The proximal origin of SARS-CoV-2

[Brian4Liberty]

The proximal origin of SARS-CoV-2

To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China1,2, there has been considerable discussion on the origin of the causative virus, SARS-CoV-23 (also referred to as HCoV-19)4. Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths5.

SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms6. Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

Notable features of the SARS-CoV-2 genome

Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies7,8,9 and biochemical experiments1,9,10, SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides8, which additionally led to the predicted acquisition of three O-linked glycans around the site.

1. Mutations in the receptor-binding domain of SARS-CoV-2

The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome1,2. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses7. With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-27. Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. 1a). On the basis of structural studies7,8,9 and biochemical experiments1,9,10, SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology7.

While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding7,11. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation.
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The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo17. Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system18.
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Conclusions

In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events. In contrast, if the adaptive process occurred in humans, then even if repeated zoonotic transfers occur, they are unlikely to take off without the same series of mutations. In addition, identifying the closest viral relatives of SARS-CoV-2 circulating in animals will greatly assist studies of viral function. Indeed, the availability of the RaTG13 bat sequence helped reveal key RBD mutations and the polybasic cleavage site.

The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV-2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible.

More scientific data could swing the balance of evidence to favor one hypothesis over another. Obtaining related viral sequences from animal sources would be the most definitive way of revealing viral origins. For example, a future observation of an intermediate or fully formed polybasic cleavage site in a SARS-CoV-2-like virus from animals would lend even further support to the natural-selection hypotheses. It would also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies. The identification of a potential intermediate host of SARS-CoV-2, as well as sequencing of the virus from very early cases, would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance.
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More: https://www.nature.com/articles/s41591-020-0820-9

[Brian4Liberty]

2. Natural selection in humans following zoonotic transfer

It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it1,2.

All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission.

Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 201923, compatible with the earliest retrospectively confirmed cases24. Hence, this scenario presumes a period of unrecognized transmission in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site. Sufficient opportunity could have arisen if there had been many prior zoonotic events that produced short chains of human-to-human transmission over an extended period. This is essentially the situation for MERS-CoV, for which all human cases are the result of repeated jumps of the virus from dromedary camels, producing single infections or short transmission chains that eventually resolve, with no adaptation to sustained transmission25.

Translation: A virus could jump from animals to humans in Chinese wet markets over and over. Eventually, the virus will mutate in a human, making it more able to transmit among humans, thus it becomes widespread enough to be detected (and possibly launch into an epidemic).

[Brian4Liberty]

Translation: A virus could jump from animals to humans in Chinese wet markets over and over. Eventually, the virus will mutate in a human, making it more able to transmit among humans, thus it becomes widespread enough to be detected (and possibly launch into an epidemic).

And this would be relevant to the current political discussion surrounding China’s early actions when COVID-19 started. Let’s assume for a minute that the above is true. Viruses, sometimes deadly, have been jumping from animals to humans regularly in China’s wet markets. But in most of the previous cases, the virus did not mutate sufficiently to easily pass from human to human.

What would the Chinese officials done when that happened? Exactly what they are accused of doing with COVID-19. They would cover it up. And it would have worked.

If true, the actions of the Chinese officials would not be an aberration. It would have been an established policy. It just didn’t work this time.

[r3volution 3.0]

Not to say that the wet markets don't play a role, but population density alone makes China a likely origin for epidemics.

I'm all for reasonable measures to prevent the emergence of future viruses, but my money would be on nature.

The focus should be on preventing the spread once something emerges, as by rapid testing, quarantines, accelerated vaccine production, etc.

[TheTexan]

The rational thing to do would be to evacuate Wuhan and burn the entire city to the ground. The US military would be happy to assist.

[tfurrh]

The rational thing to do would be to evacuate Wuhan and burn the entire city to the ground. The US military would be happy to assist.

I believe they call that "the Sherman"

[Brian4Liberty]

Not to say that the wet markets don't play a role, but population density alone makes China a likely origin for epidemics.

I'm all for reasonable measures to prevent the emergence of future viruses, but my money would be on nature.

The focus should be on preventing the spread once something emerges, as by rapid testing, quarantines, accelerated vaccine production, etc.

Overcrowding is an issue, especially for human to human transmission and mutation of existing human viruses.

Zoonotic transmission though, such as with coronavirus, requires close contact with other animals; wet markets, farms, etc. The greater the number and variety of animals, the more the risk.

[Brian4Liberty]

The proximal origin of SARS-CoV-2

Well, now we know that this "paper" was merely a diversionary tactic by Fauci and his corrupt co-conspirators.

[Brian4Liberty]

... Viruses, sometimes deadly, have been jumping from animals to humans regularly in China’s wet markets. But in most of the previous cases, the virus did not mutate sufficiently to easily pass from human to human.
...

And now we know, there was no improbable natural mutation that made the virus pass from human to human. The mutation was an intentional gain of function lab experiment, advocated and financed by Fauci.

[Brian4Liberty]

The rest of the story...

Fauci Commissioned Paper in 2020 to Discredit Lab Leak Theory

[Anti Federalist]

And now we know, there was no improbable natural mutation that made the virus pass from human to human. The mutation was an intentional gain of function lab experiment, advocated and financed by Fauci.

Exact a mundo.