Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics

Abstract

The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus-host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10^-3 to 10^-6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3' to 5' exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.

Keywords: RNA virus; SARS-CoV-2; error catastrophe; exonuclease; quasispecies; virus diversification.

Figure 1

Scheme that illustrates the difference between mutation rate and mutant frequency. Residue U (on the left), A (in the middle), and C (on the right) can be misread to incorporate a G (on the left), C (in the middle), or A (on the right) in the complementary strand at a rate of 10⁻⁴ substitutions per nucleotide in all cases. The replicative capacity of the newly G, C, and A templates determines the different mutant frequencies with 10⁻³, 10⁻⁴, and 10⁻⁵ substitutions per nucleotide, respectively.

Figure 2

Scheme that illustrates mutant spectrum complexities in the absence and presence of a 3′-5′ exonuclease activity during viral replication. Residue A (on the top) can be misread to incorporate a C in the complementary strand. In the presence of a proofreading activity, the mutant spectrum (represented by lines with mutations as colored symbols) contains a standard number of defective genomes (depicted on the left). In the absence of a proofreading activity, there is an accumulation of mutations per genome that can eliminate viral replication (indicated by discontinuous lines of mutant spectrum on the right).