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

To understand the effect of a mutagen on the relative fitness of one strain to another, we add a 870 mutation rate multiplier (mu external, σ), which multiplicatively modifies the baseline mutation 871 rate. We constrain σ to take values greater than one. The G64S mutation has two effects (see also Fig. 1F ). The mutation results in an increase in 892 fidelity, represented as a downward shift in the line. The mutation also results in relative 893 resistance to ribavirin, which manifests as a decreased slope. Both of these need to be included 894 to estimate the mutational load experienced by WT and the 3D G64S mutant replicating in the 895 presence of increasing mutagen. Linear regression fit to both the WT and 3D G64S mutation rate 896 produce a good fit (r 2 of .73 and .76 respectively) that is highly statistically significant (p < 0.001 897 for both). The fit of the linear regression was used to estimate the mutation rate for WT and 898 3D G64S in the absence of ribavirin (1.34 x 10 -5 s/n/r and 3.43 x10 -6 s/n/r respectively) and at the 899 point of equilibrium.