When Covid-19 variants arise, the accepted wisdom is that the constellation of mutations they contain developed in an immunocompromised person who contracted the virus and couldn’t shake the infection. But some scientists have an alternative theory for where the latest variant of concern, Omicron, may have acquired the unusual mutations that stud its spike protein.

They speculate the virus could have evolved in another animal species.

The theory goes that some type of animal, potentially rodents, was infected with the SARS-CoV-2 virus sometime in mid-2020. In this new species, the virus evolved, accumulating roughly 50 mutations on the spike protein before spilling back over into people.

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Kristian Andersen, an immunologist at the Scripps Research Institute, is among those who has been raising the idea that Omicron may have emerged from a reverse zoonotic event.

(A zoonotic event is when an animal pathogen starts to infect and spread among people. A reverse zoonosis is when such a virus passes back into an animal species.)

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“I know that most people think that these [come from] immunocompromised individuals, and I do think that that’s plausible, but to be perfectly honest, I actually think this reverse zoonosis followed by new zoonosis seems more likely to me given just the available evidence of the really deep branch, and then the mutations themselves, because some of them are quite unusual,” Andersen told STAT.

“I don’t think we should dismiss that possibility, because I think it’s definitely on the table.”

A number of other scientists who study the evolution of viruses have told STAT they think the idea isn’t out of the question. Some place more weight on the theory that variants develop in immunocompromised people, while others feel there isn’t enough evidence at this point to favor one option over the other.

“Personally, I think it’s probably more likely it was circulating undetected, in an immunocompromised individual,” Emma Hodcroft, a molecular epidemiologist at the Institute of Social and Preventive Medicine in Bern, Switzerland, said via email. Having said that, though, Hodcroft insisted that it is important to explore the hypothesis.

“I would certainly consider it a plausible alternative hypothesis to the evolution during a persistent infection in a human,” said Andrew Rambaut, a professor of molecular evolution at the Institute of Evolutionary Biology in Edinburgh. He cautioned that coming up with a definitive answer won’t be quick.

“I am not sure we will be in a position to say for sure for a while,” Rambaut wrote in an email.

One of the peculiar traits of SARS-2 underpins this thinking. It is what virologists describe as a promiscuous virus; it is capable of infecting a number of species. Dogs and house cats. Large cats. Mink. White-tailed deer. Given how easily the virus seems to jump from species to species, people studying it assume this list will grow.

The original virus that came out of Wuhan, China, in early 2020 did not infect rodents. But as variants — Alpha, Beta, Delta — started to emerge, those viruses could infect rodents.

Robert Garry, a professor of microbiology and immunology at Tulane Medical School, has been tracking the SARS-2 mutations that have arisen. Seven are associated with rodent adaptation — the changes that seemed to allow the virus to infect mice, rats, and related species. All seven of those mutations are in Omicron, Garry noted. He believes it’s a toss-up whether the variant developed in an animal or a human host, but if it’s the former, his bet would be on rodents.

Getting a firm answer might require enormous luck. Scientists are looking at various animal species to see if they can be infected with SARS-2; were they to find viruses like Omicron in any, that would swing the needle.

But Michael Worobey, a professor of evolutionary biology at the University of Arizona, thinks one could do some experiments on selected species of wild animals to see if they can be infected and if, when infected, similar patterns of viral evolution occur.

Studying the molecular clock of viruses that spread in animals — looking at the speed at which they evolve and comparing it to SARS-2 evolution in humans — could also provide some clues, said Worobey, who initially thought Andersen’s idea was not impossible, but not the likeliest of explanations for Omicron. After hearing details of the explosive outbreak in white-tailed deer, he’s rethinking the idea.

For Worobey, the question is whether any animal species can become chronically infected with SARS-2 — in effect, whether there are animal species in which SARS-2 lingers in the way it does in immunocompromised people. That could put positive selective pressure on the virus — in other words give it an incentive to mutate to stay ahead of the animal’s immune response.

“It does move my thinking in terms of Omicron possibly having come from a reservoir, if there are [animal] reservoirs that do chronic infections,” he said.

Part of what leads Andersen to wonder about an animal source is the fact that the variant traces back to viruses that were spreading over a year ago. “That in itself you need to be able to explain,” he said.

Angela Rasmussen, a coronavirus virologist at the University of Saskatchewan’s Vaccine and Infectious Disease Organization, agreed.

“I think it’s pretty obvious to everybody … that this virus has been on an independent evolutionary track for quite some time and it’s very surprising, which to me just kind of goes back to say well, the idea that this could be … plausible,” she said.

Regardless of whether this variant emerged in another species or not, given SARS-2’s ability to jump species, it is possible the world will face animal-derived variants in the future, Garry warned. The upshot of that? “We’re going to have to keep tweaking the vaccines.”

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