Comparative genomics confirms natural development of SARS-CoV-2

By Samantha Black, PhD, The Science Advisory Board staff writer

March 18, 2020 -- The available genetic data on SARS-CoV-2 indicate that it is not derived from any previously known virus, suggesting that it originated from either natural selection in an animal host or humans following zoonotic transfer. This analysis, presented in Nature Medicine on March 17, provides evidence for the natural evolution of this novel coronavirus amid claims of manufactured origins.

Coronaviruses are a large family of viruses that can cause illnesses that range widely in severity. On December 31, 2019, the Chinese authorities alerted the World Health Organization of an outbreak of a novel strain of coronavirus causing severe illness, which was subsequently named SARS-CoV-2.

Shortly after the epidemic began, Chinese scientists sequenced the genome of SARS-CoV-2 and made the data available to researchers worldwide. The Nature Medicine article explains some of what they have discovered.

A unique molecular backbone

The genomic comparison of the receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 against other closely related betacoronaviruses and the original SARS-CoV virus revealed that SARS-CoV-2 has significantly higher binding affinity with human angiotensin-converting enzyme 2 (ACE2) than any of the other viruses. The RBD of SARS-CoV-2 is optimized for binding human ACE2 with an efficient solution that is different from other SARS-CoV-like coronaviruses. The sequences are so different, in fact, that the scientists involved in the project concluded that they are a result of natural selection and not based on a template for genetic modification.

Analysis of the SARS-CoV-2 spike protein showed the addition of O-linked glycans, created by an inserted proline to the sequence, that flank a polybasic cleavage site in the spike are believed to be responsible for the virus's high level of infectivity and host range. Polybasic cleavage sites have not been observed in other lineage B betacoronaviruses, although other human betacoronaviruses do have those sites.

The major changes to the molecular backbone of SARS-CoV-2 compared with other coronaviruses provide evidence that the changes occurred by natural selection. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known pathogenic coronaviruses.

Where did SARS-CoV-2 come from?

There are two likely scenarios for SARS-CoV-2 origin, according to the scientists involved in this analysis. First, based on the similarity of bat SARS-CoV to SARS-CoV-2, it is likely that bats served as an animal reservoir in which natural selection occurred before jumping to humans.

No cases of direct bat-human transmission have been documented, however, suggesting that an intermediate host was likely involved between bats and humans. The spike RBD in bat SARS-CoV diverges from SARS-CoV-2, suggesting that it may not bind efficiently to human ACE2. Alternatively, some coronaviruses from pangolins -- armadillo-like mammals found in Asia and Africa -- have an RBD structure very similar to that of SARS-CoV-2.

Neither bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. While no animal betacoronavirus has been identified that is sufficiently similar to have served as the direct ancestor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled.

The mutations observed in SARS-CoV-2 can arise by natural selection, so acquisition of both mutations in the polybasic cleavage site and the spike protein would be possible in high-density populations and with an ACE2 encoding gene that is similar to the human ortholog.

In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that make it pathogenic and able to spread between people.

In the second scenario, a nonpathogenic version of the virus jumped from an animal host to humans, from which it acquired pathogenic genomic features through adaptation during undetected human-to-human transmission. As of March 17, all SARS-CoV-2 genomes sequenced from the COVID-19 coronavirus outbreak have a common ancestor. The presence of a very similar RBD in pangolins infers that they may be the animal host from which the virus jumped to humans. In this case, the insertion of the polybasic cleavage site must have occurred during human-to-human transmission.

Estimates of the timing of the most recent common ancestor of SARS-CoV-2 point to late November 2019 to early December 2019 and the earliest confirmed cases in January 2020. This timetable indicates that there could have been a presumed period of unrecognized transmissions in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site.

It is difficult, if not impossible, to know at this point which of the scenarios is most likely, cautioned study co-author Andrew Rambaut, PhD, from the University of Edinburgh. If the SARS-CoV-2 entered humans in its current pathogenic form from an animal source, it raises the probability of future outbreaks, as the illness-causing strain of the virus could still be circulating in the animal population and might once again jump to humans. The chances are lower of a nonpathogenic coronavirus entering the human population and then evolving properties similar to SARS-CoV-2.


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