Probable human origin of the SARS-CoV-2 polybasic furin cleavage site

Abstract The origin of the SARS-CoV-2 is still unclear. Simply said, its emergence was due to the acquisition of the polybasic furin cleavage site at the S protein in one of its closest relatives. The discovery in Laos of bat Rhinolophus coronaviruses that contain receptor binding domains almost identical to that of SARS-CoV-2, and despite not having that polybasic furin cleavage site, they can therefore infect human cells (1), is the cornerstone to identify the SARS-CoV-2 progenitor. However, it is not yet known where the furin site inserted at the S1/S2 junction in the S protein of the pandemic virus come from, nor the how and when of such acquisition. The CGG-CGG encoded arginine dimer is rare in coronaviruses (2), however, an arginine dimer with this code is present at the SARS-CoV-2 acquired furin site: the PRRA four amino acid residue motif. Then, my question was if the SARS-CoV-2 S gene insert encoding the furin site would match to human transcripts. Here, I address this issue by using NCBI and GISAID databases, the NCBI Human Genome Resources, sequence analysis tools and in-house developed bioinformatic tools. I found that the possible 12-nucleotide fragments which properly inserted in the S gene encode the SARS-CoV-2 furin site 100% match to several NCBI RefSeq human transcripts. Taking this into consideration and the expression patterns of these genes, together with further evidences found here, such as the codon optimization of that SARS-CoV-2 furin site arginine dimer and other PRRA-like insertions in the S protein, results provide insight into the human-virus recombination link as origin of the SARS-CoV-2 furin site, during undetected human-to-human virus transmission.