The distribution of fitness effects among synonymous mutations in a gene under selection

Abstract

The fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitness effects among synonymous mutations for a gene 15 under selection. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites.A positive correlation between fitness and the presence of synonymous substitutions across a phylogeny of related Pseudomonads suggests these mutations may be common in nature. Taken 20 together, our results provide the most compelling evidence to date that synonymous mutations with non-neutral fitness effects may in fact be commonplace.

A mutational hotspot that determines highly repeatable evolution can be built and broken by silent genetic changes

“…More recent studies have revealed that synonymous changes have an underestimated effect on fitness through their perturbances before and during translation. Synonymous sequence variance can impact fitness by changing the stability of mRNA [40][41][42] and altering codons to perturb or better match the codon-anticodon ratio 43 . We have shown here that synonymous sequence can also be essential for ensuring parallel evolutionary outcomes across genetic backgrounds.…”