Viral mutation rates

Abstract

Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10(-8) to 10(-6) s/n/c for DNA viruses and from 10(-6) to 10(-4) s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut.

FIG. 1.

Selection-correction factor α as a function of time, measured in cell infection cycles, for different values of the burst size (or viral yield) B. α is mathematically defined in Methods (equation 2 and text). It allows us to quantify the loss in mutation frequency (f_s) due to selection and thus to account for selection bias in mutation rate estimates. The expected value of α depends on whether mutation sampling is done in the absence of selection (top), as would be the case for a molecular clone sequencing experiment, or in the presence of selection (bottom), as, for instance, in direct plaque sequencing. The expected α is plotted for eight B values: 3, 10, 30, 100, 300, 10³, 3 × 10³, and 10⁴. Fitness effects of random single-nucleotide substitutions (defined in equation 8) were assumed to follow an exponential distribution with mean E(sv) = 0.12 plus a class of lethal mutations occurring with probability p_L = 0.3 (equation 7).

FIG. 2.

Relationship between mutation rate and genome size, with major virus groups indicated. Values for viroids and bacteria, the two adjacent levels of biological complexity, are also plotted. The mutation rate is expressed as the number of substitutions per nucleotide per generation, defined as a cell infection in viruses (μ_s/n/c). We obtained bacterial mutation rates from a previous study (57) and divided them by 1.46 to convert the total rate into a substitution rate, as previously suggested (27). 1, Bacillus; 2, Deinococcus; 3, enterobacteria; 4, Helicobacter; 5, Mycobacterium; 6, Sulfolobus. The star indicates the solitary rate for a viroid (37), a subviral infectious agent constituted by small noncoding RNA. This rate is in substitutions per strand copying, since viroids do not have the equivalent of a generation.