Since the virus first appeared, scientists have been struggling to find a treatment for COVID-19, or even develop a vaccine that would protect us in the long term. But many teams are also working to elucidate the starting point of the whole story: namely, where and how did the virus appear? Bat ? Pangolin? Accidental leak from a laboratory? Biological weapon? If the latter two lack formal evidence, all hypotheses have been studied … Today, American researchers confirm that the virus is from a combination of two viruses, one from the bat, the other pangolin.
The results of the genome analysis of the new coronavirus were relatively ambiguous. Some scientists have claimed that SARS-CoV-2 came from a local population of bats. Others have suspected pangolins, which are the subject of illegal trade in Southeast Asia. In reality, both are responsible: SARS-CoV-2 is mainly composed of fragments of bat virus, combined with part of the pangolin virus, which has proven to be decisive for its transmission to humans.
A mixture to better target humans
How can viruses from two different species come together in this way? Thanks to genetic recombination, an exchange of information between two different genomes or between two chromosomes. It is actually an essential process for the evolution of species. And the phenomenon is also seen in viruses, where recombination can take place in cells infected with two different viruses.
If most of the time the exchange occurs between DNA fragments, an RNA exchange is also possible (especially in the case of certain viruses such as influenza); pieces of RNA mix to form new genetic combinations. But in the case of the coronavirus, whose RNA molecule is particularly long, the process is different: the enzyme responsible for copying the RNA can suddenly detach from the strand of RNA copied, while remaining attached to the partial copy .
Then, two possible scenarios: most of the time, the copy is abandoned, but sometimes the enzyme succeeds in catching on another RNA and then resumes the copy where it left off. To do this, the two NRAs must have significant similarities. And we finally end up with a recombination of two different viruses.
To confirm the hypothesis of a recombination, American researchers examined the genome of 43 different coronaviruses, from different species (human, bat and pangolin) and known to resemble SARS-CoV-2. A first analysis showed that this coronavirus was closely linked to a bat virus; in particular, its RNA had 96.3% genetic similarity to the CoV RaTG13 virus, sampled from a bat in Yunnan in 2013. But some areas suddenly looked like a different virus, not necessarily of the same species. The proof, according to the researchers, that there was indeed recombination.
Diagram of genetic similarity between the SARS-CoV-2 virus and other coronaviruses from the bat and pangolin. The RaTG13 virus shows the greatest similarity, except in certain parts of the gene coding for the peak protein, which are more similar to two viruses originating from pangolin. Credits: Xiaojun Li et al.
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At the same time, samples of pangolin virus from the provinces of Guangdong and Guangxi showed 91.2% and 85.4% respectively of similarity with SARS-CoV-2. The latter also displays a notable difference compared to the bat virus: this difference concerns the advanced protein, which is found on the surface of the virus and which allows it to attach to human cells. However, a key region of this cutting-edge protein – the one that determines with which proteins of human cells it can interact – comes precisely from a pangolin coronavirus!
Worrisome possibilities of recombination
This genomic study of coronaviruses also revealed where exactly the changes in viral proteins were taking place. This is particularly interesting information, because an intolerance to change in a specific area of the genome can mean that the protein encoded by this part of the genome is essential.
The researchers thus identified several regions of the genome resistant to change; one is part of the cutting-edge protein, derived from the pangolin virus: among the 6,400 SARS-CoV-2 genomes isolated during the pandemic, only 8 have shown modifications at this level. This confirms that the genomic sequence from pangolin is decisive for the virus to affect humans. The virus underwent so-called “selection” pressure, which caused it to transform to be able to infect a new host, humans.
On the same topic: Coronavirus: A precise 3D model of SARS-CoV-2 unveiled
In the end, the fortuitous appearance of SARS-CoV-2 is indeed the result of natural genetic manipulation. Understanding the origin of this virus can help develop strategies to prevent future interspecies transmissions. However, a large number of coronaviruses seem to exchange genetic information regularly. If these exchanges are more frequent between viruses that target the same species, we now have proof that the contributions can also come from much more distant viruses.
Difficult in this case to consider all the possibilities and to prepare to face other viral mutations potentially dangerous for the Man …
Source: Science Advances, Xiaojun Li et al.
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