Original title: Emergence of the SARS-CoV-2 furin cleavage site in humans is constrained to late 2019: implications for COVID-19 origins
Steven E Massey · August 2026
SARS-CoV-2 carries a special genetic feature called a furin cleavage sitea specific spot on the virus spike protein that a human enzyme can cut, helping the virus enter cells, or FCS, in its spike protein. It makes the virus easily spread between humans, but other related sarbecovirusesa subgenus of coronaviruses that includes SARS-related viruses lack it. Scientists have debated whether this feature formed naturally or was an artificial insertion. The FCS also makes the spike protein unstable. Because of this instability, the virus quickly developed a balancing change called the D614G mutation. Researchers used known real-world numbers to calculate the waiting time needed to produce D614G after the FCS appeared. They found this gap lasted between 37 and 65 days. The D614G mutation was first spotted on 1 January 2020. Counting backward, the FCS must have emerged between October 28 and November 25 2019. This means hidden spread in people before late 2019 was unlikely, and long-term spread in bats without the balancing mutation is also inconsistent with the data.
You buy a new video game console that requires a special adapter to play your favorite game. But the adapter is flimsy and overheats quickly, so the company must rush out a reinforced version. Knowing when the reinforced version appeared, and how long it typically takes to develop it after the original, you can estimate when the original adapter first came out. Here, the original adapter is the virus's new cell-entry feature, the reinforced version is the second stabilizing change, and the waiting time calculation uses biological rates to find the time gap.
Knowing when and how SARS-CoV-2 gained the ability to infect humans is essential for preventing future outbreaks. This study narrows the origin window to late 2019, ruling out long-term hidden circulation. It shows how evolutionary dating can resolve debates about virus emergence.
The waiting time calculation depends on the accuracy of empirically determined mutation rates and selection coefficients, which may carry uncertainty. The study only provides an upper bound for the FCS appearance (the latest possible date), not an earliest date. It assumes a specific model of mutation and selection that may not capture all biological complexities. The conclusions about cryptic circulation rely on the absence of the compensatory mutation, but other scenarios may exist.
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Emergence of the SARS-CoV-2 furin cleavage site in humans is constrained to late 2019: implications for COVID-19 origins — Steven E Massey
Abstract licence: CC0
Explanation generated by Synthesis from the abstract — it is not the original paper. This is a preprint, so it hasn't necessarily been peer reviewed.