Whence SARS-CoV-2, the cause of so much human suffering in the US and around the world? The very first sequence of the virus genome told us much of the story.
The virus resembled that which caused the original SARS epidemic (now called SARS-CoV-1) in 2002-2003. Both were members of the same family, beta-coronaviruses. Both had close, but different, relatives in bats from southern China. Both attach to human and animal cells via the same receptor, the ACE2 protein.
Yet there are differences. SARS-2 is about 76% identical to SARS-1. SARS-2 is actually much closer to a previously isolated bat coronavirus than it is to SARS-1. The region that binds to the receptor much more closely resembles that of a pangolin coronavirus. Also the region preceding the part of the virus protein essential for penetrating cells, called the fusion peptide, contains an additional four amino acids, a feature that had not been previously observed for any other coronavirus including SARS-1.
A recent paper in the journal Current Biology describing yet another coronavirus from a bat in Southern China adds valuable information to our understanding of SARS-2. The authors isolated 227 coronaviruses from bats in the southern province of Yunnan, China. One of the isolates, RmYN02 is remarkably similar to SARS-2 (93.3% overall). That part of the virus which specifies the enzymes required for replication showed an even greater similarity (97.2%).
The region corresponding to the ACE2 receptor binding site of SARS-2 differs markedly from that of RmNY02. It is unlikely that RmYN02 uses the same receptor.
The most remarkable finding was that like SARS-2, RmYN02 carries a four amino acid insertion in precisely the same location preceding the fusion peptide. These are the only two coronaviruses known to carry such an insertion. The inserted amino acids are different between the two viruses, but share the same biochemical properties. This suggests that although the evolutionary origin of the insertion is different, the function is similar.
These observations reinforce the close relationship between SARS-2 and other coronaviruses found in nature. Recombination among coronaviruses is well documented. A likely hypothesis is that a bat coronavirus very similar to that of RmYN02 recombined with another coronavirus, possibly of pangolin origin, to acquire the ACE2 receptor binding domain. What had been thought to be a unique feature of SARS-2, namely the four amino acid sequence preceding the fusion peptide, is now shown to be a feature of other naturally occurring coronaviruses.
This work brings us one step closer to understanding the origins in nature of SARS-2. The study also reminds us that we must continue an intensive study of coronaviruses in bats and other animals. Recall that the coronavirus epidemic preceding COVID-19 is thought to have originated from an Egyptian tomb bat that infected camels. That virus continues to infect humans who are in closely proximity to camels and sometimes spreads from human to human as well. It is a shame that the US administration ordered defunding of one of the premier groups of virus hunters because of their association with a Chinese lab, especially now when we need the information most.