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

Abstract

27Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or 28 direct selection on the physicochemical cost of high fidelity. However, for many systems, it has 29 been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an 30 observed correlation between mutation rate and virulence has led many to argue that their 31 extremely high mutation rates are advantageous, because they may allow for increased 32 adaptability. This argument has profound implications, as it suggests that pathogenesis in many 33 viral infections depends on rare or de novo mutations. Here we present data for an alternative 34 model whereby RNA viruses evolve high mutation rates as a byproduct of selection for 35 increased replicative speed. We find that a poliovirus antimutator, 3D G64S , has a significant 36 replication defect and that wild type and 3D G64S populations have similar adaptability in two 37 distinct cellular environments. Experimental evolution of 3D G64S under r-selection led to 38 reversion and compensation of the fidelity phenotype. Mice infected with 3D G64S exhibited 39 delayed morbidity at doses well above the LD 50 , consistent with attenuation by slower growth as 40 opposed to reduced mutational supply. Furthermore, compensation of the 3D G64S growth defect 41 restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent 42 with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more 43 important than accuracy. In contrast to what has been suggested for many RNA viruses, we find 44 that within host spread is associated with viral replicative speed and not standing genetic 45 diversity.46 47 3 mutation rates. Since most mutations are deleterious and mutation rates are tuned by natural 53 selection, we asked why hasn't the virus evolved to have a lower mutation rate? We used 54 experimental evolution and a murine infection model to show that RNA virus mutation rates may 55 actually be too high and are not necessarily adaptive. Rather, our data indicate that viral 56 mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. 57We suggest that viruses have high mutation rates, not because they facilitate adaption, but 58 because it is hard to be both fast and accurate. 59 60 Introduction 61 Mutation is the ultimate source of genetic variation, and mutation rates can have a significant 62 impact on evolutionary rate [1-3]. The intraspecific variability in mutation rate in many viruses 63 and bacteria indicates that mutation rates have been optimized by natural selection [4-13]. 64Given that most mutations are deleterious, the burden of excess mutational load will select 65 against strains with abnormally high mutation rates [14][15][16][17]. This principle led to Sturtevant to 66 ask, "Why does the mutation rate not evolve to zero?" [18,19]. 68A large body of theoretical and experimental work suggests that the selective pressure for 69...

Possible Insights into the Use of Silver Nanoparticles in Targeting SARS-CoV-2 (COVID-19)

“…Many researchers suggest that the increased mutations enhance adaptability and the pathogenesis depends on the rare or de novo mutations. 3 Coronaviruses belong to the ssRNA with the (+) strand. Coronaviruses (CoVs) are one of the largest groups of viruses of the Nidovirales order including the families of Coronaviridae, Arteriviridae, Mesoniviridae and Roniviridae.…”