Significance
This study formally evaluates a hypothesis that has been advanced by some scientists and public commentators in support of a nonnatural origin of SARS-CoV-2. The hypothesis proposes that the unique polybasic furin cleavage motif of SARS-CoV-2 may be technically or evolutionarily derived from a mouse-adapted laboratory strain of MERS-coronavirus (MA30). While the World Health Organization’s Scientific Advisory Group on the Origins of Novel Pathogens (SAGO) concluded that the available evidence was insufficient to support the proposed link, the underlying scientific rationale for this conclusion has not been published. We systematically assessed the evidence from genomic surveillance and conducted additional experimental studies. Together, these data do not support an evolutionary or genetic relationship.
Abstract
The origin of the polybasic furin cleavage site (FCS) of SARS-CoV-2 remains a central question in debates on the emergence of COVID-19. One hypothesis proposes a genetic relationship between the SARS-CoV-2 S1/S2 motif RRAR and the RRVR sequence found in the mouse-adapted MERS-CoV strain MERS-MA30. Here, we combined large-scale bioinformatic analysis with experimental virology to evaluate this scenario. Analysis of over 17 million SARS-CoV-2 genomes revealed that the S:684V substitution corresponding to RRVR occurred repeatedly but only sporadically, never became phylogenetically basal, and showed limited geographic and temporal spread. Using reverse genetics, we generated SARS-CoV-2 variants encoding RRVR and demonstrated that S:684V consistently reduced viral entry efficiency and competitive fitness in multiple cell systems, including human respiratory epithelial cultures. RRVR variants did not evolve toward RRAR but instead accumulated alternative substitutions. These findings do not support an evolutionary relationship between MERS-MA30 and the SARS-CoV-2 FCS.
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