Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic

show that SARS-CoV-2 is unlikely to have acquired the variable loop from an ancestor of Pangolin-2019 because these two sequences are approximately 10–15% divergent throughout the entire S protein (excluding the N-terminal domain). It is RaTG13 that is more divergent in the variable-loop region (Extended Data Fig. 1) and thus likely to be the product of recombination, acquiring a divergent variable loop from a hitherto unsampled bat sarbecovirus28. This is notable because the variable-loop region contains the six key contact residues in the RBD that give SARS-CoV-2 its ACE2-binding specificity27,37. These residues are also in the Pangolin Guangdong 2019 sequence. The most parsimonious explanation for these shared ACE2-specific residues is that they were present in the common ancestors of SARS-CoV-2, RaTG13 and Pangolin Guangdong 2019, and were lost through recombination in the lineage leading to RaTG13. This provides compelling support for the SARS-CoV-2 lineage being the consequence of a direct or nearly-direct zoonotic jump from bats, because the key ACE2-binding residues were present in viruses circulating in bats. and: Although the human ACE2-compatible RBD was very likely to have been present in a bat sarbecovirus lineage that ultimately led to SARS-CoV-2, this RBD sequence has hitherto been found in only a few pangolin viruses. https://www.nature.com/articles/s41564-020-0771-4

it were shipped to the Wuhan lab, which does so-called "gain of function research"--AKA experimenting with artificially sped up mutation rates. First of all, gain-of-function does not mean "artificially sped-up mutation rates." It normally refers to specific, targeted changes to the genome, done in order to test a particular hypothesis. What you're describing is a type of experiment never done before: passaging a virus thousands of times in order to generate a massively different virus. This would be an massively time- and labor-intensive experiment, with no apparent motivation. Second of all, RaTG13 has never been isolated. It exists as fragments of RNA in a fecal swab. Its genome has been reconstructed from sequences of RNA samples, but actually extracting a replicating virus from a fecal swab is a major undertaking. To date, the WIV has only isolated three SARS-related coronaviruses, all of them much closer to the original SARS than to SARS-CoV-2. Before 2020, nobody cared much about viruses that are 20% different from the original SARS. If you read papers from the WIV before 2020, they're all about viruses like WIV-1, which is closely related to the original SARS. 1. https://www.nature.com/articles/s41564-020-0771-4

recombinogenic. ... For coronaviruses, however, recombination means that small genomic subregions can have independent origins, identifiable if sufficient sampling has been done in the animal reservoirs that support the endemic circulation, co-infection and recombination that appear to be common. [2] > Recombination seems to be rampant in HCoV-OC43 viruses and contributed to originate the A to E viral genotypes, as well as viruses that do not belong to these major genotypes. [3] Unfortunately, nature doesn't "design" anything, it's just the consequence of natural selection and fitness of new generations. While the mutation rate might low compared to influenza, the mutation rate is very high compared to something like a prokaryote, enough so that there's an article entitled "Why are RNA virus mutation rates so damn high?" We've already seen a gain of function mutation creating enhanced infectivity and a recombination event involving ferrets, so it's not a stretch that we might see a new more of this in the future. Whether or not it will impact the toxicity of the virus or whether or not its susceptible to a vaccine is up in the air, but once an effective vaccine exists strong selective pressure will be placed on versions of the viruses that evade it. [1] https://jvi.asm.org/content/84/7/3134 [2] https://www.nature.com/articles/s41564-020-0771-4 [3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111218/

pangolin viruses. Furthermore, the other key feature thought to be instrumental in the ability of SARS-CoV-2 to infect humans—a polybasic cleavage site insertion in the S protein—has not yet been seen in another close bat relative of the SARS-CoV-2 virus. https://www.nature.com/articles/s41564-020-0771-4