Long term context dependent genetic adaptation of the viral genetic cloud

RNA viruses generate a cloud of genetic variants within each host. This cloud contains high frequency genotypes, and a very large number of rare variants. While the dynamics of frequent variants are affected by the fitness of each variant, the rare variants cloud is affected by more complex genetic factors, including context dependent mutations. It serves as a spearhead for the viral population's movement within the adaptive landscape. We here use an experimental evolution system to show that the genetic cloud surrounding the Coxsackie virus master sequence slowly, but steadily, evolves over hundreds of generations. The evolution of the rare variants cloud often precedes the appearance of high frequency variants. The rare variants cloud's evolution is driven by a combination of a context-dependent mutation pattern and selection for and against specific nucleotide compositions. This combination affects the mutated dinucleotide distribution, and eventually leads to a non-uniform dinucleotide distribution in the main viral sequence. We then tested these conclusions on other RNA viruses with similar conclusions.