Phenotypic mixing and hiding may contribute to memory in viral quasispecies

Wilke, Claus O.; Novella, Isabel S.

doi:10.1186/1471-2180-3-11

Cited by 59 publications

(27 citation statements)

References 66 publications

(46 reference statements)

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“…This result is not surprising for those changes reported in isolated clones, because RNA virus populations are in a dynamic equilibrium between the input of deleterious variants and purifying selection (13). Additionally, some of these variants could have been hidden from natural selection by genetic complementation, provided that multiplicity of infection was high enough (29,44). However, 18 of the mutations introduced were not found in isolated clones but in consensus sequence characterized for laboratory populations.…”

Section: Discussionmentioning

confidence: 48%

The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus

Sanjuán

Moya

Elena

2004

Proc. Natl. Acad. Sci. U.S.A.

545

582

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Little is known about the mutational fitness effects associated with single-nucleotide substitutions on RNA viral genomes. Here, we used site-directed mutagenesis to create 91 single mutant clones of vesicular stomatitis virus derived from a common ancestral cDNA and performed competition experiments to measure the relative fitness of each mutant. The distribution of nonlethal deleterious effects was highly skewed and had a long, flat tail. As expected, fitness effects depended on whether mutations were chosen at random or reproduced previously described ones. The effect of random deleterious mutations was well described by a log-normal distribution, with ؊19% reduction of average fitness; the effects distribution of preobserved deleterious mutations was better explained by a ␤ model. The fit of both models was improved when combined with a uniform distribution. Up to 40% of random mutations were lethal. The proportion of beneficial mutations was unexpectedly high. Beneficial effects followed a ␥ distribution, with expected fitness increases of 1% for random mutations and 5% for preobserved mutations.

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Section: Discussionmentioning

confidence: 48%

The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus

Sanjuán

Moya

Elena

2004

Proc. Natl. Acad. Sci. U.S.A.

545

582

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“…The implementation can easily be changed to model other situations, for example, (i) where a mutation has a fitness effect when it occurs in the vRNA but not when it occurs in the cRNA, as those molecules are not transcribed into mRNA and translated into a protein, or (ii) to encompass the delayed phenotypes of mutations (56,57), whereby deleterious or advantageous fitness effects are not fully observed, as the respective proteins are generated in a meaningful amount only at a later time. Such mechanisms might alter the likelihood that deleterious and adaptive mutations will occur, for example, by a deleterious mutation arising as a nondeleterious mutation in the cRNA and the compensatory mutation arising in the next replication round, such that deleterious vRNA is never formed and both mutations are effectively neutral.…”

Section: Discussionmentioning

confidence: 99%

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Fonville

2015

J Virol

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Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCEAdaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models. The fitness landscape of a pathogen is likely to have a rugged shape and consist of multiple optima. Reductions in fitness occur when underlying combinations of genetic mutations lead to an unfit or deleterious phenotype, creating depressions in the...

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“…Injured RNA genomes, even if they are dead, as such, may survive for at least some generations due to complementation, i.e., help provided in trans by proteins (or RNA cis-elements) encoded by their coinfecting viruses. This mechanism of cooperative interaction was described long ago for the case of drug-sensitive and drug-resistant (or -dependent) picornaviruses (293)(294)(295)(296)(297), but its wider biological relevance became especially appreciated after the realization that viral populations are represented by quasispecies, i.e., swarms of closely related but distinct individuals (10,14,32,73,(298)(299)(300)(301). The prolonged survival of impaired genomes owing to intrapopulation complementation may provide time for their adaptive remodeling, resulting in the restoration of their capacity for independent existence.…”

Section: Natural Tools For Curing Damaged Rna Genomesmentioning

confidence: 99%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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Phenotypic mixing and hiding may contribute to memory in viral quasispecies

Cited by 59 publications

References 66 publications

The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus

The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Emergency Services of Viral RNAs: Repair and Remodeling

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