Group Selection and Contribution of Minority Variants during Virus Adaptation Determines Virus Fitness and Phenotype

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Abstract
Understanding how a pathogen colonizes and adapts to a new host environment is a primary aim in studying emerging infectious diseases. Adaptive mutations arise among the thousands of variants generated during RNA virus infection, and identifying these variants will shed light onto how changes in tropism and species jumps can occur. Here, we adapted Coxsackie virus B3 to a highly permissive and less permissive environment. Using deep sequencing and bioinformatics, we identified a multi-step adaptive process to adaptation involving residues in the receptor footprints that correlated with receptor availability and with increase in virus fitness in an environment-specific manner. We show that adaptation occurs by selection of a dominant mutation followed by group selection of minority variants that together, confer the fitness increase observed in the population, rather than selection of a single dominant genotype. When RNA viruses replicate, they do so with a high rate of error; hence, their populations are not composed of a single genotype, but of a swarm of different, yet related, genomes. This mutant spectrum has been described as the viral quasispecies, and its composition has important consequences for evolution, adaptation and emergence. In this study, we analysed adaptation in fine detail thanks to the use of the deep sequencing, and we determined the adaptative pathway of a model RNA virus, Coxsackievirus B3, to a new environment, A549 cells. Our results demonstrate that adaptation occurred in response to a differential expression of the virus receptors in the new cellular environment, compared to the former. Our experiments and mathematical analyses established that the corresponding increase in fitness resulted from the selection and contribution of a group of genotypes, including low frequency variants, and not to the effect of a single, dominant genome. Our work underscores the importance of considering group effects when studying RNA virus biology and evolution.

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