In search of Omicron's origins

Finding out how this highly transmissible variant emerged might help scientists understand the danger of future variants appearing and identify ways to reduce it, writes Dr Monish Raut

The Omicron strain of SARS-CoV-2 spread faster than any prior variety in less than two months after its discovery in South Africa. Scientists have traced it in over 120 nations, yet the origin of Omicron remains unknown. No clear transmission line connects Omicron to its forefathers. Instead, an odd assortment of mutations occurred completely out of sight of researchers. Its nearest known genetic ancestor is estimated to be more than a year old, sometime after mid-2020. The origins of Omicron are a serious matter. Finding out how this highly transmissible variant emerged might help scientists understand the danger of future variants appearing and identify ways to reduce it. The WHO’s newly constituted Scientific Advisory Group for the Origins of Novel Pathogens (SAGO) discussed Omicron’s origins in January.

According to an article published recently in Nature, three possibilities are being investigated ahead of the report. Despite sequencing millions of SARS-CoV-2 genomes, researchers may have overlooked a chain of changes that led to Omicron. Alternatively, a long-term infection might have developed the variant in one individual. Or it might have appeared in other animals like mice or rats. The most bizarre genome ever discovered in Omicron is a newcomer, say scientists. It was discovered in early November 2021 in South Africa and Botswana; retroactive testing revealed samples from England, South Africa, Nigeria, and the US in early November. The virus emerged not long before that, towards the end of September or early October of last year, based on the mutation rate in hundreds of sequenced genomes and how rapidly it moved across populations.

Tulio de Oliveira, a bioinformatician at the University of KwaZulu-Natal in Durban and Stellenbosch University’s Centre for Epidemic Response and Innovation, who has led South Africa’s efforts to track viral variants says the variant could have emerged anywhere in the world and was picked up in South Africa because of the country’s sophisticated genetic surveillance.

Omicron’s extraordinary mutation rate stands out. Compared to the original SARS-CoV-2 virus identified in Wuhan, China, this variation contains over 50 mutations. Thirty of them affect the spike protein1, which the coronavirus utilises to bind and merge with cells. Previously, only 10 such spike mutations were found in variants of concern.

Omicron grips ACE2 better than earlier variants. In addition, it is more resistant to virus-blocking antibodies generated by persons who have been vaccinated or infected with previous versions. In addition, alterations in the spike protein seem to have altered Omicron’s ability to enter cells directly, preferring instead to enter through an endosome (a lipid-surrounded bubble). Omicron also seems to have three unique sublineages (BA.1, BA.2 and BA.3) that all appear to have arisen around the same time, two of which have taken off internationally. So Omicron had time to evolve before scientists detected it. This trait, along with the number of mutations, must be included in the explanation of any origins.

Spreading silently

Researchers have explained past mutations of concern by slow evolution. SARS- CoV-2’s RNA sequence evolves randomly as it replicates and spreads from person to person. Scientists estimate that just one or two single-letter changes each month make it into the main viral circulation, half the rate of influenza.

Some experts believe that person-to-person propagation would not allow Omicron to accumulate as many modifications as it has. A year and a half seems like a very little time for so many mutations to develop and be chosen.

Something occurred recently to assist Omicron to erupt, maybe because other varieties — like Delta — were slowed by vaccination and virus immunity, but Omicron was able to overcome it.

Omicron’s mutations may have developed in an environment without person-to-person transmission networks since several have never been observed before. Omicron’s alterations don’t match those reported in the wider sarbecovirus family, which includes the virus that causes severe acute respiratory syndrome (SARS).

Long-term infection

Persistent infection is an alternate incubator for rapid evolution. The virus may proliferate for weeks or months there, mutating to avoid the body’s immune system. The virus may “play cat and mouse with the immune system” during chronic infections. It is a reasonable theory for Omicron’s birth. People with weakened immune systems who can’t readily get rid of SARS-CoV-2 have persistent
illnesses. Like Omicron, some experts believe Alpha arose from a persistent infection.

Animal reservoir?

In addition to humans, SARS-CoV-2 has infected wild leopards, domestic ferrets and hamsters. It has destroyed mink farms throughout Europe and infected white-tailed deer populations in North America. And Omicron may be able to penetrate more animals. Omicron’s spike protein can bind to the ACE2 protein of turkeys, chickens, and mice. These three possibilities are likely to be the outcome of Omicron’s emergence. But, scientists are still unable to explain how Omicron got here, much alone forecast the next version.

Omicron’s origins are unknown to many scientists. Omicron demonstrates the critical requirement for humility when considering our capacity to comprehend the mechanisms that shape the development of viruses such as SARS-CoV-2.

(The author is an academician.)