The genetic structure of SARS-CoV-2 does not rule out a laboratory origin: SARS-COV-2 chimeric structure and furin cleavage site might be the result of genetic manipulation

Abstract

Severe acute respiratory syndrome-coronavirus (SARS-CoV)-2's origin is still controversial. Genomic analyses show SARS-CoV-2 likely to be chimeric, most of its sequence closest to bat CoV RaTG13, whereas its receptor binding domain (RBD) is almost identical to that of a pangolin CoV. Chimeric viruses can arise via natural recombination or human intervention. The furin cleavage site in the spike protein of SARS-CoV-2 confers to the virus the ability to cross species and tissue barriers, but was previously unseen in other SARS-like CoVs. Might genetic manipulations have been performed in order to evaluate pangolins as possible intermediate hosts for bat-derived CoVs that were originally unable to bind to human receptors? Both cleavage site and specific RBD could result from site-directed mutagenesis, a procedure that does not leave a trace. Considering the devastating impact of SARS-CoV-2 and importance of preventing future pandemics, researchers have a responsibility to carry out a thorough analysis of all possible SARS-CoV-2 origins.

Keywords: BtCov/4991; Gain-of-function studies; RaTG13; SARS-CoV-2; furin cleavage site; pangolin CoV; receptor binding domain.

FIGURE 1

Nucleotide sequence of the S protein at the S1/S2 junction in SARS‐CoV‐2 (NC045512.2) showing the furin cleavage site (in blue) that includes a FauI enzyme restriction site

FIGURE 2

Alignment of nucleotide and amino acid sequences of the S protein from bat‐SL‐CoVZC45 (MG772933.1) and RmYN02 at the S1/S2 junction site. No insertions of nucleotides possibly evolving in a furin cleavage site can be observed (in blue)

FIGURE 3

Alignment of nucleotide and amino acid sequences of the S protein from RaTG13 (MN996532), MP789 (MT084071) and SARS‐CoV‐2 (NC045512.2) at the S1/S2 site. The common nucleotides and amino acids are given in black, SARS‐CoV‐2 unique nucleotides and amino acids in red, RaTG13 unique nucleotides and amino acids in green and common nucleotides and amino acids in SARS‐CoV‐2 and RaTG13 that differ in MP789 in blue. The codon forserine (TCA) in RaTG13 and MP789 is split in SARS‐CoV‐2 to give part of a new codon forserine (TCT) and part of the amino acidalanine (GCA)