Rates of spontaneous mutation among rna viruses

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Abstract Simple methods are presented to estimate rates of spontaneous mutation from mutant frequencies and population parameters in RNA viruses. Free full text. J W Drake. Author information Copyright and License information Disclaimer. Copyright notice. This article has been cited by other articles in PMC. Drake JW. A constant rate of spontaneous mutation in DNA-based microbes.

Rapid evolution of RNA genomes. The hypercycle. A principle of natural self-organization. Part A: Emergence of the hypercycle. The frequency distribution of spontaneous bacteriophage mutants as evidence for the exponential rate of phage reproduction. J Virol. In vitro site-directed mutagenesis: generation and properties of an infectious extracistronic mutant of bacteriophage Qbeta.

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Virus mutation frequencies can be greatly underestimated by monoclonal antibody neutralization of virions. Each culture is then screened simply for the presence or absence of mutants, and the average number N of virus particles per culture is also determined.

Strictly speaking, T is a third of the total number of different base substitutions that can be monitored. In these riboviral systems, only base-pair substitutions are scored. Thus, it is necessary to correct for all other kinds of mutations. Several mutation frequencies and references to supplementary information were considered previously 5 and either are used unchanged or are recalculated with the new equation for mutation rate.

This virus has a genome of 7, bases The number of sites at which mutation could occur was estimated from the observation that five sequenced mutations fell into four sites; assuming a Poisson distribution of mutations among sites, the most probable number of sites is 7.

The size of the measles genome is 15, bases In several instances, either recently appearing or previously analyzed data 5 are not well suited to the approach employed here. The latter include pioneering bacteriophage studies 15 , 16 , studies of VSV and poliovirus genomic RNA based on limit ribonuclease digestions rather than on genetic approaches 17 , 18 , and studies based on sequencing clonal copies of poliovirus and influenza virus genomes or involving sampling procedures that may have perturbed mutant frequencies 19 , For a set of nine values varying by about 9-fold, the median is likely to be a better estimator than the mean.

The mutation process in riboviruses can be described by a simple linear equation that reflects the repeated copying of templates that is characteristic of these organisms. This phage replicates in a complicated but fundamentally linear manner 23 , 24 , such that the mutation equations 25 , 26 are similar to the equation used here for riboviruses, although the observed rates are far lower than those of riboviruses and are instead characteristic of DNA-based microbes 3.

A similar value, 1. These values are very high in comparison to values in other organisms but were anticipated in classical studies of mutation in an RNA phage 15 , 16 and have long been known to be generally high Chao, personal communication.

Thus, the high ribovirus mutation rate seems to encompass both animal viruses and phages. The viral particles emerging from individual infected cells contain occasional mutant clones descended from new mutations. Mutation in riboviruses should produce mutant clone size distributions very different from those characteristic of exponentially replicating chromosomes.

In riboviruses, fewer mutations will occur in the first round of genome copying than in the second round, because fewer copying events occur in the first round. Therefore, a few clones will contain several mutants, whereas most clones will contain only one mutant. These are experimentally resolvable parameters. Because a single cycle of infection produces a mutant frequency twice that of the rate per genome replication, few progeny viruses escape mutation.

In general, for 1. However, many or most mutations in riboviruses are deleterious, and selection against deleterious mutations will reduce both mutant frequency and virus yield even within a single cycle of infection. Their high mutation rate renders the riboviruses particularly vulnerable to the consequences of rate increases, and both poliovirus and VSV populations are extinguished by chemical mutagenesis sufficient to increase the rate by a mere 2.