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as nurses and doctors combat With a record-breaking wave of Omicron cases, evolutionary biologists are up against a challenge of their own: figuring out how this world-dominant variant came to be.
When the Omicron variant debuted in South Africa in November, scientists were stunned 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 shockingly large leap forward in viral evolution.
In Research An international team of scientists posted online last week deepened the mystery even further. They suggested that 13 of these mutations are rarely found in other coronaviruses and that they must be harmful to Omicron. Instead, acting in concert, these mutations appear to be key to some of Omicron’s most fundamental functions.
Now researchers are trying to understand how Omicron defies normal evolutionary rules and uses these mutations to make it such a successful disease vector.
“There’s a mystery here that someone has to solve,” 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 a coronavirus. Every time a virus replicates inside a cell, there is a small chance that the cell will make a defective copy of its genes. Many of these mutations will render new viruses defective and unable to compete with other viruses.
But a mutation can also cure a virus. For example, it can make the virus stick to cells more tightly or reproduce faster. Viruses that inherit a beneficial mutation can outpace the others.
For most of 2020, scientists discovered that different coronavirus strains around the world slowly 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 shaken to discover a new variant In the UK, it carries 23 mutations that were not found in the original coronavirus, which was isolated in Wuhan a year ago.
This variant, later called Alpha, soon gained worldwide dominance. During 2021, other rapidly spreading variants appeared. While some are limited to certain countries or continents, the Delta variant is 20 distinctive mutations, overthrew Alpha and became dominant throughout the summer.
And then Omicron has arrived, with more than twice as many mutations. As soon as the Omicron comes to light, Dr. Martin and colleagues set out to reconstruct the variant’s radical evolution by comparing the 53 mutation with those of other coronaviruses. The sharing of some mutations by Omicron, Delta, and other variants suggested that they arose several times and natural selection favored them over and over again.
However, scientistsVirgoThe protein that nails the surface of the Omicron and allows it to attach to the cells.
Omicron has 30 mutations in the spike gene. The researchers found that 13 of them were 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 that scientists have sequenced throughout the pandemic.
If a mutation were beneficial or even neutral for the virus, scientists would expect it to occur more frequently in samples. But if it is rarely or completely absent, it is usually a sign that it is harmful to the virus and inhibits its replication.
Dr. “When you see this pattern, it tells you something very loud and very clear,” Martin said. “Anything that sustains a change at these sites will likely be flawed and will not survive very long and be destroyed.”
Still, Omicron ignored that logic. Dr. “The Omicron wasn’t completely destroyed,” Martin said. “It’s unlike anything we’ve seen before.”
What makes these 13 mutations even more interesting is that they are not randomly sprinkled on the spike of the Omicron. They form three clusters, each replacing a small portion of the protein. And each of these three areas plays a big part in what makes Omicron unique.
Two of the clusters change the spike near the tip, making it harder for human antibodies to attach to the virus and keep it away from the cells. As a result, Omicron is good at infecting even people who have antibodies from vaccines or a previous Covid infection.
The third set of mutations makes the crest closer to its base. Known as the fusion site, this region activates when the tip of the spike attaches to a cell, allowing the virus to transmit its genes into its new host.
Typically, coronaviruses use the fusion field to fuse with a cell membrane. Its genes can then swim deeper into the cell.
But Omicron’s fusion field often does something different. Rather than mixing with the cell membrane, the entire virus is engulfed in a kind of cellular swamp that gets trapped inside the cell to form a bubble. Once the virus is caught in the bubble, it can break and release its genes.
This new pathway to infection may help explain why Omicron is less severe than Delta. Cells in the upper respiratory tract can easily swallow Omicron as blisters. But deep in the lungsIn cases where Covid can cause life-threatening damage, coronaviruses need to fuse into cells, something Omicron doesn’t do well.
These three regions on the spike appear to be important to Omicron’s success. This makes it even more surprising that these 13 mutations were so rare before Omicron.
Dr. Martin and his colleagues suspect the cause is “epistasis”: an evolutionary phenomenon that can cause mutations to be harmful in themselves but beneficial when combined.
Omicron may have evolved under unusual conditions, turning a group of 13 bad mutations in its favor. One possibility is that it occurs after being in the body of a person with a particularly weak immune system, such as someone with HIV, for an extended period of time. People with chronic Covid infections may become evolutionary laboratories that host many generations of coronaviruses.
Evolution can occur very differently in such a host than jumping from one healthy person to another every few days or weeks.
“It’s now stuck with this individual, so all of a sudden it’s doing things it wouldn’t normally do,” said Sergei Pond, an evolutionary biologist at Temple University and author of the new study.
Because an immunocompromised host does not produce many antibodies, many viruses are left to replicate. And new mutant viruses that resist antibodies can multiply.
A mutation that allows a virus to evade antibodies is not necessarily advantageous. For example, it can destabilize the spike protein of the virus so it cannot attach quickly to a cell. But inside someone with a weakened immune system, viruses can acquire a new mutation that stabilizes the spike again.
Dr. Pond thinks similar mutations could be built over and over in the same person until they develop a spike protein with the right combination of mutations to allow Omicron to spread fantastically 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 he said scientists still need to conduct experiments to rule out alternative explanations.
For example, it is possible that the 13-pointed mutation would provide no benefit to the Omicron. Instead, some of the other spike mutations may be making the Omicron successful, and 13 of them are literally up for the ride.
Dr. “I would be careful about interpreting the data to indicate that all these previously deleterious mutations are adaptively favored,” Otto said.
Dr. Pond also acknowledged that his hypothesis still has some major loopholes. For example, it is unclear why Omicron takes advantage of the new “bubble” method of entering cells during a chronic infection.
Dr. “We just don’t have the imagination,” said Pond.
James Lloyd-Smith, a disease ecologist at UCLA who was not involved in the study, said the research reveals how difficult it is to reconstruct the evolution of a virus, even if it had emerged recently. “Nature is definitely doing its part to keep us humble,” he said.
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