Two Chilean mummies have provided scientists with the earliest known smallpox genomes found in the Americas, dating between 1492 and 1631.

The genomes are the first-ever DNA evidence that proves European colonization introduced smallpox to the Americas, according to a paper that published Thursday (July 30) in the journal Science.

Smallpox, an infection caused by the variola virus, was one of the deadliest diseases in the world until it was completely eradicated in 1980. While the disease has been found in 3,000-year-old Egyptian mummies, the first documented outbreak in the Americas was in 1518, during the Spanish conquest of the Caribbean. The virus then spread rapidly throughout Central and South America.

Experts have estimated that the disease caused the deaths of three to four million Indigenous people with no prior immunity to the disease. The combination of smallpox, violence, slavery and other diseases wiped out about 90% of the original inhabitants of the Americas by 1600.

While historians and scientists have long understood the toll of the disease, the story of smallpox's spread comes primarily from historical records, which were written by European colonizers and may not have fully captured transmission among Indigenous peoples. There's also a lot scientists don't know about the specific viral strains responsible for the pandemic because of the lack of ancient smallpox DNA evidence in the Americas.

In the new study, the researchers identified ancient smallpox virus DNA from the bones of two mummified Indigenous Inca individuals from northern Chile: an adult female and an adult male who lived between 1492 and 1631.

"None of us expected to find variola virus DNA from the sample that they collected, so it was completely a surprise," study co-author Shigeki Nakagome, a geneticist at Trinity College Dublin, told Live Science. The research team was not targeting ancient pathogens but rather looking to understand human population history in the region. "I don't think there was any historical record documenting smallpox in this particular community, so no one expected the smallpox evidence."

Analysis of the two ancient viral genomes showed them to be almost identical, suggesting the two individuals were likely infected during the same outbreak or by the same circulating strain.

Comparing the genomes of ancient and modern variola viruses, the researchers found that the genome matched an extinct lineage that split from another European strain around 1296, but that predates modern strains. That means the variola virus found in the mummies is an evolutionary step between medieval European strains and modern strains, proving that Europeans brought smallpox to the Americas.

"We provide the first molecular evidence of smallpox introduction to the Americas through colonization," Nakagome said.

"This paper is really lovely because we know from the historical record that smallpox had a huge impact on Indigenous populations in the Americas," Anne Stone, an anthropologist at Arizona State University who was not involved in the study, told Live Science. "This paper gives us the first description of the pathogen during the colonial period," she said, adding that it corroborates the "historical record that a smallpox epidemic went through [the Americas]."

The genome also showed that, through a series of mutations, the genes that enable variola to infect species other than humans — genes present in related viruses that infect animals, like mpox or cowpox — were inactivated, Bruno Romero González, a computational biologist at Trinity College Dublin and lead author of the study, told Live Science. Over time, this ancient variola strain became less able to infect animals. "Because of that, variola started to focus on targeting only humans," Romero González said, ultimately adapting to become more successful in infecting people.

The researchers hope that more samples of ancient variola virus are found throughout the Americas, to complete the picture of smallpox's evolution and movement.

Studying ancient DNA can also give scientists insight into how modern day diseases might behave, Stone said. Understanding the evolution of this pathogen is particularly important because Mpox is in the same group and closely related, she said. Studies have suggested Mpox might behave similarly to the historical variola virus, in that it seems to mutate to adapt to human hosts. "It's always useful to study ancient pathogens," Stone said, "helping us learn how these pathogens adapt to us."

The study adds to growing evidence for smallpox on ancient Indigenous skeletons, including two 16th-century toddlers buried in Peru whose bones have lesions suggestive of smallpox infection.

How much do you know about the first people to reach the Americas? Find out with our First Americans quiz.