ScienceThe COVID-19 report is supported by the Pulitzer Center and the Heising-Simons Foundation.
It is just a small change. At some point early in the pandemic, one of the 30,000 letters in the SARS-CoV-2 genome changed from A to G. Today, that mutation, at position 23,403, has spread throughout the world. It is found in the vast majority of newly sequenced viruses and has become the center of a burning scientific question: Has the mutation become so common because it helps the virus spread faster? Or is it just a coincidence?
More than 6 months after the pandemic, the virus's potential to evolve in a more unpleasant direction or, if we are lucky, to become more benign, remains unclear. In part, that's because it changes more slowly than most other viruses, giving virologists fewer mutations to study. But some virologists also raise an intriguing possibility: that SARS-CoV-2 was already well-adapted to humans when it burst onto the world stage in late 2019, having quietly honed its ability to infect people beforehand.
Related
On average, the coronavirus accumulates approximately two changes per month in its genome. Sequencing of the SARS-CoV-2 genomes helps researchers track how the virus spreads. Most changes do not affect the behavior of the virus, but some can change the transmissibility or severity of the disease.
One of the first candidates was the total deletion of 382 base pairs in a gene called ORF8, whose function is unknown. First reported by Linfa Wang and others at the Duke-NUS School of Medicine in Singapore in a March preprint, deletion has also been reported from Taiwan. A deletion in the same gene occurred early in the 2003 severe acute respiratory syndrome (SARS) outbreak, caused by a closely related coronavirus; Later, laboratory experiments showed that the variant replicates less efficiently than its father, suggesting that the mutation may have slowed the SARS epidemic. Cell culture experiments suggest that the mutation does not have the same benign effect on SARS-CoV-2, says Wang, "but there are indications that it may cause milder disease in patients."
Weak evidence of a moderate effect
The mutation at position 23,403 has attracted the most attention, in part because it changed the peak of the virus, the protein on its surface that binds to human cells. The mutation changed the amino acid at position 614 of the spike from an aspartic acid (abbreviated D) to a glycine (G), which is why it is called G614.
in a Cell In this month's article, Bette Korber and her colleagues at Los Alamos National Laboratory showed that G614 has become more common in almost every nation and region they observed, while D614 practically disappeared (see chart below). That could be a sign that G614 has passed it, but it could also be a coincidence. "Any mutation can increase at a very high frequency worldwide, just by a random chance," says Kristian Andersen, a computational biologist at Scripps Research. "This happens all the time."
Comparison of the spread of different viral variants carrying the two mutations could reveal a difference. The UK COVID-19 Genomics Consortium has sequenced 30,000 SARS-CoV-2 genomes, allowing scientists to quickly compare 43 lineages carrying the G614 and 20 mutation with the D614 spread. They estimated that the former grew 1.22 times faster than the latter, but the statistical significance was low. "The evidence for a difference is weak and if it exists, the estimated effect is moderate," says evolutionary biologist Andrew Rambaut of the University of Edinburgh.
The researchers have also turned to cell culture experiments. When Korber's group designed so-called virus-like particles to transport one pointed protein or another, the G614 variant seemed to be more efficient at entering cells. Jeremy Luban, from the University of Massachusetts School of Medicine, who discovered the same, explains that G614 causes a slight change in the shape of the spike, which apparently makes it easier for the protein to undergo structural changes caused by the virus's membranes. . and the cell to merge. "Our data appears to be three to 10 times more infectious," says Luban. "That is a pretty huge effect."
That doesn't mean the mutation has a real-world effect, says virologist Emma Hodcroft of the University of Basel. In the past, she notes, "we have cases where we really thought we had evidence of a mutation that was changing viral behavior, and as more evidence appeared, it did not appear to be the case." Increased ability to infect a laboratory cell line may not translate to billions of diverse cells in a human body, adds Angela Rasmussen, a virologist at Columbia University: "Humans are not Vero cells."
A change for the worse?
A one-letter mutation, rare in February but found in almost all recently sequenced genomes today, can make SARS-CoV-2 more transmissible.
Korber et al., Cell, DOI: 10.1016 / j.cell.2020.06.043, Adapted by N. Desai /Science
Animal experiments are another way to test the effects of G614. One option, says virologist Marion Koopmans of the Erasmus Medical Center (EMC), would be to infect ferrets with it and D614 and look for differences in the amount of virus they shed. But ferret infections only last about 1 week, Koopmans notes. “The effect would have to be very large to appear in an experiment like that.”
Another idea is to expose uninfected ferrets to animals that carry either variant and see how well they transmit. An uncontrolled transmission experiment has already been conducted on Dutch mink farms, where the new coronavirus jumped from human to mink at least five times separately. Twice it was variant D614, and three times G614, says Koopmans. Hope that the outbreak data can show if one spread faster and wider than the other. But the experiment does not have the rigor of a laboratory study, he admits. “We have a natural experiment here. The study design is not optimal. “
Whether or not G614 is more transmissible has become the dominant strain and the world is living with it, says Rambaut. The latest estimates of the virus’s breeding number, which denotes how well it spreads, are already based primarily on the mutant strain. “What we don’t know is whether D614 would have been different,” says Rambaut.
Why so little evolution?
However, the attention lavished on G614 may obscure a more important question: since the virus has spread to at least 11 million people worldwide, why don’t more mutations emerge that affect its behavior?
There may be little selection pressure on the virus as it runs through millions of immunologically naive people, scientists say. That could change with the advent of vaccines or new therapies, forcing the virus to evolve. But it could also indicate that the virus has been with people for longer than we know, and was spreading before the first known cases in Wuhan, China, in December 2019. “The evolution of this virus to become a pathogen Human may have already happened and we missed it, “says Rasmussen.
Wang believes that a version of the virus may have previously circulated in humans in South Asia, perhaps flying under the radar because it did not cause serious illness. “If it happens in a small or remote village, even with some people dying, no one will know there is a spill,” says Wang. The virus could have infected an animal that was brought to Wuhan and started the pandemic.
After all, on Dutch mink farms, the virus leaped not only from humans to animals, but also from animals to humans, says Wang. “If that can happen in the Netherlands, it surely can happen in a village in Thailand or in Yunnan province in southern China. “
