The cost of replication fidelity in an RNA virus

Abstract

It is often argued that high mutation rates are advantageous for RNA viruses, because they confer elevated rates of adaptation. However, there is no direct evidence showing a positive correlation between mutation and adaptation rates among RNA viruses. Moreover, theoretical work does not argue in favor of this prediction. We used a series of vesicular stomatitis virus clones harboring single amino acid substitutions in the RNA polymerase to demonstrate that changes inducing enhanced fidelity paid a fitness cost, but that there was no positive correlation between mutation an adaptation rates. We demonstrate that the observed mutation rate in vesicular stomatitis virus can be explained by a trade-off between replication rate and replication fidelity.fitness trade-off ͉ mutation rate ͉ adaptation ͉ experimental evolution M utation provides the allelic variation that natural selection can act on. Conversely, mutation rates show phenotypic variability, which turns out to be a target for selection. RNA viruses are characterized by high mutation rates compared with most DNA systems (1), due mainly to the lack of exonuclease proofreading activity displayed by their RNA polymerases (2). Current evidence suggests that this high mutation rate cannot simply be attributed to biochemical restrictions: in HIV-1, several antimutator retrotranscriptases have been described (3-6); Pfeiffer and Kierkegaard (7) showed that a single-residue mutation in the RNA polymerase gene of type 1 poliovirus can confer resistance to ribavirine through a 3-fold increase in fidelity; Pugachev et al. (8) suggested that mutation rate in the yellow fever virus could be as low as 2 ϫ 10 Ϫ7 mutations per nucleotidic site per replication round. Such evidence demonstrates the need for an evolutionary model that accounts for high mutation rates in RNA viruses beyond a purely mechanistic level.It is often argued that high mutation rates in RNA viruses are favored, because they confer a greater adaptive capacity (9, 10). However, there is still no experimental proof for this selective advantage: no evidence has been found to support a positive correlation between mutation and adaptation rates, as one would expect according to this hypothesis. A substantial part of our knowledge on the nexus between mutation and adaptation comes from experiments exploring the dynamics of mutator and antimutator genotypes in Escherichia coli (e.g., ref. 11), where high mutation rates have been associated with increased population fitness, because of the genetic hitchhiking of the mutator allele with beneficial changes produced at other loci. The hitchhiking hypothesis (12) might explain why high error rates could have risen and could have been maintained in RNA viruses, especially in the absence of recombination. On the other hand, the vast majority of mutations having a phenotypic effect are deleterious. Then, short-term selection should favor lower mutation rates, to minimize the genetic load (Fig. 1). Moreover, under high mutation rates, favorable alleles will frequently...

Viral Mutation Rates

“…A specific method for estimating mutation rates per strand copying which avoids this problem is the Luria-Delbrück fluctuation test (55,56). Its application to viruses has been described elsewhere (12,36,55,81,85,86). Briefly, the method consists of seeding from the same source a large number of parallel cultures using a small inoculum, harvesting them, and selecting for a specific phenotype.…”

Experimental evolution and the dynamics of genomic mutation rate modifiers

“…Given the potential for pleiotropy among diverse gene products that has been revealed by recent genomic approaches (Paaby and Rockman, 2013;Solovieff et al, 2013), there remains a clear need for experiments testing whether mutation rate modifiers themselves have direct selective effects. Limited studies, for example, have shown that enhanced replication fidelity (lower mutation rate) may decrease replication rate in some viruses and thus be directly costly (Furio et al, 2005;Furio et al, 2007). A recent study in Pseudomonas aeruginosa also showed that a mutS mutator allele can provide inherent resistance to oxidative stress and so could have a direct fitness benefit in certain environments (Torres- Barceló et al, 2013).…”

The cost of replication fidelity in human immunodeficiency virus type 1

“…Using a series of vesicular stomatitis virus (VSV) mutants carrying single amino acid substitutions in the RNA polymerase gene, it was shown that changes leading to lower mutation rates also led to slower growth rates, indicating that fidelity paid a fitness cost (Furió et al 2005). However, the biochemical basis of this cost remains unclear.…”