Monkeypox cases continue to rise throughout the world, with more than 13,000 cases reported so far. The virus, which is rarely lethal but causes painful sores on the skin, normally lives in rodents and other animals but is now spreading rapidly among humans around the world.

Monkeypox outbreaks have occurred several times since the 1970s. An outbreak in Nigeria in 2017 infected an estimated 122 people. And a more deadly version of the virus from Central Africa may have infected nearly 19,000 people in that region over the past decade.

A recent paper published in Nature Medicine shows that the current virus—a descendant of the strain that circulated in Nigeria—has been undergoing accelerated evolution over the past few years by mutating far more frequently than expected. It is unclear so far whether the mutations are just an indication that the virus has merely been mutating harmlessly in humans or if it has become better at infecting them. But experts say that as the number of infections increases, so does the chance the virus will improve its ability to infect or transmit among humans. “Once you get a virus in a population, it’s going to keep mutating to become more adapted to that species,” says Rachel Roper, a virologist at East Carolina University. “There’s no other option.”

The monkeypox virus is made of DNA, which tends to mutate less often than RNA in viruses such as SARS-CoV-2, which causes COVID. On average, poxviruses—a family that includes orthopoxviruses such as monkeypox and smallpox—tend to mutate once per year, wrote biophysicist Richard Neher of the University of Basel in Switzerland on Twitter.

But in the new study, when microbial genomics researcher João Paulo Gomes of Portugal’s National Institute of Health Dr. Ricardo Jorge (INSA) and his colleagues compared 15 virus samples from the current outbreak with viruses isolated from people who traveled to West Africa in 2018 and 2019, they found that the present-day virus had mutated about 50 times in just four years.

The pattern of these mutations provided hints as to how and when the virus made the jump from an animal host into humans. Like all DNA, the monkeypox genome contains four “letters”—A, C, G and T—that code for proteins. Gomes’s team found that new monkeypox sequences tended to contain far more As and Ts than older sequences did.

This pattern suggested that the virus was being edited by a human protein called APOBEC3, which tends to switch Cs to Ts. APOBEC3 can edit the genomes of many viruses, including SARS-CoV-2, and the sheer number of edits indicated that this human protein had been tweaking the monkeypox virus for a long time. That aligns with other evidence suggesting that the disease had been spreading among humans in Africa or Europe for years before outbreaks were detected in the latter continent in May 2022.

Because all the new monkeypox samples that have been sequenced so far are genetically similar, Gomes’s team thinks the current outbreak arose from a single origin. The current strain is also similar to strains seen in the 2017 outbreak in Nigeria, but superspreader events may have allowed the new version to infect more people traveling through the country.

Thus far, Neher wrote on Twitter, there is no indication that the mutations have helped the virus adapt to humans. In fact, most random mutations do nothing at all, so the new changes in the monkeypox genome may just be markers of human infection rather than the cause. Most of the mutations that Gomes’s team identified were small, although one gene had been deleted.

Orthopoxviruses seem to be able to survive a great deal of mutation. One study that analyzed smallpox in the skeletons of sixth-century Vikings found numerous genes that are inactivated in modern smallpox strains, suggesting that gene deletions are a normal part of how orthopoxviruses and host species adapt to one another.

That observation doesn’t mean mutations that help the monkeypox virus infect and spread in humans won’t appear in the future, says Geoffrey Smith, a virologist at the University of Cambridge. Several of the genes Gomes’s team identified occurred in proteins that interact with the human immune system, although there is no evidence that these strengthened the virus.

Roper isn’t so sure. “It’s my belief it mutated in some way early in this jump to become more transmissible in humans,” she says. Roper suspects that one of these fitter forms of the virus ended up in a so-called superspreader event. HIV followed a similar pattern: it jumped from animals into people several different times before becoming widespread. “This time [monkeypox] really got a foothold,” she says.

If mutations that helped the virus did appear, Smith says, scientists would be able to spot them. He and many others have spent decades studying the smallpox genome, whose central region is 96 percent identical to that of monkeypox. They know which proteins allow the virus to escape the immune system, for instance, or to spread more easily. “We know what to look for and haven’t seen it yet,” Smith says.

Still, Roper thinks it will likely be years before scientists can pinpoint which of the mutations that occurred are important and why. “These experiments are really hard to do,” she says. With SARS-CoV-2, for example, certain combinations of mutations seem to affect the virus’s ability to spread while other combinations do not.

In monkeypox, one protein of potential interest is F13, which helps wrap the virus in its protective shell. F13 is the target of a drug called tecovirimat (TPOXX), which is approved for treating smallpox. The U.S. has stockpiled tecovirimat in case of a smallpox outbreak, and it is now being tested in clinical trials as a treatment for monkeypox. If F13 begins to mutate, it might indicate that the virus is actively developing resistance to the drug.

Despite the rapidly rising number of monkeypox cases, Smith says it is unlikely to become a pandemic as devastating as COVID. The currently circulating virus appears to be less deadly and less easily spread than SARS-CoV-2, and existing drugs and vaccines are effective against it.

“What we don’t want this [outbreak] to do is continue for a long time,” Smith says. The longer the epidemic goes on, he says, the greater the chance that the virus will start to mutate in ways that help it infect and spread among humans.