Researchers have recovered fragments of ancient DNA from the variola virus, which causes smallpox, from the naturally mummified remains of two Indigenous people buried in northern Chile. The remains date from approximately 1492 to 1631, spanning the transition from Inca rule to the Spanish colonial period. This is the first time ancient smallpox genomes have been recovered from the Americas. The study provides molecular evidence that smallpox arrived in the Americas following European contact, as historical records had suggested. The Chilean viruses belonged to a now-extinct lineage that diverged from other known variola lineages around 1296. On the evolutionary family tree, the Chilean genomes branch after early medieval European strains and before lineages that circulated in later centuries. This supports the conclusion that smallpox reached the Americas through colonization. The genomes also reveal how variola became specialized for infecting humans. Many related poxviruses can infect multiple animal species, but variola infects only humans. During its evolution, variola lost some accessory genes that were no longer essential for transmission between people, a process known as reductive evolution. The study also found that the virus did not evolve at a constant speed. Gene inactivation continued at a steady pace until the late 16th century, after which genetic substitutions accumulated more slowly before the rate increased again. The authors suggest that during the colonial-era epidemics, variola was already well-suited to spreading among populations with little acquired immunity, so relatively few new variants gained an advantage. Vaccination, introduced in 1796, later changed the immune environment and may have altered which mutations persisted. The timing suggests a connection, although the study's genomes cannot prove what caused the changes in evolutionary rate. The Chilean sequences fill a gap between genomes recovered from medieval Europe and those belonging to later variola lineages, helping researchers trace how smallpox reached the Americas and evolved as it spread. Smallpox is the only human infectious disease to have been eradicated worldwide. The last-known naturally acquired case occurred in Somalia in 1977, and the WHO declared smallpox eradicated in 1980. The study's findings are significant for understanding the historical spread of smallpox and its evolution into a human-only virus.

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