RAPID: Analyses of polymorphism and divergence to illuminate molecular evolution permissive of zoonoses in SARS and COVID-19

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COVID-19 disease has caused the third major outbreak in the past two decades resulting from a spillover of an animal coronavirus to humans. Among them, it is by far the most severe. Novel diseases typically appear because of such spillovers. However, it is unknown what genetic changes in the virus causing COVID-19 enabled it to infect humans. To identify those genetic changes, this project will use newly developed computational methods to compare the genes in coronaviruses infecting humans to the genes in coronaviruses infecting other animal hosts. This comparison of viral genomes will provide insight into which sites within coronavirus genomes enable the switching of host species as well as which sites change following host switches. Awareness of these genetic mechanisms is critical to determining if general rules underlie the ability of coronaviruses to switch hosts, as well as to provide necessary historical context for the changes coronavirus genomes have experienced following the onset of human infections. The ensuing knowledge provides precise guidance on new targets for ongoing decisions regarding vaccine design and drug development. Results of this project will also be incorporated into multiple engaging and educational exhibits at the North Carolina Museum of Natural Sciences. This project will apply molecular evolutionary approaches to reveal the rates of evolution of SARS-CoV-1, SARS-CoV-2, and of viruses sequenced from reservoir hosts, revealing the strength of selection across sites occurring proximate to zoonosis within the viral genomes. First, phylogenetic comparisons of extant SARS-causing, SARS-like, and COVID-19-causing viral sequences collected from infected humans and from animal reservoirs will be used to reconstruct the history of coronavirus evolution. Second, the rate of change of each nucleotide within each gene—and each amino acid site within each protein—in viruses that were transmitting within the animal reservoir, in viruses transmitted among humans during the SARS outbreak, and in viruses transmitted among humans during the COVID-19 pandemic will quantified. Third, virus gene sequences that bracketed (pre- and post-) the host transition events for both SARS and COVID-19 will be estimated through phylogenetic ancestral state reconstruction methods. Finally, application of a novel computational approach comparing the divergence between reconstructed ancestors to the polymorphism present during the outbreak will identify genomic sites under selection that are associated with host transitions. This divergence will be mapped to known protein domains and structures, illuminating sites important to human infection and transmission, and thereby aiding molecularly targeted vaccine and therapy development. This RAPID award is made by the Systematics and Biodiversity Science Cluster in the Division of Environmental Biology, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.