Data from Dutch mink farms hit by the coronavirus may shed more light on a mutation that has spread widely.

By Kai KupferschmidtJul. 14, 2020 , 5:45 PM

Science's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Its only a tiny change. At some point early in the pandemic, one of the 30,000 letters in the genome of SARS-CoV-2 changed from an A to a G. Today, that mutation, at position 23,403, has spread around 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 coincidence?

More than 6 months into the pandemic, the virus potential to evolve in a nastier directionor, if were lucky, become more benignis unclear. In part thats 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 at the end of 2019, having quietly honed its ability to infect people beforehand.

On average, the coronavirus accumulates about two changes per month in its genome. Sequencing SARS-CoV-2 genomes helps researchers follow how the virus spreads. Most of the changes dont affect how the virus behaves, but a few may change the diseases transmissibility or severity.

One of the earliest candidates was the wholesale 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 Medical School in Singapore in a March preprint, the deletion has since been reported from Taiwan as well. A deletion in the same gene occurred early in the 2003 severe acute respiratory syndrome (SARS) outbreak, caused by a closely related coronavirus; lab experiments later showed that variant replicates less efficiently than its parent, suggesting the mutation may have slowed the SARS epidemic. Cell culture experiments suggest the mutation does not have the same benign effect in SARS-CoV-2, Wang says, but there are indications that it may cause milder disease in patients.

The mutation at position 23,403 has drawn the most attentionin part because it changed the virus spike, the protein on its surface that attaches 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 its called G614.

In a Cell paper this month, Bette Korber and colleagues at Los Alamos National Laboratory showed that G614 has become more common in almost every nation and region they looked at, whereas D614 is virtually gone (see graphic, below). That might be a sign that its outcompeted by G614, but it could also be a coincidence. Any one mutation may rise to very high frequency across the world, just because of random chance, says Kristian Andersen, a computational biologist at Scripps Research. This happens all the time.

Comparing the spread of different viral variants carrying the two mutations could reveal a difference. The United Kingdoms COVID-19 Genomics Consortium has sequenced 30,000 SARS-CoV-2 genomes, allowing scientists to compare how fast 43 lineages carrying the G614 mutation and 20 with D614 spread. They estimated that the former grew 1.22 times faster than the latterbut the statistical significance was low. Evidence for a difference is weak and if it does exist, the estimated effect is moderate, says evolutionary biologist Andrew Rambaut of the University of Edinburgh.

Researchers have also turned to cell culture experiments. When Korbers group engineered so-called viruslike particles to carry one spike protein or the other, the G614 variant appeared to be more efficient at entering cells. Jeremy Luban of the University of Massachusetts Medical School, who has found the same thing, explains that G614 causes a slight change in the shape of the spike, apparently making it easier for the protein to undergo the structural changes that cause the membranes of the virus and the cell to fuse. Our data looks like its somewhere between three and 10 times more infectious, Luban says. Thats a pretty enormous effect.

That does not mean the mutation has an effect in the real world, says virologist Emma Hodcroft of the University of Basel. In the past, she notes, We have cases where we really thought that we had evidence for a mutation that was changing viral behavior and as more evidence came, it didnt seem to be the case. An increased ability to infect a laboratory cell line may not translate to the billions of diverse cells in a human body, adds Angela Rasmussen, a virologist at Columbia University: Humans arent Vero cells.

A one-base mutation (D to G) in SARS-CoV-2s genome was rare in February but is found in almost every newly sequenced strain today. It may make the virus more transmissible.

Korberet al.,Cell, DOI: 10.1016/j.cell.2020.06.043, Adapted by N. Desai/Science

Animal experiments are another way to probe the effects of G614. One option, virologist Marion Koopmans of Erasmus Medical Center (EMC) says, would be to infect ferrets with it and D614 and look for differences in how much virus they shed. But infections in ferrets only last about 1 week, Koopmans notes. The effect would have to be very big to show up in an experiment like that.

Another idea is to expose uninfected ferrets to animals carrying either of the two variants and see how well they transmit. An uncontrolled transmission experiment has already taken place on Dutch mink farms, where the new coronavirusjumped from humans to minksat least five separate times. Twice it was the D614 variant, and three times G614, Koopmans says. She hopes data from the outbreaks could show whether either one spread faster and wider than the other. But the experiment doesnt have the rigor of a lab study, she concedes. We have a natural experiment here. The study design is not optimal.

Whether G614 is more transmissible or not, it has become the dominant strain and the world is living with it, Rambaut says. Most recent estimates of the virus reproduction numberwhich denotes how well it spreadsare already based mostly on the mutant strain. What we dont know is whether D614 would have been different, Rambaut says.

The attention lavished on G614 may obscure a bigger question, however: With the virus having spread to at least 11 million people worldwide, why arent more mutations that affect its behavior emerging?

Perhaps theres just little selection pressure on the virus as it races through millions of immunologically nave 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 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 human pathogen may have already happened and we missed it, Rasmussen says.

Wang thinks a version of the virus may have circulated earlier in humans in southern Asia, perhaps flying under the radar because it didnt cause severe disease. If it happens in a small or remote village, even with some people dying, nobody is going to know theres a spillover, Wang says. The virus could then have infected an animal that was brought to Wuhan and started the pandemic.

At Dutch mink farms, after all, the virus jumped not just from humans to animals, but also back from animals to humans, Wang says. If that can happen in the Netherlands, surely it can happen in a village in Thailand, or in Yunnan province in southern China.

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The pandemic virus is slowly mutating. But is it getting more dangerous? - Science Magazine