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Ancient Viking Variola Virus Genomes Shed Light on Evolution of Modern Smallpox Virus

NEW YORK – Genomic data from ancient viral samples found in Viking Age individuals from northern Europe suggest that smallpox-causing variola virus (VARV) strains from an extinct clade were circulating in humans as far back as around 1,400 years ago.

"We discovered new strains of smallpox in the teeth of Viking skeletons and found their genetic structure is different from the modern smallpox virus eradicated in the 20th century," co-senior author Eske Willerslev, director of the University of Copenhagen's Lundbeck Foundation GeoGenetics Centre, said in a statement.

"The 1,400-year-old genetic information extracted from these skeletons is hugely significant because it teaches us about the evolutionary history of the variola virus that caused smallpox," added Willerslev, who is also affiliated with the University of Cambridge and the Wellcome Sanger Institute.

For a study published in Science on Thursday, he and his colleagues started with shotgun sequencing of nearly 1,900 tooth or skeletal samples from individuals in Eurasia and the Americas going back between 150 and 31,000 years, narrowing in on more than two dozen individuals with at least one apparent VARV sequence read. Their subsequent targeted capture sequencing experiments highlighted 11 VARV infections in Viking Age individuals laid to rest in Norway, Denmark, the UK, and Russia some 970 to 1,420 years ago, and led to near-complete genome sequences for four of those isolates.

"The timeline of the emergence of smallpox has always been unclear, but by sequencing the earliest-known strain of the killer virus, we have proved for the first time that smallpox existed during the Viking Age," co-senior author Martin Sikora, a University of Copenhagen geogenetics researcher, said in a statement.

The team noted that the Viking variola viruses detected are around 1,000 older than the most recent confirmed smallpox cases identified in past studies. A phylogenetic tree containing ancient and modern VARVs, along with additional double-stranded DNA orthopoxviruses such as camelpox and taterapox, put the ancient VARVs strains in a sister clade relative to the viruses linked to smallpox in recent history, the team reported. They share a most recent common ancestor going back roughly 1,700 years ago.

"The early version of smallpox was genetically closer in the pox family tree to animal poxviruses such as camelpox and taterapox, from gerbils," co-first author Lasse Vinner, a virologist and geogenetics researcher at the University of Copenhagen, said in a statement, explaining that the newly identified variola virus "does not exactly resemble modern smallpox, which show that [the] virus evolved."

"Understanding the genetic structure of this virus will potentially help virologists understand the evolution of this and other viruses," Vinner noted, "and add to the bank of knowledge that helps scientists fight emerging viral diseases."

While the current findings point to Viking Age infections with the variola virus sister clade strains, the researchers cautioned that it is not yet clear whether these infections produced symptoms resembling modern smallpox disease. Even so, the VARV clade viruses were marked by a B16R gene inactivation implicated in fever symptoms in more well-characterized variola viruses, and both modern and ancient VARVs appeared to be peppered with gene truncations, fragmentations, or other alterations that rendered them inactive relative to non-VARV orthopoxviruses.

"The ancient viral genomes show reduction of gene content during the evolution of VARV and multiple combinations of gene inactivations have led to viruses capable of circulating widely within the human population," the authors concluded.

For a related perspectives article in Science, Autonomous University of Madrid molecular biology researcher Antonio Alcami outlined known landmarks in smallpox evolution and discussed the possibility that ancient forms of variola virus might have produced relatively mild forms of disease compared to those linked to modern VARV, which claimed hundreds of millions of lives in the 20th century.

"Maybe this [gene inactivation] drove the evolution of the modern VARV clade that caused the devastating smallpox epidemics," Alcami suggested, "whereas less aggressive and less transmissible, low-pathogenic ancient VARV clades became extinct."

The modern, often-deadly form of smallpox-causing variola virus is considered to be eradicated globally as of 1980, the team noted, with the last known viruses limited to specific laboratories. Even so, concerns around the disease have not disappeared, spurring interest in everything from variola virus evolution to the detection of related viruses in nature.

"Despite the eradication of smallpox, there are ongoing concerns regarding the re-emergence of a smallpox-like disease via accidental or deliberate reintroduction of variola virus, adaptation of monkeypox virus to humans, or zoonosis or genetic engineering of another orthopoxvirus," the authors explained.

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