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SARS-CoV-2 Evolution in Bats May Have Resulted in Highly Efficient Human Pathogen

NEW YORK – Researchers in the UK, the US, and Belgium have found that while the SARS-CoV-2 virus has undergone significant changes in its evolutionary history, those changes likely occurred while the virus was still found mainly in bats, resulting in a "relatively generalist" virus that was capable of infecting humans without the need for an intermediary species.

In a study published Friday in PLOS Biology, the researchers noted that shifts in virus hosts are usually associated with novel adaptations in the viruses themselves that allow the microbes to better exploit the cells of the new host species. However, SARS-CoV-2 apparently required little to no significant adaptation to humans from the beginning of the COVID-19 pandemic until October 2020.

The researchers assessed the types of natural selection taking place in Sarbecoviruses in horseshoe bats and compared them to early SARS-CoV-2 evolution in humans. While they did find some evidence of diversifying positive selection in SARS-CoV-2 in humans, it was moderate, limited to the early phase of the pandemic, and the purifying selection was much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, they found significant positive episodic diversifying selection acting at the base of the bat virus lineage that SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts.

Therefore, the researchers said, while it's still possible that an intermediary species facilitated the transmission of SARS-CoV-2 from bats to humans, their data suggested that the progenitor of SARS-CoV-2 was capable of efficient human-to-human transmission as a consequence of its adaptive evolutionary history in bats.

The researchers first analyzed selection acting on the encoded amino acids of SARS-CoV-2 using 133,741 genome sequences from the GISAID database as of Oct. 12, 2020, representing a sample of the variants circulating in humans during the first 11 months of the pandemic. The vast majority of the mutations they observed in these samples occurred at very low frequencies, with 79 percent of mutations observed in 10 or fewer of the 133,741 SARS-CoV-2 genome sequences.

"Our study results show changes have occurred with SARS-CoV-2, but that most of these mutations are of no evolutionary significance and accumulate by 'surfing' along the millions of transmission events, like they do in all viruses," first author and University of Glasgow researcher Oscar MacLean said in a statement. "The slow rate of evolution can be attributed to the highly susceptible nature of the human population to this new pathogen, with limited pressure from population immunity, and lack of containment, leading to exponential growth."

In contrast, however, the researchers' analysis of the Sarbecovirus clade from which SARS-CoV-2 emerged showed evidence of positive selection on the clade's deeper branches, coupled with an adaptive shift in CpG composition in this lineage. The shift in CpG suppression at the base of the novel coronavirus clade could be indicative of an immune evasion adaptation by evading known CpG-targeting mammalian immune mechanisms such as ZAP, they said.

Importantly, the researchers noted that since the end of 2020, there are indications of increased selective pressure in some recent lineages of the virus that are associated with faster spread and a higher-than-usual number of nonsynonymous substitutions — the UK (B.1.1.7) and South Africa (B.1.351) variants, for example. These lineages appear to have evolved in humans in association with human immunity, due to previous exposure and/or chronic infections of probably immunocompromised individuals, and not because of the slow rate of evolution associated with acute SARS-CoV-2 infections and transmission that had predominated in the pandemic until October 2020, they said.

More urgently, senior author and Glasgow bioinformatics researcher David Robertson noted in the statement, the virus is now making evolutionary moves away from the January 2020 variant that was used in all of the current vaccines.

"The current vaccines will continue to work against the circulating variants but the more time that passes, and the bigger the differential between vaccinated and not-vaccinated numbers of people, the more opportunity there will be for vaccine escape," he said. "The reason for the shifting of gears of SARS-CoV-2 in terms of its increased rate of evolution at the end of 2020, associated with more heavily mutated lineages, is because the immunological profile of the human population has changed. The first race was to develop a vaccine. The race now is to get the global population vaccinated as quickly as possible."

In their study, the authors also sounded a note of caution that because of the high diversity and generalist nature of Sarbecoviruses, a future spillover from bats, potentially coupled with a recombination event with SARS-CoV-2, is possible. Such an event could lead to the emergence of a SARS-CoV-3 virus, which could itself be sufficiently divergent to evade either natural or vaccine-acquired immunity.

"We must therefore dramatically ramp up surveillance for Sarbecoviruses at the human-animal interface and monitor carefully for future SARS-CoV emergence in the human population," they concluded.

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