User:Sennalen/sandbox/CovidOrigin

All coronaviruses known to infect humans prior to SARS-CoV-2 had zoonotic origins. The emergence of SARS-CoV-1 was associated with the live animal trade in Guangdong province. In 2003, animal traders without Covid diagnoses were found to have immunoglobin G levels suggestive of SARS-CoV-1 exposure, at a rate of 13% overall and greater than 50% for traders dealing in civets. In 2018, about 3% of rural residents tested near bat caves in Yunnan provice showed serological evidence of exposure to SARS-related coronaviruses. The distance between Yunan and the index cases of SARS-CoV-1 and SARS-CoV-2 presents a challenge to describing the exact sequences of events leading to their emergences. SARS-CoV-2 parallels the situation of another human coronavirus HCoV-HKU1, which is of unknown animal origin and has a furin cleavage site. Early cases of COVID-19 geographically clustered around the Huanan Seafood Market in Wuhan, China. Among cases reported in December 2019, 28% had contact tracing linked to the market. The initial outbreak had no other epicenter, including the Wuhan Institute of Virology. These results may be influenced by sampling bias and the patterns of population density in Wuhan. There were cases with no apparent link to the market, which is to be expected given some number of asymptomatic or undocumented cases. Markets in Wuhan traded a wide variety of species, including civets and raccoon dogs that are at particular risk for zoonotic transmission. Retrospective sampling of animal carcasses was negative for SARS-CoV-2, although the testing did not sample the full range of animals present. The earliest known division in SARS-CoV-2 phylogenies is between two lineages termed A and B. Both circulated early in the pandemic, but B eventually came to dominate. Cases associated with Huanan market were mostly lineage B. Viruses related to SARS-CoV-2 have been detected in bats and pangolins across Southeast Asia; however, they are separated from SARS-CoV-2 by an evolutionary gap consistent with decades of divergence. The nucleotide sequence of bat coronavirus RaTG13 differs from the Wuhan-Hu-1 SARS-CoV-2 reference sequence by about 4%. RaTG13 is not the progenitor of SARS-CoV-2. No bat or other animal has been identified as a reservoir for SARS-CoV-2. In general, most cross-species transmission events do not lead to large outbreaks. The animal origins of many viruses affecting humans have yet to be identified. A SARS-related coronavirus able to use ACE2 for cell entry was discovered in bats was reported in 2017, long after the initial SARS outbreak. There are many known cases of viruses escaping from labs. Documented laboratory escapes have all been of known viruses kept in high titers, with the exception of the Marburg virus. The 1997 A/H1N1 influenza pandemic is the only documented pandemic or epidemic with origins in research activity. There is no data that indicates SARS-CoV-2 or a progenitor of it was the subject of research in a laboratory before the pandemic. No laboratory escape has ever been found to originate with genetic sequencing activity. Contact tracing in Wuhan did not find a link to the Wuhan Institute of Virology, and no cases were reported in laboratory staff there. Out of numerous samples stored there, three SARS-related cornaviruses cultured at the Wuhan Institute have been reported as successfully cultured. Those three are more closely related to SARS-CoV-1 than SARS-CoV-2. RaTG13 has never been isolated or cultured, existing only as a computed nucleotide sequence. The three cultured samples were isolated from guano and amplified in Vero cells. That process consistently eliminates furin cleavage sites in viruses that have them, so it would not be expected to successfuly isolate infectious SARS-CoV-2 by that method. No work has been published suggesting that another method was used to propagate SARS-related virues from sequence data. Past work creating recombinant viruses at the Wuhan Institute was based on a backbone of virus WIV1, which is not related to SARS-CoV-2. There is no evidence that the Wuhan Institute sequenced any virus more similar to SARS-CoV-2 than RaTG13. SARS-CoV-2 required additional mutations to infect mouse cells, which would be inconsistent with an origin in laboratory mice. SARS-CoV-2 populations have undergone several selective sweeps for traits enhancing infectivity, entailing that it was not already perfectly optimized to infect humans. SARS-CoV-2 is capable of infecting many kinds of mammals, including mink, ferrets, cats, tigers, dogs, and raccoon dogs. Large outbreaks have affected minks and included spillback to humans. The furin cleavage site in SARS-CoV-2 has prompted speculation about its origin. None of its closest known relatives have a furin cleavage site, though the sparsity in sampling of relatives may contribute to this. Furin cleavage sites are common in some other clades of coronavirus. A short palindromic sequence upstream of the furin cleavage site suggests it is a natural recombination breakpoint. The out-of-frame insertion of a furin cleavage site in SARS-CoV-2 can be explained by natural evolution. Rather than an optimal amino acid sequence "RRSRR" used previously in artificial SARS-CoV-1 chimeras, the SARS-CoV-2 furin cleavage site contains the sequence "RRAR". Other coronaviruses with this sequence are not effectively cleaved by furin. Holmes et al. wrote that deliberately engineering a furin cleavage site with these properties would be "unusual and needlessly complex." A proline residue upstream of the furin cleavage site aids in the cleavage process and is part of SARS-CoV-2's adaptation to humans. The presence of two repeated CGG codons for arginine is unusual in coronaviruses but not unprecedented. If low fitness codons were inserted artificially, they would be rapidly selected against. The CGG codons are present in most SARS-CoV-2 isolates, indicating the sequence is highly conserved. Holmes et al. wrote that a zoonotic event is the most parsimonious explanation for the emergence of SARS-CoV-2, given that this is the origin of most human viruses. Although an animal reservoir has not been found, they cite a body of evidence supporting zoonosis and no evidence for a laboratory leak. Holmes et al. wrote that although the possibility of a laboratory accident cannot be dismissed, it is "highly unlikely" compared to an origin in the wildlife trade.