How Omicron’s Mutations Allow It To Thrive

As nurses and doctors battle a record wave of Omicron cases, evolutionary biologists are engaged in their own struggle: to understand how this globally dominant variant came to be.

When the Omicron variant took off in southern Africa in November, scientists were surprised by its genetic makeup. While earlier variants differed from the original Wuhan version of the coronavirus by a dozen or two mutations, Omicron had 53 – a surprisingly large leap in viral evolution.

In a study published online last week, an international team of scientists digs deeper into the mystery. They found that 13 of these mutations were rarely, if ever, found in other coronaviruses, suggesting they should have been harmful to Omicron. Instead, when acting in concert, these mutations seem to hold the key to some of Omicron’s most essential functions.

Now researchers are trying to figure out how Omicron defied the normal rules of evolution and used these mutations to become such an efficient vector of disease.

“There is a mystery here that someone needs to figure out,” said Darren Martin, a virologist at the University of Cape Town who worked on the new study.

Mutations are an integral part of the existence of a coronavirus. Each time a virus replicates inside a cell, there is a small chance that the cell will create a faulty copy of its genes. Many of these mutations would make new viruses defective and unable to compete with other viruses.

But a mutation can also improve a virus. This could make the virus stick more tightly to cells, for example, or cause it to replicate faster. Viruses that inherit a beneficial mutation can outcompete others.

For most of 2020, scientists found that different lineages of coronaviruses around the world gradually detected a handful of mutations. The evolutionary process was slow and steady until the end of the year.

In December 2020, UK researchers were shocked to discover a new variant in England carrying 23 mutations not found in the original coronavirus isolated in Wuhan a year earlier.

This variant, later named Alpha, quickly dominated the world. During 2021, other fast-spreading variants appeared. While some remained restricted to certain countries or continents, the Delta variant, with 20 distinct mutations, ousted Alpha and became dominant over the summer.

And then came Omicron, with more than twice as many mutations. As soon as Omicron was discovered, Dr. Martin and his colleagues set out to reconstruct the radical evolution of the variant by comparing its 53 mutations to those of other coronaviruses. Some mutations were shared by Omicron, Delta, and other variants, suggesting that they had arisen multiple times and that natural selection had repeatedly favored them.

But the scientists found a very different pattern when they looked at the ‘spike’ protein that studs Omicron’s surface and allows it to latch onto cells.

The Omicron spike gene has 30 mutations. The researchers found 13 of them to be extraordinarily rare in other coronaviruses – even their distant viral cousins ​​found in bats. Some of the 13 had never been seen before in the millions of coronavirus genomes scientists have sequenced during the pandemic.

If a mutation was beneficial to the virus, or even neutral, scientists would expect it to show up more often in samples. But if it’s rare or completely absent, it’s usually a sign that it’s harmful to the virus, preventing it from multiplying.

“When you see this pattern, it says something very strong and very clear to you,” Dr. Martin said. “Anything that changes on these sites will likely be faulty and won’t survive very long and die out.”

And yet, Omicron flouted this logic. “Omicron wasn’t exactly dying out,” Dr. Martin said. “It was just taking off like we’ve never seen before.”

What makes these 13 mutations all the more intriguing is that they are not scattered randomly across Omicron’s peak. They form three clusters, each modifying a small part of the protein. And each of these three areas plays a big role in what makes Omicron unique.

Two of the clusters modify the spike near its end, making it harder for human antibodies to stick to the virus and keep it out of cells. As a result, Omicron is effective at infecting even people who have antibodies from vaccinations or previous Covid infection.

The third group of mutations changes the tip closer to its base. This region, known as the fusion domain, comes into action once the tip of the tip has latched onto a cell, allowing the virus to deliver its genes inside its new host.

Typically, coronaviruses use the fusion domain to fuse with a cell’s membrane. Their genes can then float to the depths of the cell.

But Omicron’s fusion domain usually does something different. Rather than melting into the cell membrane, the entire virus is engulfed in a kind of cellular sinkhole, which pinches to form a bubble inside the cell. Once the virus is captured inside the bubble, it can split open and release its genes.

This new route of infection may help explain why Omicron is less severe than Delta. Upper respiratory tract cells can easily swallow Omicron as bubbles. But deep in the lungs, where Covid can cause life-threatening damage, coronaviruses need to fuse with cells, which Omicron doesn’t do well.

These three regions of the peak appear to have played an important role in Omicron’s success. This makes it all the more puzzling that these 13 mutations were so rare before Omicron.

Dr. Martin and his colleagues suspect the reason is “epistasis”: an evolutionary phenomenon that can make mutations harmful on their own, but beneficial when combined.

Omicron may have turned a batch of 13 bad mutations to his advantage by evolving under unusual conditions. One possibility is that it appeared after a prolonged period inside the body of a person with a particularly weak immune system, such as an HIV patient. People with chronic Covid infections can become evolving laboratories, harboring many generations of coronaviruses.

Evolution may proceed very differently in such a host than it would in passing from one healthy person to another every few days or weeks.

“Now he’s stuck in this individual, so all of a sudden he’s doing things he wouldn’t normally do,” said Sergei Pond, an evolutionary biologist at Temple University and author of the short story. study.

Because an immunocompromised host does not produce many antibodies, many viruses must spread. And new mutant viruses that resist antibodies can multiply.

A mutation that allows a virus to evade antibodies is not necessarily advantageous. That could make the virus’ spike protein unstable so it can’t quickly lock onto a cell, for example. But inside a person with a weakened immune system, viruses may be able to acquire a new mutation that stabilizes the spike again.

Similar mutations could have developed over and over again in the same person, Dr Pond speculates, until Omicron developed a breakthrough protein with just the right combination of mutations to allow it to spread extremely well among people. in good health.

“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 needed to conduct experiments to rule out alternative explanations.

It is possible, for example, that the 13 peak mutations offer no advantage to Omicron. Instead, some of the other peak mutations could make Omicron hit, and the 13 are just for the ride.

“I would be cautious about interpreting the data to indicate that all of these previously deleterious mutations were adaptively favored,” Dr. Otto said.

Dr. Pond also acknowledged that his hypothesis still had major flaws. For example, it is not known why, during a chronic infection, Omicron would have taken advantage of its new “bubble” method of penetrating cells.

“We just lack the imagination,” Dr. Pond said.

James Lloyd-Smith, a disease ecologist at UCLA who was not involved in the study, said the research revealed how difficult it is to piece together the evolution of a virus, even if it appeared recently. “Nature is certainly doing its part to keep us humble,” he said.