Correlated substitutions reveal SARS-like coronaviruses recombine frequently with a diverse set of structured gene pools.

Quantifying SARS-like coronavirus (SL-CoV) evolution is critical to understanding the origins of SARS-CoV-2 and the molecular processes that could underlie future epidemic viruses. While genomic analyses suggest recombination was a factor in the emergence of SARS-CoV-2, few studies have quantified recombination rates among SL-CoVs. Here, we infer recombination rates of SL-CoVs from correlated substitutions in sequencing data using a coalescent model with recombination. Our computationally-efficient, non-phylogenetic method infers recombination parameters of both sampled sequences and the unsampled gene pools with which they recombine. We apply this approach to infer recombination parameters for a range of positive-sense RNA viruses. We then analyze a set of 191 SL-CoV sequences (including SARS-CoV-2) and find that ORF1ab and S genes frequently undergo recombination. We identify which SL-CoV sequence clusters have recombined with shared gene pools, and show that these pools have distinct structures and high recombination rates, with multiple recombination events occurring per synonymous substitution. We find that individual genes have recombined with different viral reservoirs. By decoupling contributions from mutation and recombination, we recover the phylogeny of non-recombined portions for many of these SL-CoVs, including the position of SARS-CoV-2 in this clonal phylogeny. Lastly, by analyzing >400,000 SARS-CoV-2 whole genome sequences, we show current diversity levels are insufficient to infer the within-population recombination rate of the virus since the pandemic began. Our work offers new methods for inferring recombination rates in RNA viruses with implications for understanding recombination in SARS-CoV-2 evolution and the structure of clonal relationships and gene pools shaping its origins.

[Formation of population gene pools of zoonotic viruses, potentially threatening biosafety].

The possible formation of population gene pools of zoonotic viruses with a respiratory route of transmission and a possibility of a pandemic at different stages of biosphere evolution is analyzed. Forming of Poxviruses  (Entomopoxvirinae) gene pool could be the beginning of transformation from Plants to Arthropoda (Carbon - 375 million years ago) with further evolution connected with Rodentia (Pliocene - 75-70 million years ago) and further separation of genera (500-300 thousand years ago), and respiratory transmission (epidemics) between humans (10-2 thousand years BC). Smallpox comeback would be possible. Orthomyxoviruses relicts (genus Isavirus) were possibly connected with Ichthya (Silurian - 500-410 million years ago), and then close interaction with Aves (the Cretaceous, 125-110 million years ago) with the division of genera and respiratory transmission (epidemics) between humans (10-2 thousand BC). Next pandemic of influenza A could be catastrophic in terms of the number of victims and economic damage.Coronaviruses formed a gene pool by interaction with Amphibia (subfamily Letovirinae) and then with Chiroptera in Tertiary (110-75 million years ago) with transformation to Artiodactyla (Eocene - 70-60 million years ago), and only 10-2 thousand years BC acquired the ability to a respiratory transmission and became Alphaviruses, a seasonal infection of humans. A similar situation is possible in the near future with SARS-CoV-2. Pandemics associated with zoonoses even more serious than COVID-19 are likely. Constant monitoring of  populational gene pools of zoonotic viruses is necessary.