Viral quasispecies

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Viral quasispecies
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A viral quasispecies is a group of viruses related by a similar mutation or mutations, competing within a highly mutagenic environment. The theory predicts that a viral quasispecies at a low but evolutionarily neutral and highly connected (that is, flat) region in the fitness landscape will outcompete a quasispecies located at a higher but narrower fitness peak in which the surrounding mutants are unfit. This phenomenon has been called 'the quasispecies effect' or, more recently, the 'survival of the flattest'.Originally used by Manfred Eigen to model the evolution of the first macromolecules on earth, the quasispecies concept has been applied to populations of a virus within its host.JOURNAL, Nowak, M.A., 1992, What is a quasispecies?, Trends in Ecology and Evolution, 7, 4, 118–121, 10.1016/0169-5347(92)90145-2, 21235976, The quasispecies model is deemed to be relevant to RNA viruses because they have high mutation rates in the order of one per round of replication,Drake, J.W. & Holland, J.J. (1999). Proc. Natl Acad. Sci. USA. 96:13910-3 and viral populations, while not infinite, are extremely large. Thus the practical conditions for quasispecies formation are thought to exist.The significance of the quasispecies model for virology is that, if the mutation rate is sufficiently high, selection acts on clouds of mutants rather than individual sequences.Wilke, C. (2005). BMC Evol. Biol. 5:44 Therefore, the evolutionary trajectory of the viral infection cannot be predicted solely from the characteristics of the fittest sequence.The importance of quasispecies concepts in virology has been the subject of some discussion.Holmes, E.C. & Moya, A. (2002). J Virol 76:460-462Domingo, E. (2002). J. Virol. 76:463-465Tannenbaum, E.D & Shakhnovich, E. (2004). Physical Review E 70:02193 Significantly, it has been shown that there is no necessary conflict between a quasispecies model of intra-host evolution and traditional population genetics. Instead, viral quasispecies can be considered as cases of coupled mutation-selection balance models for haploid organisms.It may be useful to understand the etymology of the term. Quasispecies are clouds of related elements that behave almost (quasi) like a single type of molecule (species). There is no suggestion that a viral quasispecies resembles a traditional biological species.

Possible consequences for viral evolution

(File:Viral_quasispecies_sharp_peak.gif|thumb|fig. 1: A sharp selection profile.|200px|right|fig. 1: A sharp selection profile.)(File:Viral_quasispecies_more_realistic_peak.gif|thumb|fig. 2: A broader, more realistic selection profile.|200px|right|fig. 2: A broader, more realistic selection profile.)

Error threshold

This may be defined as “The inability of a genetic element to be maintained in a population as the fidelity of its replication machinery decreases beyond a certain threshold value”.Summers J. & Litwin, S. (2006). J. Virol. 80:20-26In theory, if the mutation rate was sufficiently high, the viral population would not be able to maintain the genotype with the highest fitness, and therefore the ability of the population to adapt to its environment would be compromised. A practical application of this dynamic is in antiviral drugs employing lethal mutagenesis. For example, increased doses of the mutagen Ribavirin reduces the infectivity of Poliovirus.Crotty, S. et al. (2001) Proc. Natl Acad. Sci. USA. 98:6895-6900However, these models assume that only the mutations that occur in the fittest sequence are deleterious, and furthermore that they are non-lethal (fig. 1). It has been argued that, if we take into account the deleterious effect of mutations on the population of variants and the fact that many mutations are lethal (fig. 2), then the Error Threshold disappears, i.e. the fittest sequence always maintains itself.Wagner G.P. & Krall, P. (1993) J. Math. Biol. 32:33–44. Empirical data on the effect of mutations in viruses is rare, but appears to correspond more closely to fig. 2.Sanjuan et al. (2004) Proc. Natl Acad. Sci. USA. 101:8396-8401

Mutational robustness

The long-term evolution of the virus may be influenced in that it may be a better evolutionarily stable strategy to generate a broad quasispecies with members of approximately equal fitness than to have a sharply defined 'most fit' single genotype (with mutational neighbours substantially less fit). This has been called 'survival of the flattest' - referring to the fitness profiles of the two strategies respectively.Wilke et al. (2001). Nature 412:331-333Over the long-term, a flatter fitness profile might better allow a quasispecies to exploit changes in selection pressure, analogous to the way sexual organisms use recombination to preserve diversity in a population. At least in simulations, a slower replicator can be shown to be able to outcompete a faster one in cases where it is more robust and the mutation rate is high.Nimwegen, E. et al. (1999). Proc. Natl Aca.d Sci. USA. 96:9716-9720(File:Visualization demonstrating survival of the flattest.gif|Visualization demonstrating the concept of the "survival of the flattest.")However, whether mutational robustness evolved or is intrinsic to genetic systems is unconfirmed, because the basic mechanism behind robustness would depend upon the peculiarities of each system.Elena, S.F., P Agudelo-Romero, P Carrasco, F M Codoñer, S Martín, C Torres-Barceló & R Sanjuán (2008) Experimental evolution of plant RNA viruses. Heredity 100: 478–483weblink


Experimental manipulation of poliovirus to give them a higher-fidelity polymerase – and hence reduce their mutation rate – showed these variants to have lower pathogenicity than wild-type sequences.Vignuzzi, M. et al. (2006) Nature 439:344-348 Pathogenicity could then be restored by mutagen application. This was interpreted to mean lower mutation rates had reduced the adaptability (or breadth) of the quasispecies. The mutant viruses extracted from brain tissue were not themselves pathogenic, and the authors speculate that there may be complementation between variant members of the quasispecies that could enable viruses to colonize different host tissues and systems.



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M.R.M. Parrott