Speaker
Description
Controversy continues to surround the evolutionary origins of SARS-CoV-2, particularly in light of the absence of an identified intermediate host. A prior outbreak of severe acute respiratory syndrome caused by SARS-CoV was traced back to palm civets from a live-animal market and farms in Guangdong Province, China. While the direct observation of zoonotic events between bats and humans via an intermediate is unlikely, sequence analyses from initial cases support the origin of SARS-CoV-2 in the Huanan seafood market in Wuhan China. Here, our functional genomic analysis finds evidence for the evolution of a small viral RNA (svRNA) in the nucleocapsid (N)-open reading frame (ORF) of SARS-CoV-2-related sarbecoviruses, including SARS-CoV-2 and SARS-CoV. In addition to the sub-genomic RNA (sgRNA) for the N protein being most abundant during SARS-CoV-2 infection, small RNA-sequencing experiments show that a highly expressed svRNA in both SARS-CoV-2 and SARS-CoV is being released from the same region of the N-ORF. We demonstrate that this highly expressed svRNA also overlaps an area of significant synonymous-site conservation among the sarbecoviruses, including greater horseshoe bat and pangolin coronaviruses. These, as well as other findings, including the co-location of two secondary RNA modifications sites in SARS-CoV-2 sgRNA, a recombination hotspot, and a covarying hairpin structure common among SARS-CoV-2-related sarbecoviruses, are all consistent with svRNA evolution as a potential driver in the ancestry of SARS-CoV-2. Importantly, our analysis draws attention to recent modifications to a putative RNAse L-dependent cleavage site in a position for the release of the svRNA from the N-ORF region and explores more broadly the potential for svRNA involvement in zoonotic spillover by progenitor of SARS-CoV-2.
