Health Organization, 2021). Examination of the locations of early cases shows that most cluster around the Huananmarket, located north of the Yangtze river (Figures 1B–1E), although case reporting may be subject to sampling biases reflecting the density and age structure of the population in central Wuhan, and the exact location of some early cases is uncertain. These districts were also the first to exhibit excess pneumonia deaths in January 2020 (Figures 1F–1H), a metric that is less susceptible to the potential biases associated with case reporting. There is no epidemiological link to any other locality in Wuhan, including the Wuhan Institute of Virology (WIV) located south of the Yangtze and the subject of considerable speculation. Although some early cases do not have a direct epidemiological link to a market (World Health ll OPEN ACCESS Cell 184, September 16, 2021 4849 Review Organization, 2021), this is expected given high rates of asymptomatic transmission and undocumented secondary transmission events and was similarly observed in early SARS-CoV cases in Foshan (Xu et al., 2004). During 2019, markets in Wuhan—including the Huanan market—traded many thousands of live wild animals including high-risk species such as civets and raccoon dogs (Xiao et al., 2021). Following its closure, SARS-CoV-2 was detected in environmental samples at the Huanan market, primarily in the western section that traded in wildlife and domestic animal products, as well as in associated drainage areas (World Health Organization, 2021). Although animal carcasses retrospectively tested negative for SARS-CoV-2, these were unrepresentative of the live animal species sold and specifically did not include raccoon dogs and other animals known to be susceptible to SARS-CoV-2 (Xiao et al., 2021). The earliest split in the SARS-CoV-2 phylogeny defines two lineages—denoted A and B (Rambaut et al., 2020)—that likely circulated contemporaneously (Figure 1A). Lineage B, which became dominant globally, was observed in early cases linked to the Huanan market and environmental samples taken there, whereas lineage A contains a case with exposure to other markets (Figures 1A and 1B) as well as with later cases in Wuhan and other parts of China (World Health Organization, 2021). This phylogenetic pattern is consistent with the emergence of SARS-CoV-2 involving one or more contacts with infected animals and/or traders, including multiple spill-over events, as potentially infected or susceptible animals were moved into or between Wuhan markets via shared supply chains and sold for human consumption (Xiao et al., 2021). The potential emergence of SARS-CoV-2 across multiple markets again mirrors SARSCoV in which high levels of infection, seroprevalence, and genetic diversity in animals were documented at both the Dongmen market in Shenzhen (Yaqing, 2004; Guan et al., 2003) and the Xinyuan market in Guangzhou (Tu et al., 2004; Wang et al., 2005). Viruses closely related to SARS-CoV-2 have been documented in bats and pangolins in multiple localities in SouthEast Asia, including in China, Thailand, Cambodia, and Japan (Lytras et al., 2021; Zhou et al., 2021), with serological evidence for viral infection in pangolins for more than a decade (Wacharapluesadee et al., 2021). However, a significant evolutionary gap exists between SARS-CoV-2 and the closest related animal viruses: for example, the bat virus RaTG13 collected by the WIV has a genetic distance of 4% (1,150 mutations) to the Wuhan-Hu-1 reference sequence of SARS-CoV-2, reflecting decades of evolutionary divergence (Boni et al., 2020). Widespread genomic recombination also complicates the assignment of which viruses are closest to SARS-CoV-2. Although RaTG13, sampled from a Rhinolophus affinis bat in Yunnan (Zhou et al., 2020b), has the highest average genetic similarity to SARSCoV-2, a history of recombination means that three other bat viruses—RmYN02, RpYN06, and PrC31—are closer in most of the virus genome (particularly ORF1ab) and thus share a more recent common ancestor with SARS-CoV-2 (Li et al., 2021; Lytras et al., 2021; Zhou et al., 2021). None of these three closer viruses were collected by the WIV and all were sequenced after the pandemic had begun (Li et al., 2021; Zhou et al., 2020a, 2021). Collectively, these data demonstrate beyond reasonable doubt that RaTG13 is not the progenitor of SARS-CoV-2, with or without laboratory manipulation or experimental mutagenesis. No bat reservoir or intermediate animal host for SARS-CoV-2 has been identified to date. This is presumably because the right animal species and/or populations have not yet been sampled and/or any progenitor virus may be at low prevalence. Initial cross-species transmission events are also very likely to go undetected. Most SARS-CoV-2 index case infections will not have resulted in sustained onward transmission (Pekar et al., 2021), and only a very small fraction of spillovers from animals to humans result in major outbreaks. Indeed, the animal origins of many well-known human pathogens, including Ebola virus, hepatitis C virus, poliovirus, and the coronaviruses HCoV-HKU1 and HCoV-NL63, are yet to be identified, while it took over a decade to discover bat viruses with >95% similarity to SARS-CoV and able to use hACE-2 as a receptor (Hu et al., 2017). COULD SARS-CoV-2