Evidence that natural selection acts on silent mutation

Analysis of nucleic acid sequence data of mammalian hemoglobin, yeast cytochrome c, and human interferon reveals strong biases in favor of specific codons. These biases do not appear to dissipate over time, suggesting that an indirect form of selection acts on silent mutations. The data are compatible with the “bootstrapping” hypothesis that silent mutations which alter the rate of evolution can hitchhike with traits whose appearance they facilitate. Selection involving modulating effects of codon usage on gene expression may also be involved, but the data appear to exclude simple maximization of gene expression.