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

William J Fitzsimmons,Madhumita Yennawar,Adam S Lauring,Craig E Cameron,Andrew Woodman,John T Mccrone,Jamie J Arnold,Richard Evans,Robert J Woods,Roland Regoes

doi:10.1371/journal.pbio.2006459

William J Fitzsimmons, Madhumita Yennawar + Show 8 more

Open Access

https://doi.org/10.1371/journal.pbio.2006459

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Abstract

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.

Highlights

Mutation is the ultimate source of genetic variation, and mutation rates can have a significant impact on evolutionary rate [1,2,3]
Many have argued for the adaptive benefit of high mutation rates in pathogenic microbes, which often exist in dynamic environments and are subject to host immune pressure [7,24,25]
The fitness of 3DG64S is 0.78 ± 0.01 (n = 3 replicates) relative to WT. This is a moderate fitness defect, falling in the 64th percentile in a dataset of 8,970 fitness values obtained for point mutants of poliovirus under similar conditions [16]

Summary

Introduction

Mutation is the ultimate source of genetic variation, and mutation rates can have a significant impact on evolutionary rate [1,2,3]. Given that most mutations are deleterious, the burden of excess mutational load will select against strains with abnormally high mutation rates [14,15,16,17]. This principle led Sturtevant to ask, “Why does the mutation rate not evolve to zero?” [18,19]. Direct selection of a variant with a higher mutation rate will only occur if it has been advantageous in the past, and in many cases, it has been difficult to separate the causes of a higher mutation rate from its consequences [19,26]

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