The Proximal Origin of Sars-Cov-2

Authors: Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes, Robert F. Garry

Introduction

The outbreak of COVID-19 from the Wuhan area of China has sparked a considerable debate on the origin of its causative agent i.e. SARS-CoV-2 which is also referred to as HCoV-19. This virus is among the seven common coronaviruses of variable virulence known to humans. The genomic analysis of the virus can help us conclude about the origin of SARS-CoV-2. The preliminary genomic analysis has made it clear that SARS-CoV-2 is a natural virus and is not engineered in laboratories.

Important Features of the SARS-CoV-2 Genome

Some notable features of the SARS-CoV-2 genome are:

1. The SARS-CoV-2 shows an optimum affinity for the various human receptors e.g. ACE2.
2. The SARS-CoV-2 has a spike protein that bears a cleavage site which can become a site of mutations.
3. The receptor-binding domain abbreviated as RBD of SARS-CoV-2 is most susceptible to the mutations as being an extremely variable part of the SARS-CoV-2 genome and at least 6 amino acids in the RBD are associated with its binding activity to the human ACE2 receptors.
4. Although the affinity of SARS-CoV-2 to the human ACE2 receptors seems to be good, it has been shown by computational analysis that this affinity is far from ideal. Thus, the current affinity could be the outcome of selection on a human or a human-like ACE2 receptor. This shows that the SARS-CoV-2 is not the product of purposeful engineering.

Theories of Origin

The genetic data strongly suggests that SARS-CoV-2 has not been developed by using the backbone of any previous virus. The two most common theories of origin are:
A natural selection has occurred on an animal host before the transfer of the virus to humans through zoonosis. The early cases of SARS-CoV-2 have occurred in the vicinity of an animal market in Wuhan, China. This supports the hypothesis that zoonosis from an animal could be a cause. Given that SARS-CoV-2 is soundly similar to the bat coronavirus, it was hypothesized that bats could be the natural reservoir of the virus. Although 96% similarity is present with the bat virus, the spike proteins in the bat virus diverge which means that it may not be able to bind to human receptors. Although the bat virus showed the highest similarity to the SARS-CoV-2, the coronaviruses from the Malayan pangolin also showed a strong similarity to the SARS-CoV-2. The polybasic cleavage sites present in the human SARS-CoV-2 are not present in the beta coronavirus of pangolin and bats. But, this could be countered by the fact that the diversity of coronaviruses in the bats has not been fully studied.
A natural selection in humans has occurred after the viral transfer through zoonosis. It could also be possible that the SARS-CoV-2 jumped into the humans and acquired the above-mentioned genetic characters through genetic adaptation. After this adaptation, the virus was able to increase its binding ability to the human receptors. This theory presumes that enough period of human to human transmission of the virus must have occurred before the acquisition of the desired characters. However, this aspect of origin is not fully known and studies are required which can determine the exact exposure of humans to the SARS-CoV-2 before the outbreak.
The selection of viruses during various passages in animal models or cell lines could have modified it. The research on the effects of serially passaging the SARS-CoV like viruses through various animal models and cell culture lines has been going on for years and there are many reports of the release of SARS-CoV from these laboratories into the environment. So the possibility of leakage of the virus after passaging through various cell lines cannot be ignored. In theory, it could be postulated that the SARS-CoV-2 acquired the desired mutations in the RBD and cleavage site during its adaptations through passaging in the cell lines.

Discussion

Although several theories about the origin of SARS-CoV-2 have been proposed, the evolving scientific data could favor any one of these theories in the future. Hence, more research on the animal data related to the functional and genetic aspects of SARS-CoV-2 including the animal models should be conducted. Irrespective of the exact origin of the virus, regular surveillance of the viruses related to pneumonia in humans should be conducted.

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