The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus

Abstract

Little is known about the mutational fitness effects associated with single-nucleotide substitutions on RNA viral genomes. Here, we used site-directed mutagenesis to create 91 single mutant clones of vesicular stomatitis virus derived from a common ancestral cDNA and performed competition experiments to measure the relative fitness of each mutant. The distribution of nonlethal deleterious effects was highly skewed and had a long, flat tail. As expected, fitness effects depended on whether mutations were chosen at random or reproduced previously described ones. The effect of random deleterious mutations was well described by a log-normal distribution, with -19% reduction of average fitness; the effects distribution of preobserved deleterious mutations was better explained by a beta model. The fit of both models was improved when combined with a uniform distribution. Up to 40% of random mutations were lethal. The proportion of beneficial mutations was unexpectedly high. Beneficial effects followed a gamma distribution, with expected fitness increases of 1% for random mutations and 5% for preobserved mutations.

Fig. 1.

Frequency of fitness values associated with single-nucleotide substitutions measured for random (A) and previously described (B) mutations.

Fig. 2.

Cumulative frequency distributions for nonlethal deleterious fitness effects associated with single-nucleotide substitutions. The observed distributions are represented by filled circles. (A) Mutations chosen randomly. The continuous line shows the predicted probabilities using a log-normal pdf; the dashed line shows the predicted probabilities using a log-normal + uniform pdf. (B) Previously observed changes. Predicted values using a β pdf are shown with a continuous line; the dashed line shows the probabilities predicted by a β + uniform pdf.

Fig. 3.

Cumulative frequency distributions for beneficial fitness effects associated with single-nucleotide substitutions measured for random (A) and previously described (B) mutations are shown. The filled circles represent the observed distributions; the accumulated probabilities predicted by using a γ pdf are shown by a continuous line.