As nurses and doctors grapple with a record wave of omicron cases, evolutionary biologists are engaged in a struggle of their own: discovering how this world-dominant variant emerged.
When the omicron variant took off in South Africa in November, scientists were surprised by its genetic makeup. While previous variants differed from the original Wuhan version of the coronavirus by a dozen or two mutations, Omicron had 53 mutations — a shocking big leap in viral evolution.
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In a study published online last week, an international team of scientists deepened the mystery. They found that 13 of these mutations were rarely, if any, found in other coronaviruses, indicating that they were harmful to the omicron. Instead, when working collectively, these mutations appear to be key to some of the omicron’s most important functions.
Researchers are now trying to figure out how Omicron defied the natural rules of evolution and used these mutations to become a successful vector of disease.
“There is a mystery here that someone has to figure out,” said Darren Martin, a virologist at the University of Cape Town who worked on the new study.
Mutations are a regular part of the existence of the coronavirus. Each time the virus replicates inside the cell, there is a small chance that the cell will create a defective copy of its genes. Many of these mutations will make the new viruses defective and unable to compete with other viruses.
But the mutation can also improve the virus. It can make the virus stick more firmly to cells, for example, or make it multiply faster. Viruses that inherit a beneficial mutation may outperform others.
For most of 2020, scientists found that different strains of the coronavirus around the world gradually picked up a handful of mutations. The evolutionary process was slow and steady until the end of the year.
In December 2020, British researchers were shocked to discover in England a new variant carrying 23 mutations not found in the original coronavirus isolated in Wuhan, China, a year earlier.
This variant, later called Alpha, quickly swept into worldwide dominance. Over the course of 2021, other rapidly spreading variants emerged. While some remained limited to certain countries or continents, the delta variant, with 20 distinct mutations, ousted alpha and became dominant over the summer.
Then came the Omicron with more than double the mutations.
Once the omicron appeared, Martin and his colleagues set out to reconstruct the radical evolution of the variant by comparing its 53 mutations with those of other coronaviruses. Some mutations were shared by omicron, delta and other variants, indicating that they arose multiple times and were repeatedly favored by natural selection.
But the scientists found a different pattern when they looked at the “spike” protein that attaches to the surface of the omicron and allows it to stick to cells.
The Omicron’s spike gene contains 30 mutations. The researchers found that 13 of them were unusually rare in other coronaviruses — even their distant viral cousins found in bats. Some of the 13 have never been seen before in the millions of coronavirus genomes that scientists have sequenced over the course of the pandemic.
If the mutation is beneficial to the virus, or even neutral, scientists expect it to appear more often in samples. But if it is rare or completely missing, this is usually a sign that it is harmful to the virus, preventing it from reproducing.
“When you see this pattern, it tells you something very loud and very clear,” Martin said. “Anything that keeps the change in those locations is likely to be defective and won’t last very long and will die.”
However, Omicron was scornful of this reasoning. “Omicron wasn’t quite dying,” Martin said. “It was taking off like nothing we’ve seen before.”
What makes these 13 spikes even more interesting is that they are not randomly scattered across an omicron fork. They form three groups, each of which changes a small portion of the protein. Each of these three areas plays a large role which makes the omicron unique.
Two clusters alter the spike near its tip, making it difficult for human antibodies to stick to the virus and keep it out of cells. As a result, omicron is good at infecting people who have had antibodies from vaccines or a previous COVID infection.
The third group of spikes shifts the spike closer to its base. This region, known as the fusion domain, swings into action once the tip of the spike attaches to the cell, enabling the virus to deliver its genes within its new host.
Coronaviruses typically use a fusion domain to fuse with the cell membrane. Their genes can then float away deep within the cell.
But the omicron fusion field usually does something different. Instead of incorporating into the cell membrane, the virus is swallowed whole into a kind of cellular trough hole, which pinches to form a bubble inside the cell. Once the virus is caught inside the bubble, it can break away and release its genes.
This new infection pathway may help explain why Omicron is less severe than Delta. Cells in the upper airway can easily swallow the oomicron in the form of bubbles. But deep in the lungs, where the novel coronavirus can cause life-threatening damage, coronaviruses must embed in cells, which Omicron does not do well.
It appears that these three regions of the spike were important to the success of the omicron. This makes it very confusing because these 13 mutations were very rare before the advent of the omicron.
Martin and his colleagues think the cause is “epistasis”: an evolutionary phenomenon that can cause harmful mutations on its own but is beneficial when combined.
Omicron may have turned a group of 13 bad mutations in its favour by evolving under unusual circumstances. One possibility is that it originated after a long time inside the body of someone with a particularly weak immune system, such as an HIV patient. People with chronic COVID-19 infection can become evolutionary laboratories, which host many generations of coronaviruses.
Development in such a host can occur differently from hopping from one healthy person to another every few days or weeks.
“Now it’s stuck in this individual, so suddenly it’s doing things it wouldn’t normally do,” said Sergey Bond, an evolutionary biologist at Temple University and author of the new study.
Since the immunocompromised host does not produce many antibodies, many viruses are left to spread. New mutated viruses that are resistant to antibodies can multiply.
A mutation that allows the virus to avoid antibodies is not necessarily beneficial. The spiky protein can make the virus so unstable that it cannot attach quickly to a cell, for example. But inside someone with a weakened immune system, viruses may be able to acquire a new mutation that stabilizes the spike again.
Bond speculates that similar mutations could have built on themselves over and over again in the same person, until Omicron developed a spike protein with the correct combination of mutations to allow it to spread very well among healthy people.
“It certainly seems plausible,” said Sarah Otto, an evolutionary biologist at the University of British Columbia, who was not involved in the study. But she said scientists still need to conduct experiments to rule out alternative explanations.
It is possible, for example, that the 13 spike mutations provide no benefit to the omicron at all. Alternatively, some other spike spike can make the omicron successful, and 13 spikes along the way.
“I would be cautious about interpreting the data to indicate that all of these previously deleterious mutations were adaptively favored,” Otto said.
Bond also admitted that his hypothesis still had some big gaps. For example, it is not clear why, during chronic infection, omicron could have gained an advantage from the new “bubble” method of entering cells.
“We just lack imagination,” Bond said.
James Lloyd-Smith, a disease ecologist at the University of California, Los Angeles, who was not involved in the study, said the research revealed how difficult it is to reconstruct the evolution of the virus, even the most recently emerged one. “Nature is certainly doing its part to keep us humble,” he said.
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