....Both BatCoVs display an average nucleotide identity of ~95% with SARS-CoV-2, although with variations through the genome, and they were detected in bats sampled in Yunnan province, China, in 2019 and 2013, before the first detection of SARS-CoV-2 in humans (
Zhou et al., 2020b).
Both the place and timing of BatCoV RmYN02 and RaTG13 detection, as well as their levels of identity with SARS-CoV-2, indicate that these viruses are not direct progenitors of the SARS-CoV-2 pandemic strain, but clearly support the view that the latter had an ultimate bat origin (
Zhou et al., 2020b) (
Fig. 1A).
....First, most although not all, early COVID-19 detected cases were associated with the Huanan seafood and wildlife market in Wuhan city, where several mammalian species were traded (
Huang et al., 2020). This is reminiscent of the circumstances associated with the initial phases of SARS-CoV spread, as palm civets were sold in wet markets and their meat consumed (
Cui et al., 2019)
One possible explanation for this observation is that the RBDs of SARS-CoV-2 and Guangdong pangolin viruses have been progressively optimized through natural selection (convergent evolution) to bind ACE2 molecules from humans and pangolins (and possibly other non-bat mammalian species) (
Lam et al., 2020).
An alternative possibility is that recombination events among coronaviruses hosted by bats, pangolins, and possibly other mammals originated the progenitor of SARS-CoV-2 (
Lam et al., 2020; Cagliani et al., 2020).
It is presently impossible to disentangle these two alternative scenarios, and only the sequencing of additional related sarbecoviruses might eventually clarify the evolutionary history of SARS-CoV-2 RBD.
It is also worth mentioning here that, as previously noted (
Andersen et al., 2020), the similarity of the SARS-CoV-2 RBD with that of viruses only recently sequenced from pangolins can be regarded as a major evidence against the circulating theory that SARS-CoV-2 is the result of deliberate human manipulation.
In any case, these data do not necessarily imply that pangolins had a role in the emergence of SARS-CoV-2 and in its spread to humans, as these animals might have in turn contracted infection from a bat or other reservoir.
Moreover, the SARS-CoV-2 spike protein displays a unique feature that is not shared with either BatCoV RaTG13 or the pangolin viruses, namely the presence of a furin cleavage site insertion (PRRA) at the S1-S2 junction (
Walls et al., 2020) (
Fig. 1D and F). This feature, also absent in SARS-CoV, was suggested to increase viral infectivity and/or pathogenicity (
Walls et al., 2020; Andersen et al., 2020).
It is presently unknown how and when SARS-CoV-2 acquired the furin cleavage site, but it is equally unexplored whether it affects any viral phenotype or if it contributed to adaptation to humans or other hosts. Importantly, though, the presence of a similar insertion in a virus isolated from wild bats is another strong indication in favor of a natural animal origin of SARS-CoV-2 (
Zhou et al., 2020a).