A team led by Christian Drosten’s group at the Charité – Universitätsmedizin Berlin has published the first systematic experimental and genomic evaluation of a prominent hypothesis linking the SARS-CoV-2 furin cleavage site to a laboratory-adapted MERS coronavirus strain, and the results are unequivocal: the data do not support the proposed connection.
The study, published in PNAS, directly tests a hypothesis that has featured prominently in debates about the origins of the COVID-19 pandemic. The hypothesis proposed that the unique polybasic furin cleavage site (FCS) motif “RRAR” found in SARS-CoV-2 could have been derived, either technically or evolutionarily, from the “RRVR” motif present in the mouse-adapted MERS-CoV laboratory strain MA30.
What the team did
The researchers pursued three independent lines of evidence. First, they conducted a large-scale genomic analysis of more than 17 million SARS-CoV-2 genomes deposited in GISAID, searching specifically for the S:684V mutation that would convert the RRAR motif to the MA30-like RRVR sequence. Second, they engineered live SARS-CoV-2 variants encoding the RRVR motif and measured their entry efficiency across multiple cell types, including human respiratory epithelial cultures. Third, they performed competitive fitness assays and passaging experiments to observe the evolutionary trajectory of RRVR variants.
The results
The genomic analysis showed that the S:684V mutation occurred repeatedly but only sporadically, it was never phylogenetically basal and showed limited geographic and temporal spread, with no sustained transmission chains. There was no evidence that RRVR variants were ancestral to the circulating RRAR-bearing SARS-CoV-2.
The experimental results were equally clear. RRVR-engineered viruses showed consistently reduced entry efficiency compared to wild-type RRAR virus across all cell systems tested. In direct competition assays, RRVR variants were outcompeted by wild-type virus, they had lower fitness. And when passaged, RRVR variants did not evolve toward RRAR. Instead, they accumulated alternative substitutions, showing no selective pressure to regain the native furin cleavage motif.
“Together, these data do not support an evolutionary or genetic relationship between MERS-MA30 and the SARS-CoV-2 FCS,” the authors conclude.
Context
The WHO’s Scientific Advisory Group on the Origins of Novel Pathogens (SAGO) had previously concluded the link was unsupported in 2025. Drosten was a member of SAGO and declared this as a competing interest. This study provides the underlying scientific rationale for that conclusion, which had not previously been published in a peer-reviewed format.
The paper’s code and data are publicly available on GitHub.
Sources:
1. Metzger SM, Jones TC, Meier JIJ, Richter A, Klassen MC, Olmer R, Diegmüller N, Heimsch KC, Drosten C. “Evaluation of a proposed link between the SARS-CoV-2 furin cleavage site and mouse-adapted MERS-coronavirus MA30.” PNAS. 2026;123(27):e2601806123. DOI: 10.1073/pnas.2601806123