Key Points
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Viral mutation rates vary over five orders of magnitude, whereas viral substitution rates vary over six orders of magnitude.
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Instead of simplifying the differences by stating that RNA viruses mutate faster than DNA viruses owing to differences in polymerase fidelity, it seems more likely that small viruses mutate faster than large viruses irrespective of the nucleic acid of their genome.
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Single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) viruses have non-overlapping ranges of mutation and substitution rates, with ssDNA viruses behaving more like RNA viruses. However, there are currently no good estimates of substitution rate for dsRNA viruses.
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There are several sources of mutation in addition to polymerase error. These include host antiviral enzymes, spontaneous chemical reactions and environmental mutagens such as ultraviolet irradiation.
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Various processes shape the evolution of mutation rates in viruses, although more research is needed to determine their precise contribution, and whether and how natural selection has acted to optimize these rates.
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Coalescent methods that use serially sampled data represent a powerful way to estimate substitution rates from rapidly evolving RNA and ssDNA viruses.
Abstract
Understanding the factors that determine the rate at which genomes generate and fix mutations provides important insights into key evolutionary mechanisms. We review our current knowledge of the rates of mutation and substitution, as well as their determinants, in RNA viruses, DNA viruses and retroviruses. We show that the high rate of nucleotide substitution in RNA viruses is matched by some DNA viruses, suggesting that evolutionary rates in viruses are explained by diverse aspects of viral biology, such as genomic architecture and replication speed, and not simply by polymerase fidelity.
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Acknowledgements
This work was supported by a National Science Foundation grant, DBI 06-03070, to S.D. We thank A. Rambaut for his comments.
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human immunodeficiency virus type-1
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FURTHER INFORMATION
Glossary
- Generation time
-
The time between rounds of production of viral progeny, including any time required for virions to seek a susceptible host cell, followed by adsorption and infection of the susceptible cell, then viral replication and release.
- Coalescent
-
A population genetic theory that links the divergence times of a phylogenetic tree of individuals sampled from the same population with the demographic history (that is, rates of population growth and decline) of that population.
- Positive selection
-
The fixation of advantageous alleles as a result of differential reproductive success.
- Hypermutation
-
The long stretches of nucleotide transitions observed in RNA virus sequences (first noticed in human immunodeficiency virus with G-to-A transitions). This term can also be used to describe an elevated mutation rate of any kind, not necessarily in a run of adjacent nucleotides.
- Amber mutaton reversion
-
The change of an amber stop codon (UAG) within a gene to a codon for an amino acid. This typically restores protein function in a gene that had been purposefully selected to contain an amber nonsense mutation as a genetic marker.
- Stamping machine
-
Linear stamping machine replication is when the single virus that initiates an infection is the direct parent of all progeny genomes. That is, the parental genome (or its single complement) is the template for the semi-conservative replication of all the genomes that are produced in an infected cell. As there is only one template within the cell, progeny genomes accumulate linearly over time.
- Geometric genome replication
-
A mode of viral replication in which the progeny genomes that are replicated early during infection can become templates for further genome replication. As the infection progresses, the number of templates for semi-conservative replication increases, and progeny genomes can be produced at an exponential, or geometric, rate.
- Effective population size
-
The smallest theoretical population size that can evolve in the same way as the actual population under study. It is strongly influenced by population bottlenecks, such as those that occur during transmission of viruses between hosts, and therefore is often smaller than the total population size.
- Linear regression
-
The estimation of a first-order relationship between two variables (for example, number of nucleotide substitutions and time), which involves fitting the best straight line to the data.
- Constant molecular clock
-
The idea that nucleotide substitutions accumulate at a fixed (constant) rate over time, and that this can be used to estimate divergence times between sequences.
- Maximum likelihood
-
A statistical method that selects the hypothesis (for example, the phylogenetic tree) that has the highest probability of explaining the data, under a specific model.
- Bayesian Markov chain Monte Carlo
-
(MCMC). Bayesian methods incorporate prior information in assessing the probability of model parameters. Because the prior distribution (the users' belief about the probabilities of different parameter values before the data have been analysed) can have a large affect on the posterior distribution (the results) it must be chosen carefully. MCMC methods allow sampling from the posterior distribution to get an estimate of the distribution.
- Relaxed molecular clock
-
A form of molecular clock in which rates of nucleotide substitution are allowed to vary among lineages.
- Purifying selection
-
The purging of deleterious alleles as a result of differential reproductive success.
- Cytotoxic T-lymphocyte
-
An antigen-specific T-cell of the vertebrate immune system that recognizes and destroys virus-infected cells.
- Co-divergence
-
The parallel diversification or speciation of a parasite and its host, which is inferred when there is strong congruence between the phylogenetic trees of the host and parasite, and similar divergence times of corresponding nodes on the phylogenies.
- Population bottleneck
-
The smallest size of a viral population at any point in viral propagation. A common bottleneck for viral populations occurs during transmission between hosts, when the population size can be as small as one virus or as large as several million virions.
- Error threshold
-
The theoretical limit to the mutation rate of viruses, beyond which too many errors accumulate and populations of the virus become extinct. It is used to explain why it is difficult to generate RNA viruses with much higher mutation rates than those observed in natural isolates, and why RNA viruses have constrained genome sizes.
- Burst size
-
The (average) number of progeny viruses produced from a single infected cell. This is more straightforward to measure for obligately lytic viruses than for viruses that can integrate into their host genomes.
- Robustness
-
The constancy of a phenotype in the face of changing environments or changing genetics (mutations). Current research indicates that robustness is a trait that is under selection in viruses, and changes in viral robustness can be observed in laboratory experimental evolution.
- Fitness landscape
-
A metaphorical contour map of the varied fitness values that are experienced by different genotypes of an organism. As a genotype moves through genotype space, it can climb to a higher fitness peak, or stumble down to a less-fit genotype.
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Duffy, S., Shackelton, L. & Holmes, E. Rates of evolutionary change in viruses: patterns and determinants. Nat Rev Genet 9, 267–276 (2008). https://doi.org/10.1038/nrg2323
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DOI: https://doi.org/10.1038/nrg2323
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