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Extinct hepatitis B virus discovered in Bronze Age remains by Cambridge geneticists


By Paul Brackley


A mass burial of battle victims from the Xiongnu period in Omnogobi, Mongolia, from which scientists extracted ancient DNA from for the study. One of these Xiongnu warriors who fell in battle in Omnogobi carried an ancient HBV sequence. Picture: Alexey A Kovalev
A mass burial of battle victims from the Xiongnu period in Omnogobi, Mongolia, from which scientists extracted ancient DNA from for the study. One of these Xiongnu warriors who fell in battle in Omnogobi carried an ancient HBV sequence. Picture: Alexey A Kovalev

Finding by Department of Zoology researchers could help develop future vaccines

A mass burial of battle victims from the Xiongnu period in Omnogobi, Mongolia, from which scientists extracted ancient DNA from for the study. One of these Xiongnu warriors who fell in battle in Omnogobi carried an ancient HBV sequence. Picture: Alexey A Kovalev
A mass burial of battle victims from the Xiongnu period in Omnogobi, Mongolia, from which scientists extracted ancient DNA from for the study. One of these Xiongnu warriors who fell in battle in Omnogobi carried an ancient HBV sequence. Picture: Alexey A Kovalev

Hepatitis B has been infecting humans for at least 4,500 years, Cambridge geneticists have discovered.

In pioneering work, they found an extinct strain of the virus in Bronze Age skeletons in burial sites across Europe and Asia.

The findings – compared to the discovery of the first fossils – changes our understanding of the evolution of the disease and could help improve future vaccines.

The research was led by a group of academics at the Centre for Pathogen Evolution in the Department of Zoology at the University of Cambridge and the Centre for GeoGenetics at the University of Copenhagen.

Barbara Mühlemann, joint first author on the research paper and a graduate student at the University of Cambridge, said: “People have tried to unravel the history of the hepatitis B virus for decades – this study transforms our understanding of the virus and proves it affected people as far back as the Bronze Age.

“We have also shown that it is possible to recover viral sequences from samples of this age, which will have much wider scientific implications.”

The scientists took 304 genetic samples from skeletons from the Bronze Age to the medieval period. Some 25 of the skeletons tested positive for hepatitis B, including the remains of a warrior buried in a mass grave in Mongolia

Twelve of these had enough of the virus’ genome to enable detailed analyses, the oldest of which was 4,500 years old.

The team then extracted the genetic sequences of the virus that infected the individuals. As it is fragmented, there is no chance of becoming infected through contact with the skeletons.

Previous attempts to estimate how long the virus has infected humans have ranged from 400 to 34,000 years.

Hepatitis B, first discovered in the 1960s, affects millions of people worldwide today. In 2015, it was estimated that 257 million people were chronically infected with the virus and 887,000 died due to associated complications, such as liver cancer, according to the World Health Organisation.

Despite its prevalence, little is known about its origin and evolution. Like many viruses, that is primarily due to a lack of historical evidence.

Until this study, the oldest human viruses recovered were about 450 years old, with most no more than half a century old.

This research, published in the journal Nature, forms the oldest and largest datasets scientists have of ancient human viruses.

Joint first author Dr Terry Jones, based at the University of Cambridge’s Department of Zoology, said: “Scientists mostly study modern virus strains and we have mainly been in the dark regarding ancient sequences – until now.

“It was like trying to study evolution without fossils. If we only studied the animals living today it would give us a very inaccurate picture of their evolution – it is the same with viruses.”

To recover the virus, the researchers used an approach called ‘shotgun sequencing’, which examines all the genetic material present in a sample, in contrast to ‘genome bio-capture’, which focuses only on the human genome.

Professor Eske Willerslev, who led the study and holds positions both at St John’s College, Cambridge, and the University of Copenhagen, said: “We have screened what we normally call the waste product.”

Shotgun sequencing is used to blast apart strands of DNA that are too long for the more typical Sanger sequencing method. The numerous, random small segments are sequenced using a chain termination method to obtain reads. After several rounds of fragmentation and sequencing, computational methods are used to assemble the continuous sequence. The process teases out non-human DNA – such as, in this case, the virus entombed in bones.

Prof Willerslev suspected it may be possible to find viruses in human remains based on previous research he completed at the University of Copenhagen.

He approached the other academics, who have specialised in identifying and studying the evolution of viruses.

Prof Willerslev said: “This data gives us an idea of how this virus behaves, and it provides us with a better idea of what is biologically possible in the future.

“Analysis of other ancient DNA samples may reveal further discoveries and this pioneering study could have huge implications for how the virus affects humans today.”

The work also rewrites our understanding of where the virus infected people.

It shows the existence of ancient hepatitis B genotypes in locations incompatible with their present-day distribution. It disproves the suggestion that hepatitis B originated in the New World and spread to Europe half a century ago.

Prof Willerslev said: “This study is just the start. We’re talking about one virus here, but there are a lot of other viruses we could look for.”

‘Truly remarkable study’ has widespread implications

The study has been praised for its widespread implications by an academic peer.

Peter Simmonds, professor of virology at the Medical Sciences Division of the University of Oxford, who was not involved in the work, said further discoveries will inevitably follow the “pioneering work”.

“This is a truly remarkable study that quite transforms our understanding of the origins and epidemiology of an important human pathogen, hepatitis B virus (HBV), and the evidence that it may have similarly afflicted human populations as far back as the Bronze Age and likely even earlier,” he said.

“The study is clearly important as a history of an important virus causing hepatitis but the study has wider and potentially even more important implications.

“Firstly, the authors have demonstrated that relic sequences of DNA viruses can be recovered from archaeological remains of considerable age.

“Thus, the current study can in some senses be regarded as a pioneering case study – other human viruses may lurk in the genomic libraries the

authors analysed and further discoveries from ancient DNA undoubtedly await.

“Secondly, the findings dramatically revise the timescale for the evolution of HBV – the finding that some of the common genotypes of the virus were circulating several thousand years ago is quite unexpected, based on previously proposed timescales for their appearance, extrapolated from contemporary samples.”

He added: “Direct genetic analysis of viruses in these truly archaic humans provides a direct and much more cogent dataset with which to better understand the long-term evolution of viruses.”

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