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

William Fitzsimmons; Robert J. Woods; John T. McCrone; Andrew Woodman; Jamie J. Arnold; Madhumita Yennawar; Richard Evans; Craig E. Cameron; Adam S. Lauring

direct selection for a higher mutation rate [19, 23, 26] ). Similarly, we find that the widely accepted 274 link between within host genetic diversity and virulence is confounded by the fact that faster 275 replicating viruses are both more virulent and have higher mutation rates. The high mutation 276 rates of RNA viruses and the highly deleterious fitness effects of mutations ensure that most 277 genetic diversity is extremely rare and unlikely to be consistently maintained in the face of 278 intrahost and interhost bottlenecks [52]. We do not dispute that virus populations will harbor 279 minority variants, that a subset of these mutations may be adaptive or beneficial to the virus, 280 and that some may be virulence determinants. However, the observation of genetic diversity is 281 not in and of itself evidence that selection has optimized mutation rates for the future benefit of 282 novel mutations. Indeed, our data show little adaptive benefit to a marginally increased mutation 283 rate and identify no plausible mechanism whereby the observed increase in rare genetic 284 diversity can influence pathogenesis. We suspect that RNA viruses are subject to other trade-12 offs of evolutionary significance, perhaps between polymerase speed and recombination rate or 286 recombination rate and polymerase fidelity. Here too, it will be important to define the selective 287 forces at play, thereby separating the causes from the consequences.