Wuhan wildlife markets suggests SARS-CoV-2 has a natural origin Robert F. Garry1.2 Introduction Our previous commentary on the Proximal Origins of SARS-CoV-2 (Andersen et al., 2020) concluded that, "SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus (Andersen et al., 2020)." The possibility of a laboratory release or Lab Leak was also considered, but it was determined that a natural origin ofSARS-CoV-2 is much more likely. Recently, a team of scientists under the auspices of the World Health Organization (WHO) reached similar conclusions (WHO Report, 2021). Other groups have speculated that SARS-CoV-2 may be the result of undisclosed research on SARS-CoV-2 or a close progenitor and accidental release [Relman, 2020; Parisite 1, 2]. Some Lab Leak proponents have suggested that SARS-Cov-2 may be the product of laboratory passage of a progenitor virus in cell culture or animals, or Gain-of-Function research [ref]. New data presented by the WHO study provides clear findings in support of the Natural origin of SARS-CoV-2. Results The study of SARS-CoV-2 origins conducted by the WHO team provided important new data regarding the role ofwildlife markets in the emergence of SARS-CoV-2. The large Huanan seafood market, which also sold wildlife and wildlife products, was a focus of early attention because it was linked to the majority of early cases of COVID-19 inWuhan. The WHO report documented that early cases were not only linked to the Huanan market, but that other early cases were linked to different markets that sold wildlife or wildlife products. Among the first 168 diagnosedcases of COVID-19 in Wuhan with onset date prior to December 31, 2019 and a known history of exposure towildlife markets 55.4% (93/168) reported such exposures. Of the 168 cases, 28% (47/168) had only been to the Huanan market, 22% (38/168) had exposure to another wildlife market and 4.7% (8/168) had exposure to the Huanan market and another market (ref table). The genetic lineages of SARS-CoV-2 associated with early cases in Wuhan were documented in the WHO report. Previously, Rambaut et al, (2020) noted that at the root of the phylogeny of SARS-CoV-2 are two lineagesdesignated lineage A and B. Early lineage A viruses, include SARS-Cov-2 isolate EPI_ISL_529213 sampled on30Dec19 from a person linked to a wildlife market different than the Huanan market (Table 7, S13, WHO report2021). Linage A viruses share two nucleotides (T8,782 in ORF1ab and C28,144 in ORF8) with the bat viruses RaTG13 and RmYN02 and other sarbecoviruses. It is likely that the most recent common ancestor (MRCA) ofSARS-CoV-2 shares the same genome sequence as these early lineage A sequences (Rambaut et al., 2020).Different nucleotides (C8,782 in ORF1ab and T28,144 in ORF8) are present at those sites in viruses assigned tolineage B, such as SARS-CoV-2 isolate Wuhan-Hu-1 (GenBank accession no. MN908947, Table 7, S13, WHO report,) sampled from the Huanan market on 30Dec19. All virus positive samples from the Huanan market, fromvenders or customers of the market or from environmental samples, contained SARS-CoV-2 of lineage B. There was limited genetic diversity in the lineage B samples from the Huanan market, which is consistent with the marketas a site of a super-spreader event. Lineage A and Lineage B viruses spread throughout Wuhan and to other countries [ref]. [shared file(s): image.png, image.png]