Selection for Robustness in Mutagenized RNA Viruses

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Abstract
Mutational robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Whether robustness can be directly favored by natural selection remains controversial. Theory and in silico experiments predict that, at high mutation rates, slow-replicating genotypes can potentially outcompete faster counterparts if they benefit from a higher robustness. Here, we experimentally validate this hypothesis, dubbed the “survival of the flattest,” using two populations of the vesicular stomatitis RNA virus. Characterization of fitness distributions and genetic variability indicated that one population showed a higher replication rate, whereas the other was more robust to mutation. The faster replicator outgrew its robust counterpart in standard competition assays, but the outcome was reversed in the presence of chemical mutagens. These results show that selection can directly favor mutational robustness and reveal a novel viral resistance mechanism against treatment by lethal mutagenesis. Understanding the conditions that favor the constancy of phenotypes in the face of deleterious mutation pressure—mutational robustness—is an outstanding question in evolutionary biology. Theoretical and in silico studies utilizing digital organisms predict that slow-replicating populations can outcompete those with higher individual fitness if the former show greater robustness. This “survival of the flattest” hypothesis sits in contrast to most models of natural selection based on individual fitness, and hence challenges the “survival of the fittest” paradigm. In this work, the authors use experimental populations of the rapidly evolving vesicular stomatitis RNA virus to provide the first evidence of natural selection for mutational robustness. Based on the analysis of fitness distributions, genetic variability, and the ability to tolerate mutation accumulation, two populations with different levels of robustness were characterized. At artificially enhanced mutation rates following the application of mutagens, the more robust viral population outcompeted the other population despite having a lower replication rate. This study has important implications for lethal mutagenesis—an antiviral strategy that consists of increasing viral mutation rates through the use of mutagenic drugs—since selectively favored mutational robustness may allow RNA viruses to evolve resistance to this form of treatment.

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