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arXiv · 2608.20416

Emergence of the SARS-CoV-2 furin cleavage site in humans is constrained to late 2019: implications for COVID-19 origins

Steven E Massey
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Abstract

SARS-CoV-2 possesses a furin cleavage site (FCS) insertion in its spike protein, that is not found in other sarbecoviruses, and is responsible for its transmissibility in humans. The origin of the FCS insertion is unclear, and has been a point of debate regarding whether it arose naturally, or represents an artificial insertion. The FCS is destabilizing to spike protein, and as a consequence a compensatory mutation, D614G, rapidly emerged during the early pandemic and swept to fixation. Using a range of empirically determined parameters, a waiting time calculation can be used to determine the time interval between the appearance of the FCS and generation of the compensating D614G mutation. The waiting time is estimated to range from 37 to 65 days. Given the earliest detection of D614G on 1 January 2020, the latest dates for the appearance of the FCS range from October 28 to November 25 2019. This timeline is consistent with dates generated from phylogenetic considerations for the emergence of SARS-CoV-2 in late 2019, indicating that FCS appearance and virus emergence correspond. The waiting time approach enables discrimination between various scenarios of SARS-CoV-2 emergence, in particular cryptic circulation of a FCS-containing progenitor in the human population prior to late 2019 is unlikely, while prolonged circulation of a FCS-containing progenitor in bats appears inconsistent with absence of the compensatory mutation.

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Steven E Massey. 2026-08-17. Emergence of the SARS-CoV-2 furin cleavage site in humans is constrained to late 2019: implications for COVID-19 origins. https://arxiv.org/abs/2608.20416

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