The 3 main theories for Omicron's origins

 Omicron’s arrival in November 2021 took scientists by surprise. Not because there was a new variant on the block, but because it had many and unusual mutations—some rare and others that had never been seen before. Also, its closest relatives weren’t recent variants but earlier versions of SARS-CoV-2, the virus that causes COVID-19, circulating more than a year ago.

That left the scientific community wondering where, exactly, Omicron came from. Some research suggests that this variant may have evolved in the body of someone who was immunocompromised; other molecular clues suggest that the virus jumped from a human to an animal where it evolved before jumping back into a human host.

It’s normal for a virus to mutate as it spreads from person to person, inevitably producing errors in its genetic code as it multiples. While most mutations may be benign, if any give the virus a survival advantage by making it, say, more transmissible or by aiding its ability to escape the host’s immune system, it may persist and result in new variants with more worrying traits.

“I don’t think other variants of concern are that much of a surprise compared to Omicron, which kind of came out of nowhere,” says Angela Rasmussen, a virologist at the University of Saskatchewan in Canada.

Analysis of its genome suggests that Omicron likely diverged from the original SARS-CoV-2 lineage in mid-2020. The SARS-CoV-2 virus typically acquires two mutations per month. For every lineage that’s been in circulation, “that [rate of mutation] has been pretty constant,” says Francois Balloux, a computational biologist at the University College London Genetics Institute in the United Kingdom. Over the course of about 18 months, that rate of mutation would suggest that the divergent virus strain would have acquired roughly 36 mutations.

But sequencing the Omicron’s genetic code revealed more than 50 mutations, of which at least 30 are in its critically important spike protein, which is essential for infecting human cells. “That’s a big jump,” Balloux says. Also, many of these mutations are clustered around the region in the spike where antibodies bind, blocking the ability of SARS-CoV-2 to enter the cell. 

“All of them in a constellation like that,” says Rasmussen, “was certainly very different to anything we’ve been seeing circulating in the human population.”

Prolonged COVID-19 infections

Over the last two years, reports of COVID-19 infections that can persist for months to nearly a year in certain immunocompromised people have emerged. In the absence of a robust immune system, the virus can keep multiplying and pile up mutations that change its appearance and enable it to escape from antibodies produced to block infection.

“We know from other viruses, when you have an infection in an immunocompromised person, the lineage can accumulate more mutations than expected compared to the virus transmitting from person to person,” Balloux says.

New combinations of mutations can emerge, especially when an individual’s immune system doesn’t swiftly eradicate new viruses. Then certain individual mutations that otherwise might not survive are enshrined in the virus’s genetic code and accumulate under low immunity. Some of these individual mutations together could benefit the virus, he says.

In South Africa, for instance, virologist Tongai Maponga at Stellenbosch University and his colleagues recorded more than 20 mutations in a SARS-CoV-2 Beta variant that evolved over at least nine months in a patient struggling with advanced HIV disease. Scientists in the U.K. recorded novel mutations in three other patients with advanced HIV who had been harboring a SARS-CoV-2 Alpha infection for several months. In Portugal, scientists recorded unusually high number of SARS-CoV-2 mutations in an immunocompromised cancer patient whose infection persisted for at least six months and who was treated with the antiviral drug remdesivir and anti-inflammatory corticosteroids. These drugs may have suppressed the patient’s immune system and made it easier for SARS-CoV-2 to mutate and adapt.

Observing the evolution of SARS-CoV-2 in certain immunocompromised patients infected for longer durations, “we have some similarities and mutations that we’ve seen in variants of concern,” says Richard Lessells, an infectious disease physician at the University of KwaZulu-Natal in South Africa. That’s probably how Omicron evolved, according to some scientists.

Although it’s unclear how common such long-lasting COVID-19 infections may be in human populations, especially when several such patients are asymptomatic, Lessells says, “it doesn’t really matter—even if it’s an extremely rare event, if variants emerge that can then successfully spread into a population, then in only has to happen once or twice for that to be significant.”

This could also explain why genomic surveillance efforts in many parts of the world may not have detected a rare SARS-CoV-2 evolution event until it was too late to prevent transmission as the variant infected many people.

Could limited surveillance have let Omicron arise undetected?

But there’s another hypothesis that has gained attention: Perhaps Omicron simply evolved in a relatively isolated region that had limited capacity to analyze the genetic sequences of COVID-19 virus samples. That means Omicron could have circulated undetected in a population for a long time.

For instance, the B.1.620 variant of interest was first detected in Lithuania in April 2021, but researchers traced back its origin to central Africa, where some countries have grappled with limited genomic surveillance capabilities. Although the variant was potentially prevalent in the region, the hypothesis goes, its presence remained undetected and only became known from cases in people who had traveled between Europe and Cameroon and Mali.

Rasmussen, however, thinks this hypothesis may not apply in the case of Omicron. “I think that’s unlikely because there aren’t many populations on Earth that are that isolated,” she says. “We would have seen ancestors of Omicron emerging in other populations [over time], and it would have been picked up at some point by genomic surveillance.” 

Is Omicron a product of an animal host?

Wenfeng Qian, a geneticist at the Chinese Academy of Sciences, on the other hand, suspects that Omicron may have emerged in an animal—most likely mice and rats. Over the last year, SARS-CoV-2 has infected pet cats, dogs, and ferrets, ravaged mink farms, and spread to tigers and hyenas in zoos and white-tailed deer in the forests of North America.

Although mice initially served as poor hosts for SARS-CoV-2—because the protein receptors on the surface of the rodent cells blocked the virus from binding and entering—a study showed that newer variants like Alpha, Beta, and Gamma had a mutation called N501Y in their spike protein that allowed the virus to infect mice cells in laboratory tests. This mutation also occurs in Omicron. This mutation also occurs in Omicron. There are also a handful of other mutations, associated with rodent adaptation, which are seen in this variant.

Qian and his colleagues studied 45 mutations, including N501Y, in Omicron’s genome and noted that some of them matched the mutations typically seen in coronaviruses evolving in mice. They also found that the mutational signatures of Omicron’s predecessors weren’t consistent with patterns one might observe if SARS-CoV-2 evolved in a human host. RNA viruses, which include SARS-CoV-2, tend to rack up more mutations in which the genetic building block guanine is replaced with one called uracil—a so-called G-to-U mutation—when they infect and evolve in humans. But the limited number of G-to-U mutations in Omicron’s predecessors suggested to Qian it evolved in an animal host. However, with this, “we cannot identify the exact animal,” he says.

It’s possible that SARS-CoV-2 jumped from an infected person to mice or rats, spread among mice and evolved into Omicron, and then infected a human who might have come into contact with such an animal. This would be similar to the case of mink farmers who were infected with a mutated version of SARS-CoV-2 circulating among minks that caught COVID-19 from a human.

Still, many scientists support the hypothesis that Omicron may have evolved in an immunocompromised person with a prolonged COVID-19 infection. “The type of mutations we see in particular in poorly or untreated HIV patients are very reminiscent of Omicron,” Balloux says. Rasmussen agrees, but to her it doesn’t disprove the animal origin hypothesis or erase the potential risks from exposure to infected animals.

Maponga, Lessells, and their colleagues in South Africa are planning to closely monitor the trajectory of the SARS-CoV-2 virus in severely immunocompromised HIV patients. Rasmussen and her colleagues, on the other hand, are planning to survey domestic animals like horses, cows, sheep, and goats, as well as wildlife like white-tailed deer, raccoons, and small carnivores in Canada to understand their susceptibility to SARS-CoV-2, and in particular Omicron infections.

Finding the origin of Omicron may not help us get over the pandemic, she says. “But it can improve how we monitor for new variants.”