scholarly journals A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus

2018 ◽  
Author(s):  
William Fitzsimmons ◽  
Robert J. Woods ◽  
John T. McCrone ◽  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Experimental Evolution ◽  
Rna Viruses ◽  
Fundamental Problem ◽  
Rna Virus ◽  
Mutation Rates ◽  
Direct Selection ◽  
Growth Defect ◽  
Infection Model ◽  
Selection For

AbstractMutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous, because they may allow for increased adaptability. This argument has profound implications, as it suggests that pathogenesis in many viral infections depends on rare orde novomutations. Here we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild type and 3DG64Spopulations have similar adaptability in two distinct cellular environments. Experimental evolution of 3DG64Sunder r-selection led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64Sexhibited delayed morbidity at doses well above the LD50, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64Sgrowth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast to what has been suggested for many RNA viruses, we find that within host spread is associated with viral replicative speed and not standing genetic diversity.Author SummaryMutation rate evolution has long been a fundamental problem in evolutionary biology. The polymerases of RNA viruses generally lack proofreading activity and exhibit extremely high mutation rates. Since most mutations are deleterious and mutation rates are tuned by natural selection, we asked why hasn’t the virus evolved to have a lower mutation rate? We used experimental evolution and a murine infection model to show that RNA virus mutation rates may actually be too high and are not necessarily adaptive. Rather, our data indicate that viral mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. We suggest that viruses have high mutation rates, not because they facilitate adaption, but because it is hard to be both fast and accurate.

scholarly journals Upper-limit mutation rate estimation for a plant RNA virus

2009 ◽  
Vol 5 (3) ◽  
pp. 394-396 ◽  
Author(s):  
Rafael Sanjuán ◽  
Patricia Agudelo-Romero ◽  
Santiago F. Elena
Keyword(s):  
Mutation Rate ◽  
Rna Viruses ◽  
Rna Virus ◽  
Plant Viruses ◽  
Mutation Rates ◽  
Methodological Error ◽  
Direct Estimate ◽  
Rate Estimation ◽  
Mutation Rate Estimation

It is generally accepted that mutation rates of RNA viruses are inherently high due to the lack of proofreading mechanisms. However, direct estimates of mutation rate are surprisingly scarce, in particular for plant viruses. Here, based on the analysis of in vivo mutation frequencies in tobacco etch virus , we calculate an upper-bound mutation rate estimation of 3×10 −5 per site and per round of replication; a value which turns out to be undistinguishable from the methodological error. Nonetheless, the value is barely on the lower side of the range accepted for RNA viruses, although in good agreement with the only direct estimate obtained for other plant viruses. These observations suggest that, perhaps, differences in the selective pressures operating during plant virus evolution may have driven their mutation rates towards values lower than those characteristic of other RNA viruses infecting bacteria or animals.

scholarly journals The Rate and Character of Spontaneous Mutation in an RNA Virus

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1505-1511 ◽  
Author(s):  
José M Malpica ◽  
Aurora Fraile ◽  
Ignacio Moreno ◽  
Clara I Obies ◽  
John W Drake ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Movement Protein ◽  
Rna Viruses ◽  
Rna Virus ◽  
Spontaneous Mutation ◽  
Mutation Rates ◽  
Lower Side ◽  
Mutation Process ◽  
Spontaneous Mutation Rate ◽  
Mutant Frequency

Abstract Estimates of spontaneous mutation rates for RNA viruses are few and uncertain, most notably due to their dependence on tiny mutation reporter sequences that may not well represent the whole genome. We report here an estimate of the spontaneous mutation rate of tobacco mosaic virus using an 804-base cognate mutational target, the viral MP gene that encodes the movement protein (MP). Selection against newly arising mutants was countered by providing MP function from a transgene. The estimated genomic mutation rate was on the lower side of the range previously estimated for lytic animal riboviruses. We also present the first unbiased riboviral mutational spectrum. The proportion of base substitutions is the same as that in a retrovirus but is lower than that in most DNA-based organisms. Although the MP mutant frequency was 0.02-0.05, 35% of the sequenced mutants contained two or more mutations. Therefore, the mutation process in populations of TMV and perhaps of riboviruses generally differs profoundly from that in populations of DNA-based microbes and may be strongly influenced by a subpopulation of mutator polymerases.

scholarly journals Viral Mutation Rates

2010 ◽  
Vol 84 (19) ◽  
pp. 9733-9748 ◽  
Author(s):  
Rafael Sanjuán ◽  
Miguel R. Nebot ◽  
Nicola Chirico ◽  
Louis M. Mansky ◽  
Robert Belshaw
Keyword(s):  
Mutation Rate ◽  
Rna Viruses ◽  
Experimental Testing ◽  
Mutation Rates ◽  
Cell Infection ◽  
Nucleotide Substitutions ◽  
Data Set ◽  
Dna Viruses ◽  
Double Stranded Dna ◽  
Viral Mutation

ABSTRACT Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10−8 to10−6 s/n/c for DNA viruses and from 10−6 to 10−4 s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut .

scholarly journals The evolution of bacterial mutation rates under simultaneous selection by interspecific and social parasitism

2013 ◽  
Vol 280 (1773) ◽  
pp. 20131913 ◽  
Author(s):  
Siobhán O'Brien ◽  
Antonio M. M. Rodrigues ◽  
Angus Buckling
Keyword(s):  
Mutation Rate ◽  
Social Parasitism ◽  
Mutation Rates ◽  
Bacterial Populations ◽  
Simultaneous Selection ◽  
Bacterial Mutation ◽  
Selection For ◽  
Intraspecific Parasitism ◽  
Theory And Experiments ◽  
Mutation Rate Evolution

Many bacterial populations harbour substantial numbers of hypermutable bacteria, in spite of hypermutation being associated with deleterious mutations. One reason for the persistence of hypermutators is the provision of novel mutations, enabling rapid adaptation to continually changing environments, for example coevolving virulent parasites. However, hypermutation also increases the rate at which intraspecific parasites (social cheats) are generated. Interspecific and intraspecific parasitism are therefore likely to impose conflicting selection pressure on mutation rate. Here, we combine theory and experiments to investigate how simultaneous selection from inter- and intraspecific parasitism affects the evolution of bacterial mutation rates in the plant-colonizing bacterium Pseudomonas fluorescens. Both our theoretical and experimental results suggest that phage presence increases and selection for public goods cooperation (the production of iron-scavenging siderophores) decreases selection for mutator bacteria. Moreover, phages imposed a much greater growth cost than social cheating, and when both selection pressures were imposed simultaneously, selection for cooperation did not affect mutation rate evolution. Given the ubiquity of infectious phages in the natural environment and clinical infections, our results suggest that phages are likely to be more important than social interactions in determining mutation rate evolution.

scholarly journals Epistatic interactions within the influenza virus polymerase complex mediate mutagen resistance and replication fidelity

2017 ◽  
Author(s):  
Matthew D. Pauly ◽  
Daniel M. Lyons ◽  
Adam S. Lauring
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Influenza Virus ◽  
Mutation Rate ◽  
Rna Viruses ◽  
Nucleoside Analogs ◽  
Mutation Rates ◽  
Epistatic Interactions ◽  
Polymerase Complex ◽  
Lethal Mutagenesis

AbstractLethal mutagenesis is a broad-spectrum antiviral strategy that employs mutagenic nucleoside analogs to exploit the high mutation rate and low mutational tolerance of many RNA viruses. Studies of mutagen-resistant viruses have identified determinants of replicative fidelity and the importance of mutation rate to viral population dynamics. We have previously demonstrated the effective lethal mutagenesis of influenza virus using three nucleoside analogs as well as the virus’s high genetic barrier to mutagen resistance. Here, we investigate the mutagen-resistant phenotypes of mutations that were enriched in drug-treated populations. We find that PB1 T123A has higher replicative fitness than the wild type, PR8, and maintains its level of genome production during 5-fluorouracil treatment. Surprisingly, this mutagen-resistant variant also has an increased baseline rate of C to U and G to A mutations. A second drug-selected mutation, PA T97I, interacts epistatically with PB T123A to mediate high-level mutagen resistance, predominantly by limiting the inhibitory effect of nucleosides on polymerase activity. Consistent with the importance of epistatic interactions in the influenza polymerase, we find that nucleoside analog resistance and replication fidelity are strain dependent. Two previously identified ribavirin-resistance mutations, PB1 V43I and PB1 D27N, do not confer drug resistance in the PR8 background, and the PR8-PB1 V43I polymerase exhibits a normal baseline mutation rate. Our results highlight the genetic complexity of the influenza virus polymerase and demonstrate that increased replicative capacity is a mechanism by which an RNA virus can counter the negative effects of elevated mutation rates.ImportanceRNA viruses exist as genetically diverse populations. This standing genetic diversity gives them the potential to adapt rapidly, evolve resistance to antiviral therapeutics, and evade immune responses. Viral mutants with altered mutation rates or mutational tolerance have provided insights into how genetic diversity arises and how it affects the behavior of RNA viruses. To this end, we identified variants within the polymerase complex of influenza virus that are able tolerate drug-mediated increases in viral mutation rates. We find that drug resistance is highly dependent on interactions among mutations in the polymerase complex. In contrast to other viruses, influenza virus counters the effect of higher mutation rates primarily by maintaining high levels of genome replication. These findings suggest the importance of maintaining large population sizes for viruses with high mutation rates and show that multiple proteins can affect both mutation rate and genome synthesis.

scholarly journals Biased Mutation and Selection in RNA Viruses

2020 ◽  
Author(s):  
Talia Kustin ◽  
Adi Stern
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Purifying Selection ◽  
Nucleotide Composition ◽  
Host Cells ◽  
Mutational Bias ◽  
Data Set ◽  
Coding Sequences ◽  
Sequence Composition ◽  
Selection For

Abstract RNA viruses are responsible for some of the worst pandemics known to mankind, including outbreaks of Influenza, Ebola, and COVID-19. One major challenge in tackling RNA viruses is the fact they are extremely genetically diverse. Nevertheless, they share common features that include their dependence on host cells for replication, and high mutation rates. We set out to search for shared evolutionary characteristics that may aid in gaining a broader understanding of RNA virus evolution, and constructed a phylogeny-based data set spanning thousands of sequences from diverse single-stranded RNA viruses of animals. Strikingly, we found that the vast majority of these viruses have a skewed nucleotide composition, manifested as adenine rich (A-rich) coding sequences. In order to test whether A-richness is driven by selection or by biased mutation processes, we harnessed the effects of incomplete purifying selection at the tips of virus phylogenies. Our results revealed consistent mutational biases toward U rather than A in genomes of all viruses. In +ssRNA viruses, we found that this bias is compensated by selection against U and selection for A, which leads to A-rich genomes. In −ssRNA viruses, the genomic mutational bias toward U on the negative strand manifests as A-rich coding sequences, on the positive strand. We investigated possible reasons for the advantage of A-rich sequences including weakened RNA secondary structures, codon usage bias, and selection for a particular amino acid composition, and conclude that host immune pressures may have led to similar biases in coding sequence composition across very divergent RNA viruses.

Experimental evolution with Drosophila

2009 ◽  
Vol 296 (6) ◽  
pp. R1847-R1854 ◽  
Author(s):  
Molly K. Burke ◽  
Michael R. Rose
Keyword(s):  
Stress Resistance ◽  
Experimental Evolution ◽  
Life History Traits ◽  
Model Organism ◽  
Direct Selection ◽  
Genomic Technologies ◽  
Drosophila Model ◽  
Powerful Approach ◽  
Selection For ◽  
Insight Into

Experimental evolution is a powerful approach that can be used for the study of adaptation. Evolutionary biologists often use Drosophila as a model organism in experiments that test theories about the evolution of traits related to fitness. Such evolution experiments can take three forms: direct selection for a trait of interest; surveys of traits of interest in populations selected for other traits; and reverse selection. We review some of the Drosophila experiments that have provided insight into both the evolution of particular physiological traits and the correlations between physiological and life history traits, focusing on stress resistance. The most common artifacts that can obscure the results from evolution experiments are discussed. We also include a treatment of genomic technologies that are now available for the Drosophila model. The primary goal of this review is to introduce the kind of experimental evolution strategies and technologies that evolutionary physiologists might use in the future.

scholarly journals Host proteostasis modulates influenza evolution

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Angela M Phillips ◽  
Luna O Gonzalez ◽  
Emmanuel E Nekongo ◽  
Anna I Ponomarenko ◽  
Sean M McHugh ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Viral Evolution ◽  
Virus Evolution ◽  
Critical Force ◽  
Host Cells ◽  
Mutation Rates ◽  
Biophysical Properties ◽  
And Function ◽  
Protein Variants

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host–pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.

scholarly journals The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates

2017 ◽  
Vol 13 (4) ◽  
pp. e1006254 ◽  
Author(s):  
Everett Clinton Smith
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Mutation Rates

scholarly journals Replication Mode and Landscape Topology Differentially Affect RNA Virus Mutational Load and Robustness

2009 ◽  
Vol 83 (23) ◽  
pp. 12579-12589 ◽  
Author(s):  
Josep Sardanyés ◽  
Ricard V. Solé ◽  
Santiago F. Elena
Keyword(s):  
Mutation Rate ◽  
Fitness Landscape ◽  
Rna Virus ◽  
Geometric Model ◽  
Mutation Rates ◽  
Machine Model ◽  
Wide Range ◽  
String Models ◽  
Complementary Sense ◽  
Geometric Growth

ABSTRACT Regardless of genome polarity, intermediaries of complementary sense must be synthesized and used as templates for the production of new genomic strands. Depending on whether these new genomic strands become themselves templates for producing extra antigenomic ones, thus giving rise to geometric growth, or only the firstly synthesized antigenomic strands can be used to this end, thus following Luria's stamping machine model, the abundances and distributions of mutant genomes will be different. Here we propose mathematical and bit string models that allow distinguishing between stamping machine and geometric replication. We have observed that, regardless the topology of the fitness landscape, the critical mutation rate at which the master sequence disappears increases as the mechanism of replication switches from purely geometric to stamping machine. We also found that, for a wide range of mutation rates, large-effect mutations do not accumulate regardless the scheme of replication. However, mild mutations accumulate more in the geometric model. Furthermore, at high mutation rates, geometric growth leads to a population collapse for intermediate values of mutational effects at which the stamping machine still produces master genomes. We observed that the critical mutation rate was weakly dependent on the strength of antagonistic epistasis but strongly dependent on synergistic epistasis. In conclusion, we have shown that RNA viruses may increase their robustness against the accumulation of deleterious mutations by replicating as stamping machines and that the magnitude of this benefit depends on the topology of the fitness landscape assumed.

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