Ancestral reconstruction of ACE2 binding in coronaviruses

Tyler Starr is at it again:

I’ll add more details later.


From the abstract:

Yet another example of how pervasive epistatic effects are.


The abstract is quite explanatory:

Two different sarbecoviruses have caused major human outbreaks in the last two decades. Both these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 via the spike receptor-binding domain(RBD)2-6. However, binding to ACE2 orthologs from humans, bats, and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses7-11. Here, we use high-throughput assays12 to trace the evolutionary history of ACE2 binding across a diverse range of sarbecoviruses and ACE2 orthologs. We find that ACE2 binding is an ancestral trait of sarbecovirus RBDs that has subsequently been lost in some clades. Furthermore, we demonstrate for the first time that bat sarbecoviruses from outside Asia can bind ACE2. In addition, ACE2 binding is highly evolvable: for many sarbecovirus RBDs there are single amino-acid mutations that enable binding to new ACE2 orthologs. However, the effects of individual mutations can differ markedly between viruses, as illustrated by the N501Y mutation which enhances human ACE2 binding affinity within several SARS-CoV-2 variants of concern12 but severely dampens it for SARS-CoV-1. Our results point to the deep ancestral origin and evolutionary plasticity of ACE2 binding, broadening consideration of the range of sarbecoviruses with spillover potential.

Sarbecoviruses are basically the clade of SARS and SARS-like viruses, including SARS-CoV-2. These results demonstrate that rather than SARS-CoV-1 and SARS-CoV-2 independently evolving the ability to bind to ACE2 receptors, this was an ancestral trait. In fact, even binding to human ACE2 is an ancestral trait.

Earlier ancestors were limited to binding to the ACE2 receptor in certain bats, but in the ancestor of Asian sarbecoviruses, this ACE2 binding ability broadened to other mammals including humans.

Additionally, they say:

Our work also shows that ACE2 binding is a highly evolvable trait of sarbecovirus RBDs. For every ACE2-binding RBD we studied, there were single amino-acid mutations that enhanced affinity for ACE2 orthologs the RBD could already bind or conferred binding to new ACE2 orthologs from different species.

An example of this can be seen in figure 3D:

Strain BtKY72 is the pink line along the bottom of the graph, failing to bind to human ACE2, but introducing a single mutation, T498W, results in the green line, much higher on the graph, and when two mutations are introduced, T498W and K493Y, this binding is enhanced, approaching the level of binding of SARS-CoV-2.

Their results for all mutations are summaries in figure 3C:

In other words, most sarbecoviruses either already bind, or are just a single mutation away from binding the ACE2 receptors of all the species shown there, not least human ACE2.


I also wanted to zoom in on this part of figure 1:

Notice those 3 strains at the bottom? WIV1, Rs7327, and Rs4231? They’re the strains studied in this now apparently controversial paper from 2017: Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus

Controversial, at least, among people like Senator Rand Paul, who had a heated exchange with Dr Fauci at a hearing in Congress yesterday: Dr. Anthony Fauci to Sen. Rand Paul at hearing: You do not know what you're talking about - YouTube

Paul references the 2017 paper and describes their work as:

“viruses in nature that only infect animals were manipulated in the Wuhan lab to gain the function of infecting humans”


“they took animal viruses that only occur in animals and increased their transmissibility to humans”

What they did is take WIV1 (which is easy to culture in the lab), and replace it’s spike protein with the spike proteins from Rs7327 and Rs4321 (which are difficult to culture in the lab). This was done to see if the spike proteins from Rs7327 and Rs4321 were able to bind to human ACE2 and therefore infect human cells. They were able to, just as well as WIV1 with it’s native spike protein (not better). Their results are basically recapitulated in this new study, as shown by the fact that the left-most box is coloured dark blue for all 3 strains, indicating they all bind human ACE2 well.

The chimeric viruses created in the 2017 study didn’t gain anything! The wild-type WIV1 virus is just as capable of binding human ACE2 and infecting human cells as the WIV1-7327S and WIV1-4321S viruses, and it turns out that’s because it’s an ancestral trait.


Which is consistent with the routine observation that functions are easy to “find” in sequence space.


Bu…but…mutations cannot add new information…blablabla

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Or in this case, “the information was already there”, etc. etc…


Rand Paul has no idea what he’s talking about and his insinuations are extremely misleading. It is honestly disgusting.

According to Paul’s logic, as soon as researchers at the Wuhan lab performed gain of function studies they were now liable for any pandemic that occurred after that date, no matter where the virus came from. It’s ridiculous. The least ridiculous part is that Paul didn’t even cite a gain of function study.


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