Monkeypox DNA hints virus has been spreading outside Africa for years

Genome sequencing confirms that monkeypox cases outside Africa are all related and suggests the virus responsible may have been circulating in people since 2017

By Michael Le Page

Rather than jumping to humans from animals recently, the monkeypox virus variant responsible for the worldwide outbreak may have been circulating in people for years, DNA sequencing suggests.

“We therefore suggest that the pattern we see… means that there has been sustained human to human transmission since at least 2017,” states an initial report by Áine O’Toole and Andrew Rambaut at the University of Edinburgh in the UK.

Because monkeypox normally circulates in animals in some African countries and occasionally jumps to people there, person-to-person spread is more likely to have gone unnoticed for years on that continent, says Emma Hodcroft at the University of Bern in Switzerland.

But sometime this year, the virus spread to Europe and beyond. As of 6 June, monkeypox infections have been confirmed in more than 900 people in 27 countries, including more than 200 in England. Most cases are in men who have sex with men.

Genome sequencing shows that the monkeypox viruses responsible for these cases are closely related to ones detected in a small number of cases in Israel, Nigeria, Singapore and the UK between 2017 and 2019.

There are up to 47 DNA-letter changes in the latest viruses compared with these earlier cases. That is an unexpectedly high number given that monkeypox is thought to evolve slowly, by around one mutation per year.

What is striking is that 42 of these 47 changes involve the DNA letters TT changing to TA, or GA to AA. There is a group of human enzymes called APOBEC3 that help defend against viruses by inducing mutations in their DNA, and these are the kinds of changes they produce.

“If these APOBEC3 edits are specifically indicative of replication in humans as opposed to another host species then this would confirm this entire clade to be representative of the emergence of a human epidemic by 2017,” O’Toole and Rambaut stated in a 5 June update to their report.

On 3 June, the US Centers for Disease Control and Prevention reported that three of the 10 monkeypox viruses sequenced there were a bit different to others, while still related to the 2017 virus. These three viruses were found in people who had travelled to different countries in Africa and the Middle East in 2021 or 2022.

The three cases could be due to independent instances of the virus jumping from some animal reservoir into people. However, because they also have lots of APOBEC3-like mutations, another explanation is that monkeypox has been spreading quite widely in people in Africa since 2017.

Surprisingly, rather than having evolved to be fitter and better at spreading in people, the existing viruses may be less fit than the 2017 ones, because they are accumulating lots of mutations that are probably detrimental.

“The mutations we see in the virus today are certainly not ones that kill the virus or we wouldn’t be seeing them, the virus would be dead,” says Hodcroft. “But there may still be some that are dragging it down a little bit, that are adding to the mutational burden.”

While this is reassuring, we shouldn’t assume that monkeypox won’t evolve to be better at spreading in people if we give it a chance to do so, she says.

“It’s much better for us to do what we can to ensure we don’t find out the answer to that question,” she says. “The less a virus circulates in a host, the less chance it has for that kind of adaption.”

There were some researchers who thought the SARS-CoV-2 coronavirus wouldn’t be able to evolve into different variants in the way it is doing, says Hodcroft.

And while the monkeypox cases so far may have been mild, this might not be true if the monkeypox virus starts infecting children or people who are immunocompromised, she says.

“I don’t think there is any reason to panic and I do think this is something we can absolutely get under control,” says Hodcroft. “But this is something we should take seriously. We don’t want to swing too far the other way because we are really sick of viruses.”