On the evolution of codon volatility

Volatility of a codon is defined as the probability that a random point mutation in the codon generates a nonsynonymous change. It has been proposed that higher-than-expected mean codon volatility of a gene indicates that positive selection for nonsynonymous changes has acted on the gene in the recent past. I show that strong frequency-dependent selection (minority advantage) in large populations can increase codon volatility slightly, whereas directional positive selection has no effect on volatility. Factors unrelated to positive selection, such as expression-related or GC-content-related codon usage bias, also affect volatility. These and other considerations suggest that codon volatility has only limited utility for detecting positive selection at the DNA sequence level.