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 to10 ؊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.The mutation rate is a critical parameter for understanding viral evolution and has important practical implications. For instance, the estimate of the mutation rate of HIV-1 demonstrated that any single mutation conferring drug resistance should occur within a single day and that simultaneous treatment with multiple drugs was therefore necessary (72). Also, in theory, viruses with high mutation rates could be combated by the administration of mutagens (1,5,21,44,53,83). This strategy, called lethal mutagenesis, has proved effective in cell cultures or animal models against several RNA viruses, including enteroviruses (11,39,44), aphtoviruses (83), vesiculoviruses (44), hantaviruses (10), arenaviruses (40), and lentiviruses (15, 53), and appears to at least partly contribute to the effectiveness of the combined ribavirin-interferon treatment against hepatitis C virus (HCV) (13). The viral mutation rate also plays a role in the assessment of possible vaccination strategies (16), and it has been shown to influence the stability of live attenuated polio vaccines (91). Finally, at both the epidemiological and evolutionary levels, the mutation rate is one of the factors that can determine the risk of emergent infectious disease, i.e., pathogens crossing the species barrier (46). Slight changes of the mutation rate can also determine whether or not some virus infections are cleared by the host immune system and can produce dramatic differences in viral fitness and virulence (75,90), clearly stressing the need to have accurate estimates. However, our knowledge of viral mutation rates is somewhat incomplete, partly due to the inherent difficulty of measuring a rare and r...

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