A minimal role for synonymous variation in human disease

Synonymous mutations change the DNA sequence of a gene without affecting the amino acid sequence of the encoded protein. Although some synonymous mutations can affect RNA splicing, translational efficiency, and mRNA stability, studies in human genetics, mutagenesis screens, and other experiments and evolutionary analyses have repeatedly shown that most synonymous variants are neutral or only weakly deleterious, with some notable exceptions. Based on a recent study in yeast, there have been claims that synonymous mutations could be as important as nonsynonymous mutations in causing disease, assuming the yeast findings hold up and translate to humans. Here, we argue that there is insufficient evidence to overturn the large, coherent body of knowledge establishing the predominant neutrality of synonymous variants in the human genome.

Automated summary

Synonymous mutations change the DNA sequence of a gene without affecting the protein sequence. Most synonymous variants are neutral or weakly deleterious, except for some exceptions. A recent study in yeast suggests that synonymous mutations could be as important as nonsynonymous mutations in causing disease, but there is currently insufficient evidence to support this claim.