evolutionarily neutral

Synonymous mutations are changes in the DNA sequence that do not affect the type of amino acids produced. For this reason they have been thought of as neutral in terms of evolution and thus unaffected by selection (although see here for criticisms of tests using the synonymous/non-synonymous ratio to detect selection).

The new paper in Science shows how synonymous mutations affect gene expression, and thus phenotypes. From ScienceDaily:

Synonymous mutations do not change the amino-acid sequence of a protein, but they can nevertheless influence the amount of the protein that is produced. The researchers identified the mechanism underlying this regulation: synonymous mutations determine mRNA folding and thereby the eventual protein level. The researchers also identified a class of mutations that did not directly affect protein levels but slowed bacterial growth.

For biologists, these results fundamentally change the understanding of the role of synonymous mutations, which were previously considered evolutionarily neutral.

Science doi:10.1126/science.1170160

Coding-Sequence Determinants of Gene Expression in Escherichia coli

Grzegorz Kudla et al.

Abstract

Synonymous mutations do not alter encoded protein, but they can influence gene expression. To investigate how, we engineered a synthetic library of 154 genes that varied randomly at synonymous sites, but all encoded the same green fluorescent protein (GFP). When expressed in Escherichia coli, GFP protein levels varied 250-fold across the library. GFP messenger RNA (mRNA) levels, mRNA degradation patterns, and bacterial growth rates also varied, but codon bias did not correlate with gene expression. Rather, the stability of mRNA folding near the ribosomal binding site explained more than half the variation in protein levels. In our analysis, mRNA folding and associated rates of translation initiation play a predominant role in shaping expression levels of individual genes, whereas codon bias influences global translation efficiency and cellular fitness.

Link