Congruent Evolution of Fitness and Genetic Robustness in Vesicular Stomatitis Virus

Abstract

bQuasispecies theory is a case of mutation-selection balance for evolution at high mutation rates, such as those observed in RNA viruses. One of the main predictions of this model is the selection for robustness, defined as the ability of an organism to remain phenotypically unchanged in the face of mutation. We have used a collection of vesicular stomatitis virus strains that had been evolving either under positive selection or under random drift. We had previously shown that the former increase in fitness while the latter have overall fitness decreases (I. S. Novella, J. B. Presloid, T. Zhou, S. D. Smith-Tsurkan, B. E. Ebendick-Corpus, R. N. Dutta, K. L. Lust, and C. O. Wilke, J. Virol. 84:4960 -4968, 2010). Here, we determined the robustness of these strains and demonstrated that strains under positive selection not only increase in fitness but also increase in robustness. In contrast, strains under drift not only decreased in fitness but also decreased in robustness. There was a good overall correlation between fitness and robustness. We also tested whether there was a correlation between fitness and thermostability, and we observed that the correlation was imperfect, indicating that the fitness effects of mutations are exerted in part at a level other than changing the resistance of the protein to temperature. E rror-prone replication in RNA viruses results in the development of quasispecies populations (1-4), clouds of closely related mutants in mutation-selection balance (5-7). In quasispecies populations, increased genetic robustness can provide a selective advantage (8-11), because a smaller number of offspring are lost to deleterious or lethal mutations. Genetic robustness here is defined as phenotypic invariance despite mutational pressure (12). In terms of fitness landscapes, selection for robustness favors those populations that sit on broad fitness peaks instead of narrow fitness peaks. Studies on digital organisms showed the preference for this type of broad peaks and led to the expression "survival of the flattest" (13). Many of the studies addressing the relevance of genetic robustness on the evolution of RNA molecules are computer analyses and simulated evolution (11,(14)(15)(16)(17). This approach has led to the identification of selection for robustness in hepatitis C virus genomes (18) and microRNA (19).Vesicular stomatitis virus (VSV) provided the first evidence that a low-fitness strain could outcompete a high-fitness strain (20), and these results were confirmed with phage phi-6 (21). One can predict that, all else being equal, the evolution of robustness is a function of the strength of selection, and that environmental factors that diminish selection also result in less robustness. Complementation is one such factor (22-25), because the phenotype of one strain is not always determined by its genetic makeup and, instead, is the result of a gene product from another strain. High levels of complementation, which occur at a high multiplicity of infection (MOI), would result in lower overall...

The Mutational Robustness of Influenza A Virus

“…An alternative approach commonly used in RNA viruses is to accelerate mutation accumulation by passaging virus in the presence of mutagenic drugs [30–32]. While both methods provide valuable information about the average fitness impact of random mutation, uncertainty about the number of mutations per clone and the fitness effect of each individual mutation makes it difficult to accurately model a distribution.…”

Antigenic diversification is correlated with increased thermostability in a mammalian virus

“…All of the 40-adapted viruses were more stable to the 37°C (Figure 2a), and three of six were more stable to the 42°C (Figure 2b) treatment than the average of the WT ancestor, with averages of 35% virus survival/day (p = 0.0026) and 1.2% survival/day (p = 0.0334), respectively. We had shown previously that adapted controls had no overall increase in thermostability at 37°C or 39°C [29]. The 37-adapted strains were not significantly more thermostable than these adapted controls at 37°C (p = 0.9900) while the 40-adapted strains were (p = 0.0103).…”

“…The literature is even scarcer for animal viruses. Work with VSV showed an imperfect correlation between mutational robustness and thermostability [29]. Specifically, virus strains that evolved under selection were found to have increased their genetic robustness without an overall change in thermostability.…”

Determining the Cellular Diversity of Hepatitis C Virus Quasispecies by Single-Cell Viral Sequencing

“…This may be the case with the synonymous transitional substitution at position 272 (an A-to-G nucleotide change), which was particularly, although not exclusively, associated with the T287A mutation. Synonymous substitutions are associated with robustness within a quasispecies, allowing exploration of sequence space without phenotypical changes and increasing the potential for rapid adaptation (42). The silent substitution at position 272 did not alter the single-step mutational availability of amino acids compared to the wt.…”