Hearing silence: non-neutral evolution at synonymous sites in mammals

Abstract

Contrary to the neutral theory, silent mutations can be under natural selection. This is often seen in organisms from large populations, but the authors present evidence that it also occurs in mammals, because synonymous mutations affect mRNA stability and splicing. Although the assumption of the neutral theory of molecular evolution — that some classes of mutation have too small an effect on fitness to be affected by natural selection — seems intuitively reasonable, over the past few decades the theory has been in retreat. At least in species with large populations, even synonymous mutations in exons are not neutral. By contrast, in mammals, neutrality of these mutations is still commonly assumed. However, new evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or mRNA stability. This has implications for understanding disease, optimizing transgene design, detecting positive selection and estimating the mutation rate.