Virus Evolution


Viruses are transmissible deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) genetic elements that require a cell for multiplication. Viruses are diverse and ubiquitous in nature. They evolve in continuous interaction with their host cells and organisms, following Darwinian principles: genetic variation, competition among variant forms, selection of the most fit variants in a given environment, and random drift of genomes favoured by bottleneck events. Viruses probably had an ancient origin and survived as agents of gene transfer and promoters of cell variation. Disease is a side effect of virus‐host interactions. RNA viruses and some DNA viruses can evolve very rapidly, fuelled by limited template‐copying fidelity of the polymerases that catalyse their replication. Their populations are extremely complex mutant clouds termed viral quasispecies, with a continuously changing mutant composition. Interactions of cooperation or interference can be established among genomes and their expression products within a mutant spectrum, giving rise to new phenotypic traits. Adaptability mediated by quasispecies dynamics represents a problem for disease prevention and control, but it has inspired new strategies to combat viral disease, such as new vaccine designs, recognition of the need of combination therapies in antiviral pharmacology and the development of lethal mutagenesis or viral extinction driven by an excess of mutations.

Key Concepts

  • Virions are the virus particles produced upon completion of the intracellular replication cycle.
  • Cells can be infected via different entry pathways, and by single virions or multiple particles through vesicles or cell‐to‐cell contacts. Inter‐host transmission of virions can give rise to disease outbreaks, epidemics or pandemics (worldwide epidemics).
  • Deep sequencing methodology has unveiled great diversity of viruses during infection, as well as in natural habitats. The ensemble of viruses in our biosphere is termed the ‘virosphere’.
  • The total number of virus particles in the biosphere at any given point in time is estimated from 1031 to 1032, 10 times more than cells.
  • Mutation, recombination, segment reassortment, and gene transfers between cells and viruses contribute to virus diversity.
  • Several theories of virus origins have been proposed. A currently favoured view is that viruses have an ancestral origin and have contributed to shape the cellular world mainly through gene transfers.
  • RNA viruses and some DNA viruses are replicated by low‐fidelity polymerases (with a propensity to introduce mutations). As a consequence, such viruses constitute mutant spectra (swarms or clouds) termed viral quasispecies.
  • There is an arms race between viruses and the host response to prevent infection. Some proteins that play physiological functions in cells can be recruited as part of the innate immunity against viruses.
  • Viral fitness measures the relative replicative capacity of a virus in a given environment. Population bottlenecks may alter viral fitness and influence evolutionary outcomes.
  • The adaptive potential of viral quasispecies has encouraged research in new strategies for viral disease prevention and control.

Keywords: genome replication; genetic variation; coevolution; quasispecies; antiviral strategies

Figure 1. Some general concepts of virus evolution. (a) Genomic sequence alignments of related viruses often show conservation of functional domains (blocks) although they may vary in size, nucleotide sequence, relative position or orientation (block depicted by an arrow in the last two genomes). Sequence alignments of related viral genomes are the first data sets to be used for phylogenetic analyses. (b) Viral genomic sequences can be related by phylogenetic trees. Branches represent minimal genetic distances (nucleotide differences) among the different isolates. Clusters of related viruses are often referred to as clades, types or subtypes. Each tip of a branch is represented by a cloud to indicate the multiple variants that are often found in each viral isolate. Clouds are generally larger for RNA viruses than for complex DNA viruses. Deviant representatives of a distant cloud (arrow) may originate a new virus group that will undergo further diversification.
Figure 2. Mutation rates and frequencies. Cellular DNA replication is several orders of magnitude more accurate than RNA virus genome replication or retrotranscription. An average mutation rate of 10−4 means that one misincorporation error at a given nucleotide template will occur once every 10 000 times that the polymerase copies this specific nucleotide. For both cellular DNA and viral RNA, mutation rates and frequencies much higher than average have been described (hypermutability). For RNA genomes mutation rates and frequencies lower than average may also occur (hypomutability). For specific studies on mutation rates and frequencies see the References and Further Reading. Terms are defined in Table .
Figure 3. Viral quasispecies and the effect of sampling events. (a) Horizontal lines represent genomes and symbols on lines represent different types of mutations. A selection event (or a transmission bottleneck; that is, a single genome is the origin of next distribution) leads to a change in the average sequence (discontinuous arrow, right, where a single genome depicted as a discontinuous line generates the progeny displayed in the distribution on the right). In contrast, the large shaded arrow depicts replication of multiple genomes (massive infections) that give rise to the new distribution on the left, endowed with higher replicative fitness. The average sequence is also termed the consensus sequence, and it is the one that includes at any position the nucleotide found most frequently in that position of the sequence distribution. Sequence distribution is also termed the mutant spectrum or mutant cloud of the quasispecies. Massive infections may result in an invariant consensus sequence despite a dynamic (changing) mutant spectrum. Source: From Domingo, E., Sheldon, J., & Perales, C. . Viral Quasispecies Evolution. Microbiology and Molecular Biology Reviews, 76(2), 159–216. doi: 10.1128/mmbr.05023‐11. © 2012 American Society for Microbiology. (b) Deep sequencing has evidenced a time‐dependent changing complexity of viral quasispecies in vivo and in cell culture. The two panels display the frequency variation of specific mutations (colour coded) of HCV passaged 200 times in human hepatoma cells. The coloured lines are included for visualisation of mutant frequency differences between the five experimental points. The agreement between the results obtained by molecular cloning‐Sanger sequencing and pyrosequencing excludes that fluctuations are a consequence of a sampling artefact. Source: From Moreno, E., Gallego, I., Gregori, J., Lucía‐Sanz, A., Soria, M. E., Castro, V., … Perales, C. . Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment. Journal of Virology, 91(10). doi:10.1128/jvi.02505‐16. © 2017 American Society for Microbiology. (c) The effect of population size on the heterogeneity of an infecting viral population. In the population delimited by the large external rectangle, four types of relevant variants exist (for example drug‐resistant mutants depicted as a circle, triangle, square and star). Depending on the sampled size (circles of different diameters) different variants will participate in the next round of infection. Source: Adapted from Domingo, E., Sheldon, J., & Perales, C. . Viral Quasispecies Evolution. Microbiology and Molecular Biology Reviews, 76(2), 159–216. doi:10.1128/mmbr.05023‐11.
Figure 4. Genetic shift and drift. Two forms of a virus consisting of a genome with eight segments, depicted in black or white, can form a reassortant made of different numbers of black and white segments when the two virus forms coinfect the same cell. The event that leads to the reassortment is genetic shift. When the reassorted (white) segments encode different antigenically relevant proteins the phenomenon is termed antigenic shift. Further evolution through point mutations (depicted as different symbols on the white segments) is termed genetic or antigenic drift.


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Further Reading

Domingo E, Parrish C and Holland JJ (eds) (2008) Origin and Evolution of Viruses, 2nd edn. Elsevier: Oxford.

Eigen M (1992) Steps Towards Life. Oxford University Press: Oxford.

Eigen M (2013) From Strange Simplicity to Complex Familiarity. Oxford University Press: Oxford.

Ehrenfeld E, Domingo E and Ross RP (2010) The Picornaviruses. ASM Press: Washington DC.

Flint SJ, Racaniello VR, Rall GF, Skalka AM and Enquist LW (2015) Principles of Virology, 4th edn. ASM Press: Washington DC.

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Domingo, Esteban, and Perales, Celia(Dec 2020) Virus Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0029222]