Mutation rate is one of the most fundamental parameters in genetics and evolutionary biology because mutation rate has major impacts on the incidence of disease, the amount of genetic variation, and the rate and trajectory of evolution. Based on estimates of synonymous nucleotide diversity in Escherichia coli, a recent study claimed that the per-nucleotide mutation rate in a gene decreases with the rise of its expression level or the intensity of purifying selection and that this trend reflects adaptive risk management. Here, we demonstrate that this argument is theoretically untenable, especially in the lack of mechanisms that simultaneously tune the mutabilities of multiple genes with similar fractions of deleterious mutations. Analyzing publishedgenome sequences of E. coli mutation accumulation lines, we show that mutation rates are actually higher in more highly expressed genes, similar to previous genome-wide observations in Salmonella typhi-murium, Saccharomyces cerevisiae, and the human germline. These general patterns likely arise from transcription-associated mutagenesis that exceeds transcription-coupled repair.
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