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  • Review Article
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The role of mutational robustness in RNA virus evolution

Nature Reviews Microbiology volume 11, pages 327–336 (2013)Cite this article

Subjects

Key Points

  • RNA viruses have extremely high mutation rates that are orders of magnitude greater than those of DNA-based organisms. Although some of these mutations are beneficial, the vast majority are detrimental to fitness.

  • Mutational robustness describes the preservation of phenotype in the face of ongoing mutation. Evolutionary theory suggests that high mutation rates drive the selection of mutational robustness.

  • The relative mutational robustness of an RNA virus can be measured by experiments assessing the accumulation of mutations, the effects of random mutations or mutagen sensitivity.

  • Factors such as a large population size and the ability to infect at high multiplicity can lead to increased robustness.

  • In silico modelling and experimental evolution suggest that viral RNA structures are genotypically diverse but preserve a native fold. Codon usage might also confer mutational robustness at the level of the viral genome.

  • Cellular chaperones might confer mutational robustness to RNA viruses by stabilizing mutant proteins and preventing their misfolding or aggregation.

  • Mutational robustness might favour viral evolvability and increase the ability of a virus to survive in the dynamic host environment. Evolved robustness could complicate efforts to control viral infections through drug-induced increases in the viral mutation rate.

Abstract

RNA viruses face dynamic environments and are masters at adaptation. During their short 'lifespans', they must surmount multiple physical, anatomical and immunological challenges. Central to their adaptative capacity is the enormous genetic diversity that characterizes RNA virus populations. Although genetic diversity increases the rate of adaptive evolution, low replication fidelity can present a risk because excess mutations can lead to population extinction. In this Review, we discuss the strategies used by RNA viruses to deal with the increased mutational load and consider how this mutational robustness might influence viral evolution and pathogenesis.

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Figure 1: Viral populations as mutant networks.
Figure 2: High mutation rates and survival of the flattest.
Figure 3: Using synonymous mutation to place populations in distinct fitness landscapes.
Figure 4: Dynamics of viral networks under selection in the host.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, 5510B MSRB I, SPC 5680, 1150 West Medical Center Drive, Ann Arbor, 48109-5680, Michigan, USA

    Adam S. Lauring

  2. Department of Microbiology and Immunology, University of Michigan Medical School, 5510B MSRB I, SPC 5680, 1150 West Medical Center Drive, Ann Arbor, 48109-5680, Michigan, USA

    Adam S. Lauring

  3. Department of Biology, Stanford University, Clark Center E200, 318 Campus Drive, Stanford, 94305, California, USA

    Judith Frydman

  4. Department of Microbiology and Immunology, University of California, 600 16th Street, GH-S572, UCSF Box 2280, San Francisco, 94143-2280, California, USA

    Raul Andino

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Glossary

Fitness

The ability of an entity to survive and reproduce. In experimental virology, replicative efficiency is often used as a surrogate for fitness. In this Review, we define viral fitness as the capacity of a virus to generate infectious progeny.

Evolvability

The capacity of a virus or organism with a particular genotype to gain fitness over time after evolving in a given environment.

Epistatic interaction

An interaction between mutations such that their combined effect on fitness is different to that expected from their effects in isolation.

Mutational fitness effect

The effects of mutations on fitness; often described in a model that combines both the strength and distribution of these effects.

Bottleneck

In genetics: a dramatic reduction in the number of individuals that can reproduce. Bottlenecks reduce genetic variation and are not necessarily selective events.

Negative selection

The removal of deleterious alleles from a population by natural selection. Also called purifying selection.

Effective population size

The size of an idealized population that would experience genetic drift in the same way as the actual population. The effective population size (Ne) is often smaller than the total population size.

Multiplicity of infection

In virology, the ratio of infectious particles to target cells.

Complementation

In the context of this Review: the process by which a defective virus can take advantage of functional nucleic acid sequences or proteins from another virus that is infecting the same cell. As a result, the defective virus does not experience loss of fitness from its mutation (or mutations).

Viral sex

The process by which genetic information is exchanged between two different strands of viral nucleic acid. In RNA viruses, this occurs most commonly through switching the replicative template (recombination) or through the exchange of genomic segments (reassortment).

Fitness landscapes

Spatial models that link fitness values to individual sequences.

Sequence space

All possible mutations and combinations of mutations present in a given DNA or amino acid sequence.

Digital organisms

Self-replicating computer programs that mutate and evolve, often in competition with each other for CPU (central processing unit) cycles.

Synonymous mutations

Codon mutations that do not alter the amino acid specificity of the codons. By contrast, non-synonymous mutations do change the encoded amino acid.

Volatile codons

Codons with a propensity to mutate non-synonymously, as opposed to synonymously.

Codon bias

A difference in the observed frequencies of synonymous codons in a given set of sequences.

Codon pair bias

A difference in the observed frequencies of 6-nucleotide codon pairs in a given set of sequences.

Phylodynamic study

A study that develops a quantitative model, incorporating both a pathogen phylogeny and epidemiological or immunological data, to describe an infectious disease.

Error catastrophe

The loss of meaningful genetic information when a population is pushed beyond its maximum mutation rate. In theoretical models, the error catastrophe has been compared to a chemical phase transition, and a true error catastrophe has not been observed experimentally.

Lethal mutagenesis

The process whereby the number of viable individuals, or viruses, in a population is reduced through increases in the mutation rate.

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Lauring, A., Frydman, J. & Andino, R. The role of mutational robustness in RNA virus evolution. Nat Rev Microbiol 11, 327–336 (2013). https://doi.org/10.1038/nrmicro3003

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