Recombination events are concentrated in the spike protein region of Betacoronaviruses

Author summary The high mutation rate of RNA viruses makes it problematic to understand and resolve the role of recombination in generating genomic variation. Frequent mutations will (1) increase the likelihood of convergent mutations, particularly in regions subject to strong positive selection, causing sequence similarities that can be mistaken for recombination events, and (2) introduce new changes that accumulate and obscure recognition of past recombination events. We analyzed the patterns of recombination across Betacoronarivuses using a dedicated approach to distinguish true recombination from convergent mutations. The Betacoronaviruses comprise several populations that could be considered distinct biological species in that they do not engage in gene flow with one another. Moreover, recombination events within the Sarbecovirus subgenus, which includes SARS-CoV-2, are highly biased and predominate in the spike protein region, implicating recombination as a having a substantial role in host tropism and viral ecology. The Betacoronaviruses comprise multiple subgenera whose members have been implicated in human disease. As with SARS, MERS and now SAR-CoV-2, the origin and emergence of new variants are often attributed to events of recombination that alter host tropism or disease severity. In most cases, recombination has been detected by searches for excessively similar genomic regions in divergent strains; however, such analyses are complicated by the high mutation rates of RNA viruses, which can produce sequence similarities in distant strains by convergent mutations. By applying a genome-wide approach that examines the source of individual polymorphisms and that can be tested against null models in which recombination is absent and homoplasies can arise only by convergent mutations, we examine the extent and limits of recombination in Betacoronaviruses. We find that recombination accounts for nearly 40% of the polymorphisms circulating in populations and that gene exchange occurs almost exclusively among strains belonging to the same subgenus. Although experimental studies have shown that recombinational exchanges occur at random along the coronaviral genome, in nature, they are vastly overrepresented in regions controlling viral interaction with host cells.