What the surprising mutations in the monkeypox virus could indicate about the new outbreak

When scientists investigate the spread of an infectious disease, one area they look at is the genetic sequences of the pathogen. But there’s a snag when it comes to the monkeypox virus, which is now causing an unprecedented outbreak of several hundred infections in some 30 countries where it’s not typically seen.

DNA viruses, particularly those with relatively big genomes like poxviruses (the family that includes monkeypox), generally accrue mutations much more slowly than, say, an RNA virus like SARS-CoV-2, which causes Covid-19. That means that examining the sequences might be less fruitful in terms of tracking how the virus is spreading from person to person. There are fewer changes to the virus’ genome that might shine a light on transmission chains.

But as researchers around the world share sequences from the current outbreak, the genomes have revealed something odd: There are way more mutations than expected.

So many mutations in such a short amount of time might seem worrisome, if, perhaps, it meant the virus was evolving to spread more efficiently among people. But scientists have a different hypothesis (still a hypothesis, they stress, one that needs to be further studied) about what these mutations say about these infections — and, in turn, what that can illuminate about this outbreak.

Below, STAT explores some questions the sequences have raised, with insights from Richard Neher, a computational evolutionary biologist at the University of Basel.

What do these sequences show in terms of mutations?

Most notably, there are a whole lot of mutations that appear across the new sequences. The genomes from the current outbreak share 40-some mutations with each other that distinguish them from their closest relatives, which were from around 2018. (The exact number of mutations varies depending on how certain changes are counted.)

Based on normal evolutionary timelines, scientists would expect a virus like monkeypox to pick up that many mutations over perhaps 50 years, not four, Neher said.

“That is somewhat remarkable,” he said.

Why are there so many mutations?

A lot of mutations could be bad — perhaps the virus has changed so much because it’s grown more fit and gotten better at transmitting among people. Monkeypox, unlike something like SARS-2, has historically not been considered to be a particularly efficient person-to-person spreader.

But there could be another explanation.

We tend to think of mutations as the result of haphazard mistakes that occur as genetic material is copied. Some mutations don’t have any real effect on the virus, some can actually be harmful, and some can give it an advantage over other strains.

But changes to viral genomes happen as a result of other mechanisms as well — and there are clues this is what’s happening with these monkeypox sequences.

The majority of the changes, for example, are specific swaps in the “letters” that make up DNA — namely G to A or C to T. Not only that, but those mutations are happening at particular locations within sequences.

“These aren’t just sort of random collections of mutations,” Neher said. “These are mutations of a very specific type.”

Here’s what might be happening: Some hosts (in this case, that’s people) have, as part of their immune systems, enzymes that are designed to induce mutations in whatever viruses they encounter. The idea behind such a sabotage scheme is that if you trigger enough mutations, certainly some of them will be deleterious. The virus won’t be able to replicate, and what will be left “is just a dead piece of DNA,” Neher said. It’d be like rearranging the letters on your enemy’s typewriter so they can’t get a clear message out.

(There are different types of enzymes that play this role, but with the monkeypox outbreak, scientists have narrowed in on a family known as APOBEC3 as a prime candidate.)

The strategy is not always foolproof, and some viruses might not pick up enough harmful mutations to be stopped. These survivors will, however, carry evidence of the genetic onslaught they encountered in the form of certain mutations, perhaps those that weren’t all that harmful or were neutral. The mutations might appear repeatedly, just like the ones in these monkeypox sequences. Scientists have likened these mutations to scars leftover from past fights with the host.

The enzyme vs. virus battles could also explain why the virus picked up so many mutations so fast. The mutations are not from the typical copying mistakes the virus made as it replicated. They’re battle wounds from when the host tried to fight the virus off.

What do these sequences mean for this outbreak?

This accelerated evolution seems to have taken off in about 2017, based on available sequences. The pattern of mutations could be evidence that the virus has been circulating among people at low levels since then. The lineage only gained notice more recently as cases outside the virus’ endemic area exploded, perhaps propelled by events like festivals and the return of global travel.

One explanation then, according to Neher, “would be, yes, it’s been circulating in humans since 2017, and in humans, we have a mutation rate which is about 10 times higher [than the virus’s normal rate]. But this is not so much a copying problem, but some sort of action of a host-mediated process.”

Notably, Nigeria has been experiencing an outbreak of monkeypox since 2017, though as of now, it’s not known where the cases in places including the Americas and Europe originally emerged from. Nigerian public health officials have said they sought international help to figure out what was happening with monkeypox, but didn’t get much interest.

Neher said there were other possibilities that could explain the mutations. Perhaps this lineage spilled back into animals at some point, and continued to accrue mutations through a similar antiviral enzyme process in that species before crossing over into humans once again. The point is that, while scientists look at the sequences as a suggestion the virus has been circulating among people for years, there are other potential explanations that warrant study.

One pressing mystery about the current outbreak has been whether the virus took off because it did evolve to be more transmissible, or because it got into networks of people who were having lots of close contacts with lots of other people. Neher said studying the sequence data alone can’t answer that question. It’s not possible, he explained, to look at the individual mutations or the combination of them and infer if they result in functional changes, or if they confer an evolutionary advantage. (Researchers determine whether mutations result in changes in the virus’s fitness both by studying epidemiological data and through lab experiments.) 

“We don’t have a good enough understanding of how this virus interacts with the host, or what these individual mutations could do,” he said.

But as the outbreak grows and more infections are detected, scientists are going to have more genomes to study. That could help them refine their current hypotheses, or introduce new ones entirely.