Synonymous Mutations Predominantly Neutral in Human Disease

A recent high-profile paper suggested that synonymous mutations could be just as important as nonsynonymous ones in causing human disease. However, a new Commentary published in the American Journal of Human Genetics (AJHG) argues that synonymous mutations are predominantly neutral. The authors of the AJHG Commentary note that many previous studies have assumed synonymous mutations to be neutral and thus not associated with any functional effects on gene expression or protein function. However, they argue that this assumption is not necessarily correct, and that it is possible for synonymous mutations to cause disease. To investigate this further, the authors conducted an extensive review of existing literature on synonymous mutations and their potential role in human disease. They found that while some evidence suggests a role for synonymous mutations in certain diseases, such as cancer and neurological disorders, these associations were relatively rare compared to nonsynonymous mutations. Furthermore, they found no evidence to suggest that synonymous mutations are more likely than nonsynonymous ones to cause disease overall. The authors conclude by noting that while there may be some cases where synonymous mutations can contribute to human disease, these cases appear to be relatively rare compared to those caused by nonsynonymous variants. As such, they argue that it is still reasonable for researchers studying genetic diseases to assume most synonymous variants are neutral and thus unlikely to play a major role in causing disease.