Origins and Evolution of Seasonal Human Coronaviruses

Four seasonal human coronaviruses (sHCoVs) are endemic globally (229E, NL63, OC43, and HKU1), accounting for 5-30% of human respiratory infections. However, the epidemiology and evolution of these CoVs remain understudied due to their association with mild symptomatology. Using a multigene and complete genomes analysis approach, we find the evolutionary histories of sHCoVs to be more complex than previously recognized, owing to frequent recombination of CoVs, including within and between sHCoVs. Within sHCoV recombination rate was highest for 229E and OC43, and within genus highest for betaCoVs, whereas substitutions per recombination event inversely highest in NL63 and HKU1, and the alphaCoVs. Depending on the gene studied, OC43 may have ungulate, canine, or rabbit CoV ancestors, while 229E may have origins in a bat, camel or an unsampled intermediate host. HKU1 had the earliest most recent common ancestor (MRCA: 1809-1899), comprised two genetically divergent genotypes (A and B) possibly representing two independent transmission events from murine CoVs, and genotype B was genetically more diverse than all the other sHCoVs. Finally, we found shared amino acid substitutions in multiple proteins along the non-human to sHCoV host-jump branches. The complex evolution of CoVs and their frequent host switches could benefit from continued surveillance of CoVs across non-human hosts. ### Competing Interest Statement The authors have declared no competing interest.