Ancient smallpox genomes reveal how European colonisation brought the disease to the Americas

Researchers have recovered and analysed the first ancient smallpox virus genomes ever identified in the Americas, providing the strongest direct evidence to date that the disease was introduced through European colonisation.

Smallpox, caused by variola virus, played a major role in the catastrophic population decline experienced by Indigenous peoples after European arrival. Such was the extent of those declines, that many claim smallpox and other introduced diseases entirely reshaped societies, killing hundreds of millions of people.

Until now, however, there had been no direct genetic evidence linking colonial-era outbreaks in the Americas to strains circulating in the Old World.

The study, just published in leading international journal Science and funded through the Research Ireland Frontiers for the Future Programme, analysed ancient viral DNA recovered from two individuals from a local community buried in northern Chile between the late 15th and early 17th centuries. The researchers found that the viruses belonged to a now-extinct lineage of variola virus that sits evolutionarily between medieval European strains and the strains that circulated in later centuries.

“This discovery provides the first molecular confirmation that smallpox was carried to the Americas during the colonial period,” said Dr Shigeki Nakagome, from Trinity’s School of Medicine, “but beyond tracing the disease’s arrival, our study also sheds new light on how smallpox evolved.

“We found that the virus underwent a long period of genetic change up to the 16th century, but that its evolution slowed markedly during the height of colonial expansion and major smallpox epidemics in the 17th and 18th centuries,” said Dr Lara Cassidy, from Trinity’s School of Genetics and Microbiology.

“This suggests that the virus may have reached an evolutionary optimum, allowing it to spread successfully with little further adaptation – possibly aided by the lack of immunity newly exposed populations had.”

The team also found evidence that this period of evolutionary stability may have ended in the 19^th century when vaccination became increasingly widespread. As immunity levels rose, the pace of viral evolution appears to have increased again.

What is the potential impact of this research?

Bruno Romero González, a PhD student in Trinity’s School of Medicine, said: “Taken together, the findings show how major historical events including colonisation, population change and vaccination likely shaped the evolution of one of humanity’s most devastating infectious diseases, while also demonstrating the power of ancient DNA to address longstanding historical questions.”

Specifically, the work:

• Provides the first direct genetic evidence that Old World smallpox strains were present in Indigenous communities in the Americas during the colonial period, offering molecular support for historical accounts of smallpox introduction through European colonisation.
• Reveals how human societies shape pathogen evolution. The researchers suggest that when a pathogen can spread easily through large, susceptible populations, evolutionary pressures may favour maintaining a successful form, rather than driving further genetic changes. Conversely, the apparent rebound in evolutionary rates after vaccination became widespread hints that public health interventions can alter the evolutionary landscape of pathogens.
• Informs modern infectious disease research, highlighting how population movement, immunity and public health measures can influence pathogen evolution. Related questions remain highly relevant for modern diseases such as influenza, COVID-19 and mpox.
• Expands the field of ancient pathogen genomics, demonstrating how ancient DNA can uncover aspects of disease history that are invisible in historical records alone. This opens new opportunities to study past epidemics and their impacts on global human populations. 

The research was funded through the Research Ireland Frontiers for the Future Programme and Agencia Nacional de Investigación y Desarrollo.