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SARS-CoV-2 Result of Bat, Pangolin Virus Recombination, Purifying Selection, Study Suggests

NEW YORK – SARS-CoV-2 may have emerged through recombination between a bat and a pangolin coronavirus and purifying selection, a new study has found.

Previous studies reported that SARS-CoV-2 appears to be genetically most similar to a coronavirus isolated from a bat in Yunnan in 2013, called RaTG13, but also that some parts of the virus resemble coronaviruses found among Malayan pangolins. Some research groups have concluded that pangolins may have served as an intermediate host for the emerging SARS-CoV-2, but other teams consider a scenario of direct evolution unlikely.

Researchers led by Duke University Medical Center's Feng Gao analyzed the SARS-CoV-2 genome and compared it to other members of the Betacoronavirus family, including SARS-CoVs, RaTG13, and pangolin SARS-like CoVs. As they reported on Friday in Science Advances, they found that recombination and purifying selection were likely involved in the evolution of SARS-CoV-2. They also suggested that cross-species infections may have fueled its development by enabling bat RaTG13-like viruses to recombine with viruses similar to pangolin SARS-like CoVs.

"We hypothesize that this, and/or other ancestral recombination events between viruses infecting bats and pangolins, may have played a key role in the evolution of the strain that led to the introduction of SARS-CoV-2 into humans," Gao and his colleagues wrote in their paper.

The researchers analyzed 43 complete coronavirus genome sequences, including those from bats, pangolins, and humans, to confirm that overall, the bat RaTG13 virus is most closely related to SARS-CoV-2, followed by the pangolin viruses Pan_SL-CoV_GD from Guangdong and Pan_SL-CoV_GX from Guangxi.

While the bat RaTG13 virus is broadly the most similar virus to SARS-CoV-2, there are two regions of the SARS-CoV-2 genome where they diverge, namely the ORF1a gene and the part of the spike glycoprotein gene that encodes the ACE2 receptor binding motif (RBM). SARS-CoV-2, the researchers noted, relies on the RBM for its entry into host cells.

At the ORF1a gene, SARS-CoV-2 is more similar to the otherwise divergent bat ZXC21 and ZC45 coronaviruses, while at the RBM, it is more similar to the pangolin Pan_SL-CoV_GD virus.

 By comparing the various coronaviruses, the researchers uncovered signs of recombination breakpoints before and after the ACE2 receptor binding motif within SARS-CoV-2, suggesting it was acquired through recombination. The Pan_SL-CoV_GD RBM differs from that of SARS-CoV-2 by one amino acid, which falls at the edge of the ACE2 contact interface.

This suggests that a RaTG13-like virus may have obtained this RBM from a Pan_SL-CoV_GD-like virus through recombination, the researchers noted. 

This change may have enabled the virus to be better able to infect human cells, as a recent study reported RaTG13 pseudoviruses were less efficient than SARS-CoV-2 pseudoviruses in their ability to use ACE2 to infect cells.

Through their comparison of coronavirus genomes, the researchers also uncovered indicators of strong purifying selection. The S2 subunit of the S gene, for instance, is highly conserved among SARS-CoV-2, RaTG13, and Pan_SL-CoV, and the researchers wrote that given its important role in cell entry, purifying selection at this site is not surprising. 

They further noted signs of selection in other regions of the coronavirus genome, such as the E and M genes. Some viruses exhibited signs of selective pressure at the same genes, while other viruses had increased pressure at other genes, suggesting that some but not all hosts exerted similar evolutionary constraints. Still, the researchers said those similar pressures might make cross-species transmissions easier.

Continuous surveillance of coronaviruses in their natural hosts and in humans will be needed to stem new outbreaks, they suggested. "While the direct reservoir of SARS-CoV-2 is still being sought, one thing is clear: reducing or eliminating direct human contact with wild animals is critical to preventing new coronavirus zoonosis in the future," they wrote. 

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