RaTG13 is a SARS-related coronavirus found in bats and is highly similar to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Specifically, the spike domain is highly similar, however, the receptor-binding site of SARS-CoV-2 diverges genomically and is closer to pangolin SARS-CoVs suggesting a possible recombination event between these viruses in the evolution of SARS-CoV-2.
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Bat RaTG13
Bat RaTG13 is a SARS-related coronavirus that primarily infects bats. It is a linear 29855bp RNA virus of the betacoronavirus subtype (sarbecovirus). RaTG13 binds to the bat ACE2 receptor through its spike glycoprotein (S-domain).
The bat RaTG13 virus contains a Leu486 in its (S-domain) which accounts for a small buried surface within the viral S-domain and ACE2, allowing it to bind to bat ACE2 (but weaker compared to SARS-CoV-2, discussed below).
Furthermore, there is a tyrosine at the location of Gln493 of SARS-CoV-2 (discussed later), whereas RaTG13 contains a tyrosine residue that does not bind strongly to ACE2 receptor residues. Therefore, RaTG13 does not typically result in infection in bats due to the weaker affinity between its S-domain and bat ACE2 receptor compared to SARS-CoV-2 and human ACE2.
Links to SARS-CoV-2
SARS-CoV-2 is the virus that causes COVID-19 and is a beta-coronavirus that shares a high degree of sequence homology with horseshoe bat RaTG13 (Yunnan).
The viral S domain shares up to 97.8% conservation in the ectodomain, however, there are many nuclei acid substitutions within the receptor-binding domain; RBD (89.6%). See genomic differences between SARS-CoV-2 and other viruses for more discussion.
As previously mentioned, RaTG13’s S-domain contains a Leu486 whereas human SARS-CoV-2 contains a bulkier Phe486 that binds to a hydrophobic pocket on the surface of ACE2 formed by specific residues e.g. Phe28 & Leu79.
Furthermore, human SARS-CoV-2 contains a Gln493 in the S-domain which makes hydrogen bind with Glu35 of ACE2 that in turn makes a salt bridge link with Lys31 that in itself makes a salt bridge with Gln493, strengthening the binding of SARS-CoV-2 to ACE2.
As discussed, the largest sequence difference is between the bat and the human receptor-binding site (RBD). Compared to the bat RaTG13, the RBD site of SARS-CoV-2 is more closely related to pangolin-SARS-CoV from Guangzhou (MP789/Guandong/2019). It is 97% related, compared to only 77% to bat RaTG13.
The RaTG13 RBD differs to SARS-CoV-2 in that its spike protein does not contain the furin cleavage motif present in SARS-CoV-2.
More conserved features include the RNA-dependent RNA polymerase gene which is highly related between SARS-CoV-2 and RaTG13. However, due to the RBD site being closer to pangolin SARS-CoV, evidence of a recombination event between bat RaTg13 and pangolin SARS-CoV(MP789/Guandong/2019) seems a likely event in SARS-CoV-2 evolution.
Despite the high degree of similarity in parts related to bat RaTG13 and RBD to pangolin SARS-CoV(MP789/Guandong/2019), the immediate predecessor to human SARS-CoV-2 remains unclear. It is highly likely that pangolin SARS-CoV originated from bat RaTG13 as a result of animal mixing in smuggling centers or animal markets in Wuhan, China.
The ability of SARS-CoV-2 to infect humans and bind with a high affinity to human ACE2 receptors is probably due to the RBD sequence from several bat strains incorporating a pangolin or civet SARS-CoV that has recombinantly evolved due to cross mixing.
Previously, civets in Yunnan, China carrying the bat-borne SARS virus evolved to infect humans in the SARS outbreak of 2002-2003. Thus, it is highly likely a recombination event involving bat RaTG13 amongst other bat SARS-CoVs, pangolin, and/or civet viruses to form SARS-CoV-2.
The origins of SARS-CoV-2
Summary
In summary, bat RaTG13 is a betacoronavirus and is highly similar in most parts to human SARS-CoV-2, and as such, is thought to be one of the main contenders as a direct ancestor to SARS-CoV-2.
However, whilst the overall sequence is related to RaTG13, the RBD site shares a higher homology to pangolin SARS-CoV. This implies that SARS-CoV-2 may have undergone a recombination event due to animal mixing between bats and pangolins in Wuhan, China at some point, before infecting humans.
However, the immediate ancestor to SARS-CoV-2 remains to be identified.
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References
- Lau et al, 2020. Possible Bat Origin of Severe Acute Respiratory Syndrome Coronavirus 2. Emerg Infect Dis. 26(7):1542-1547. https://dx.doi.org/10.3201/eid2607.200092
- Li et al, 2020. The divergence between SARS-CoV-2 and RaTG13 might be overestimated due to the extensive RNA modification. Future Virology (ahead of print) https://doi.org/10.2217/fvl-2020-0066
- Lv et al, 2020. Comparative genomic analysis revealed a specific mutation pattern between human coronavirus SARS-CoV-2 and Bat-SARSr-CoV RaTG13. bioRxiv (preprint) https://doi.org/10.1101/2020.02.27.969006
- Makarenkov et al, 2021. Horizontal gene transfer and recombination analysis of SARS-CoV-2 genes helps discover its close relatives and shed light on its origin. BMC Ecology and Evolution. https://doi.org/10.1186/s12862-020-01732-2
- Malaiyan et al, 2020. An update on the origin of SARS‐CoV‐2: Despite closest identity, bat (RaTG13) and pangolin derived coronaviruses varied in the critical binding site and O‐linked glycan residues. Journal of Medical Virology. https://doi.org/10.1002/jmv.26261
- Matyasek & Kovarik, 2020. Mutation patterns of human SARS-COV-2 and bat RaTG13 coronaviruses genomes are strongly biased towards C>U indicating rapid evolution in their hosts. (preprint) https://doi.org/10.21203/rs.3.rs-21377/v1
- Wrobel et al, 2020. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat Struct Mol Biol. https://doi.org/10.1038/s41594-020-0468-7
- Zhou et al, 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 579:270-273 https://www.nature.com/articles/s41586-020-2012-7
[further reading: coronavirus disease COVID-19]