Chapter 12 : Mutation, Quasispecies, and Lethal Mutagenesis

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Viral pathogenesis is not alien to the evolutionary history of a virus. Picornaviruses, simply by the fact of sharing a phylogenetic position, need not be associated with similar diseases, reflecting that the nature of the interactions with their host organisms may depend in a subtle manner on minimal genetic change of the virus. Picornaviruses have served to establish core concepts in the understanding of viruses as mutated collectivities and in establishing the relevance of quasispecies for viral pathogenesis. The adaptive potential of RNA viruses is also manifested in the response to selective agents administered to inhibit their replication. High mutation rates result in the almost-systematic selection of viral mutants resistant to antiviral inhibitors, either because resistant mutants are present in mutant spectra or because they are rapidly generated during viral replication. The participation of interfering genomes in virus extinction constitutes the basis of the lethal defection model of virus extinction by enhanced mutagenesis. The initial experiments to test the validity for RNA viruses of the error threshold concept consisted of documenting an adverse effect on viral infectivity as a result of increasing the mutation rate of poliovirus (PV) and vesicular stomatitis virus by chemical mutagens and base and nucleoside analogues added during viral RNA replication. Genetic modifications upon extensive passage of FMDV in BHK- 21 cells included genomes with internal in-frame deletions that were infectious by complementation in the absence of standard, wildtype genomes.

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12
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Image of Figure 1.
Figure 1.

Scheme of a viral quasispecies and the effects of population size on the evolution of fitness values. Distribution 1 is a typical mutant spectrum in which individual genomes are depicted as horizontal lines and mutations as various symbols on the lines. Replication of distribution 1 as large population passages results in a new mutant distribution (depicted on the right) and fitness gain (triangle below the mutant distributions). Fitness gain can occur with or without variation of the consensus sequence (top lines). When a single genome from distribution 1 is allowed to replicate, the most severe form of bottleneck occurs. This results in a modification of the consensus sequence, because the mutations present in the founder genome are maintained in progeny genomes (distribution 2). Multiple bottleneck events (realized in the laboratory as plaque-to-plaque transfers) result in accumulation of mutations in the consensus sequence and fitness loss (distribution on the left; subjected to N plaque transfers [N]). Fluctuations in fitness values are observed when viral populations reach very high or very low fitness values. The scheme is based on results with several RNA viruses described or reviewed in references , and . (Modified from reference .)

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12
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Image of Figure 2.
Figure 2.

Schematic representation of intra-mutant spectrum interactions. With standard mutation rates (left), complementing interactions, promoted mainly by -acting gene products, dominate (thin arrows). As mutation rates increase (right), defective, -acting products are produced that interfere with replication of other individuals (thick arrows). (Based on references , and .)

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12
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Image of Figure 3.
Figure 3.

Molecular representation of the inhibitor of picornavirus replication, guanidine, and the standard nucleosides and mutagenic nucleoside analogs used in studies on lethal mutagenesis of FMDV described in this chapter.

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12
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Table 1.

Some biological consequences of quasispecies dynamics for RNA virus behavior

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12
Generic image for table
Table 2.

Examples of the frequency of drug-escape mutants in picornaviruses

Citation: Domingo E, Perales C, Agudo R, Arias A, Escarmís C, Ferrer-Orta C, Verdaguer N. 2010. Mutation, Quasispecies, and Lethal Mutagenesis, p 197-211. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch12

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