Team pinpoints the origin story of SARS-CoV-2

The lineage that gave rise to the SARS-CoV-2, the virus that is responsible for the COVID-19 pandemic, has been circulating in bats for decades, researchers report.

They also warn it likely includes other viruses with the ability to infect humans.

The discoveries, which researchers made by reconstructing the evolutionary history of SARS-CoV-2, have implications for the prevention of future pandemics stemming from this lineage.

“Coronaviruses have genetic material that is highly recombinant, meaning different regions of the virus’s genome can be derived from multiple sources,” says Maciej Boni, associate professor of biology at Penn State.

“This has made it difficult to reconstruct SARS-CoV-2’s origins. You have to identify all the regions that have been recombining and trace their histories.”

A SARS-CoV-2 ‘family tree’

The team used three different bioinformatic approaches to identify and remove the recombinant regions within the SARS-CoV-2 genome. Next, they reconstructed phylogenetic histories for the non-recombinant regions and compared them to each other to see which specific viruses have been involved in recombination events in the past.

They were able to reconstruct the evolutionary relationships between SARS-CoV-2 and its closest known bat and pangolin viruses.

The researchers found that the lineage of viruses to which SARS-CoV-2 belongs diverged from other bat viruses about 40-70 years ago. Importantly, although SARS-CoV-2 is genetically similar (about 96%) to the RaTG13 coronavirus, which was sampled from a Rhinolophus affinis horseshoe bat in 2013 in Yunnan province, China, the team found that it diverged from RaTG13 a relatively long time ago, in 1969.

“The ability to estimate divergence times after disentangling recombination histories, which is something we developed in this collaboration, may lead to insights into the origins of many different viral pathogens,” says Philippe Lemey, principal investigator in the evolutionary and computational virology department at KE Leuven.

The team found that one of the older traits that SARS-CoV-2 shares with its relatives is the receptor-binding domain (RBD) located on the spike protein, which enables the virus to recognize and bind to receptors on the surfaces of human cells.

“This means that other viruses that are capable of infecting humans are circulating in horseshoe bats in China,” says David L. Robertson, professor of computational virology, MRC-University of Glasgow Centre for Virus Research.

The leap from bats to humans

Will these viruses be capable of jumping directly from bats into humans or will an intermediate species be required to make the leap? According to Robertson, for SARS-CoV-2, other research groups incorrectly proposed that key evolutionary changes occurred in pangolins.

“SARS-CoV-2’s RBD sequence has so far only been found in a few pangolin viruses,” says Robertson. “Furthermore, the other key feature thought to be instrumental to SARS-CoV-2’s ability to infect humans—a polybasic cleavage site insertion in the spike protein—has not yet been seen in another close bat relative of the SARS-CoV-2 virus.

“Yet, while it is possible that pangolins may have acted as an intermediate host facilitating transmission of SARS-CoV-2 to humans, no evidence exists to suggest that pangolin infection is a requirement for bat viruses to cross into humans. Instead, our research suggests that SARS-CoV-2 likely evolved the ability to replicate in the upper respiratory tract of both humans and pangolins.”

Better surveillance next time?

The team concludes that preventing future pandemics will require better sampling within wild bats and the implementation of human disease surveillance systems that are able to identify novel pathogens in humans and respond in real time.

“The key to successful surveillance,” says Robertson, “is knowing which viruses to look for and prioritizing those that can readily infect humans. We should have been better prepared for a second SARS virus.”

Boni adds, “We were too late in responding to the initial SARS-CoV-2 outbreak, but this will not be our last coronavirus pandemic. A much more comprehensive and real-time surveillance system needs to be put in place to catch viruses like this when case numbers are still in the double digits.”

Additional coauthors are from Xi’an Jiaotong-Liverpool University; University of Hong Kong; University of Texas at Arlington; and the University of Edinburgh.

Support for this research came from the European Research Council, the Medical Research Council, the Research Foundation-Flanders, and the National Natural Science Foundation of China.

Source: Penn State

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