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Oldest evidence of HBV found in 4,500-year-old human remains
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Researchers at the University of Cambridge and the University of Copenhagen have identified hepatitis B viruses, including a genome that is now extinct, in human remains that date as far back as the Bronze Age, the oldest being around 4,500 years old.
Their study, published recently in Nature, reveals a complex evolution of HBV, which could have implications for future research.
“People have tried to unravel the history of HBV for decades — this study transforms our understanding of the virus and proves it affected people as far back as the Bronze Age,” Barbara Mühlemann, PhD student at the University of Cambridge, said in a press release. “We have also shown that it is possible to recover viral sequences from samples of this age, which will have much wider scientific implications.”
According to WHO, approximately 257 million people are infected with HBV worldwide. In 2015, an estimated 887,000 people died from HBV-related complications, including cirrhosis and hepatocellular carcinoma. However, despite the impact of HBV on public health, little is known about its origin.
“Scientists mostly study modern virus strains, and we have mainly been in the dark regarding ancient sequences — until now,” Terry Jones, PhD, of the University of Cambridge’s zoology department, said in the release. “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.”
Mühlemann, Jones and colleagues used a shotgun sequencing method to analyze human remains from the Bronze Age to the Medieval period that were exhumed in Europe and Asia. Samples from 25 skeletons tested positive for HBV. Of these, 12 had enough viral material for detailed analyses.
During their investigation, the researchers identified “important spatiotemporal reference points in the evolutionary history of HBV.” A geographical analysis showed that the location of several ancient genotypes do not match the locations of modern-day genotypes. Some genotypes typically found today in Africa and Asia, as well as a subgenotype found in India, had mixed European and Asian origins. Data also provided “strong evidence” that an ancient strain known as HBV-DA51 and an unknown parent recombined to form genotype A sequences, suggesting the abundance of HBV genotypes circulating today are just “a subset of the diversity that has ever existed,” the researchers wrote.
“The most interesting difference we see [between ancient and modern HBV] is that three of the sequences older than 3,700 years are closer genetically to viruses present in nonhuman primates than human viruses,” Mühlemann told Infectious Disease News. “Furthermore, we see three different sequences that lack two amino acids relative to the modern sequences. We don’t yet know what the functional implications of those changes are.”
Before this discovery, the earliest strain of HBV was sequenced from 450-year-old mummified remains of a small child in Naples, Italy. The newly identified sequences represent the oldest evidence of any virus recovered from human DNA, according to the researchers. Other ancient viruses that have been previously identified include a strain of influenza from approximately 100 years ago and a strain of variola virus from approximately 350 years ago.
Mühlemann said she hopes to investigate the origin and evolution of other viruses. However, the shotgun sequencing method that was used in this study is unable to detect RNA, limiting their efforts. Further, she added, it will be difficult to locate remains with virus titers that are high enough to be detected.
“The lack of ancient sequences limits our understanding of the evolution of HBV and very probably of other viruses,” the researchers concluded. “Discovery of additional ancient viral sequences may provide a clearer picture of the true origin and early diversification of HBV, enable us to address questions of paleo-epidemiology, and broaden our understanding of the contributions of natural and cultural changes (including migrations and medical practices) to human disease burden and mortality.” – by Stephanie Viguers
Disclosures: The authors report no relevant financial disclosures.
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