Follis et al., 2006). Further, there is no evidence of prior research at the WIV involving the artificial insertion of complete furin cleavage sites into coronaviruses. The recurring P681H/R substitution in the proline (P) residue preceding the SARS-CoV-2 furin cleavage site improves cleavFigure 2. Evolution of the furin cleavage site in the spike protein of betacoronaviruses (A) Sequence alignment of the region around the furin cleavage site (FCS) in SARS-CoV-2 (NCBI: MN908947) and bat coronavirus RaTG13 (NCBI: MN996532) showing that the former was the result of an out-of-frame nucleotide sequence insertion. (B) Amino acid sequence alignment of the FCS region in representative members of the different subgenera of betacoronaviruses, highlighting the evolutionary volatility of this site and that the relevant amino acid motif (RRAR) in SARS-CoV-2 is functionally suboptimal. The residues predicted to be O-linked glycans are also marked. See also Document S1. age of the spike protein and is another signature of ongoing human adaptation of the virus (Peacock et al., 2021a). The SARS-CoV-2 furin site is also lost under standard cell culture conditions involving Vero E6 cells (Ogando et al., 2020; Peacock et al., 2021b), as is true of HCoVOC43 (Follis et al., 2006). The presence of two adjacent CGG codons for arginine in the SARS-CoV-2 furin cleavage site is similarly not indicative of genetic engineering (Maxmen and Mallapaty, 2021). Although the CGG codon is rare in coronaviruses, it is observed in SARS-CoV, SARS-CoV-2, and other human coronaviruses at comparable frequencies (Maxmen and Mallapaty, 2021). Further, if low-fitness codons had been artificially inserted into the virus genome they would have been quickly selected against during SARS-CoV-2 evolution, yet both CGG codons are more than 99.8% conserved among the >2,300,000 near-complete SARS-CoV-2 genomes sequenced to date, indicative of strong functional constraints (supplemental information; Table S1). CONCLUSIONS As for the vast majority of human viruses, the most parsimonious explanation for the origin of SARS-CoV-2 is a zoonotic event. The documented epidemiological history of the virus is comparable to previous animal market-associated outbreaks of coronaviruses with a simple route for human exposure. The contact tracing of SARS-CoV-2 to markets in Wuhan exhibits striking similarities to the early spread of SARS-CoV to markets in Guangdong, where humans infected early in the epidemic lived near or worked in animal markets. Zoonotic spillover by definition selects for viruses able to infect humans. Although strong safeguards should be consistently employed to minimize the likelihood of laboratory accidents in virological research, those laboratory escapes documented to date have almost exclusively involved viruses brought into laboratories specifically because of their known human infectivity. There is currently no evidence that SARS-CoV-2 has a laboratory origin. There is no evidence that any early cases had any connection to the WIV, in contrast to the clear epidemiological ll OPEN ACCESS 4852 Cell 184, September 16, 2021 Review links to animal markets in Wuhan, nor evidence that the WIV possessed or worked on a progenitor of SARS-CoV-2 prior to the pandemic. The suspicion that SARS-CoV-2 might have a laboratory origin stems from the coincidence that it was first detected in a city that houses a major virological laboratory that studies coronaviruses. Wuhan is the largest city in central China with multiple animal markets and is a major hub for travel and commerce, well connected to other areas both within China and internationally. The link to Wuhan therefore more likely reflects the fact that pathogens often require heavily populated areas to become established (Pekar et al., 2021). We contend that although the animal reservoir for SARS-CoV2 has not been identified and the key species may not have been tested, in contrast to other scenarios there is substantial body of scientific evidence supporting a zoonotic origin. Although the possibility of a laboratory accident cannot be entirely dismissed, and may be near impossible to falsify, this conduit for emergence is highly unlikely relative to the numerous and repeated humananimal contacts that occur routinely in the wildlife trade. Failure to comprehensively investigate the zoonotic origin through collaborative and carefully coordinated studies would leave the world vulnerable to future pandemics arising from the same human activities that have repeatedly put us on a collision course with novel viruses. SUPPLEMENTAL INFORMATION Supplemental information can be found online at https://doi.org/10.1016/j.cell. 2021.08.017. ACKNOWLEDGMENTS We gratefully acknowledge the authors and the laboratories responsible for the genome sequence data shared via the GISAID Initiative, and we provide a complete acknowledgment table for the data used in Data S1. E.C.H. is supported by an ARC Australian Laureate Fellowship (FL170100022). S.A.G. is supported by the NIH (F32AI152341). J.O.W. acknowledges support from the NIH (AI135992). A.L.R. acknowledges that VIDO receives operational funding from the Canada Foundation for Innovation-Major Science Initiatives Fund and from the Government of Saskatchewan through Innovation Saskatchewan and the Ministry of