Codon Usage Determines the Mutational Robustness, Evolutionary Capacity, and Virulence of an RNA Virus

Abstract

Summary RNA viruses exist as dynamic and diverse populations shaped by constant mutation and selection. Yet little is known about how the mutant spectrum contributes to virus evolvability and pathogenesis. Because several codon choices are available for a given amino acid, a central question concerns whether viral sequences have evolved to optimize not only the protein coding consensus, but also the DNA/RNA sequences accessible through mutation. Here we directly test this hypothesis by comparing wild type poliovirus to synthetic viruses carrying reengineered capsid sequences with hundreds of synonymous mutations. Strikingly, such rewiring of the population's mutant network reduced its robustness and attenuated the virus in an animal model of infection. We conclude that the position of a virus in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenicity. This organizing principle for RNA virus populations confers tolerance to mutations and facilitates replication and spread within the dynamic host environment.

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

“…We determined that the influenza virus RdRp has a strong bias toward transition mutations, especially A to G and U to C. This mutational bias suggests that influenza virus populations may more thoroughly explore the sequence space accessible through these mutation types. This natural exploration could confer a certain level of genetic robustness to the detrimental effects of A-to-G and U-to-C transitions (65,66). Therefore, mutagens that induce the same types of mutations as influenza virus's normal bias may be less effective at inducing lethal mutagenesis.…”

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

“…This is likely due to the competitive nature of house mice, which vigorously compete with one another over resources. Differences in physiological performance that are too cryptic, diffuse, or subtle to cause gross defects may nonetheless lower fitness in a competitive environment and this concept has driven the use of fitness assays in Drosophila, RNA virus, and yeast communities (e.g., Shabalina et al 1997;Thatcher et al 1998;Lauring et al 2012); unfortunately, similar approaches have not been adopted by those working with vertebrate model systems (with the notable exception of genes involved in sperm function or competition, e.g., Sutton et al 2008). In addition to the Hoxb1 A1 phenotypes herein, OPAs have revealed adversities associated with three other genetic treatments, including cousin-and sibling-level inbreeding and bearing the selfish genetic element known as the t complex, which had escaped detection for decades (Meagher et al 2000;Carroll et al 2004;Ilmonen et al 2008).…”

Contribution of Silent Mutations to Thermal Adaptation of RNA Bacteriophage Qβ

“…Synonymous positions are important for mRNA folding and stability (18), and the mRNA folding free energy of one-third of mRNA 5= sequences was shown to be related to the protein expression level (19). Moreover, synonymous mutations were shown to result in fitness differences in poliovirus (20), and the impact of mutations in cis-regulatory sequences on the fitness improvements of X174 that was selected at high temperature has also been reported (24).…”

“…There have been reports that synonymous mutations affect mRNA stability and protein expression levels, thus resulting in phenotypic changes (18)(19)(20). Preferred codon usage is correlated with the abundance of isoaccepting tRNAs, and the extent of this correlation is related to the level of protein production (21,22).…”