Ancient hepatitis B viruses from the Bronze Age to the Medieval period

Abstract

Hepatitis B virus (HBV) is a major cause of human hepatitis. There is considerable uncertainty about the timescale of its evolution and its association with humans. Here we present 12 full or partial ancient HBV genomes that are between approximately 0.8 and 4.5 thousand years old. The ancient sequences group either within or in a sister relationship with extant human or other ape HBV clades. Generally, the genome properties follow those of modern HBV. The root of the HBV tree is projected to between 8.6 and 20.9 thousand years ago, and we estimate a substitution rate of 8.04 × 10-1.51 × 10 nucleotide substitutions per site per year. In several cases, the geographical locations of the ancient genotypes do not match present-day distributions. Genotypes that today are typical of Africa and Asia, and a subgenotype from India, are shown to have an early Eurasian presence. The geographical and temporal patterns that we observe in ancient and modern HBV genotypes are compatible with well-documented human migrations during the Bronze and Iron Ages. We provide evidence for the creation of HBV genotype A via recombination, and for a long-term association of modern HBV genotypes with humans, including the discovery of a human genotype that is now extinct. These data expose a complexity of HBV evolution that is not evident when considering modern sequences alone.

Unravelling the history of hepatitis B virus genotypes A and D infection using a full-genome phylogenetic and phylogeographic approach

“…In contrast, during the same period, human mobility was relatively limited in sub-Saharan Africa, thus leading to regional dispersal of HBV-A. Our findings are corroborated by the recently published analysis of HBV from ancient samples (Mühlemann et al, 2018; Krause-Kyora et al, 2018), which show that HBV was already circulating in humans at least 7,000 years ago and, in agreement with our analyses, place the putative origin of genotypes A and D in the Middle East/Central Asia.…”

“…This is in line with our previous observations, about the co-expansion of HBV with its host and the central role of North Africa and the Middle East regions as hubs for human expansion and consequent dissemination and genetic shuffling of genotype D (Paraskevis et al, 2013). Notably we also found that this area provides the putative origin for genotype D. This conclusion is supported by the finding that the location of the HBV sequence that clustered at the root of genotype D and sampled 2,300 years ago, was in Central Asia (data not shown) (Mühlemann et al, 2018). On the other hand, regarding Greenland and New Zealand, we found almost 100% monophyletic clustering suggesting that the genotype D infection in these areas were because of onward transmissions among the local population(s) and not due to introduction from recent human migrations into these areas.…”

“…The ancient origin of HBV has been also confirmed by analysis of HBV sequences from two 16th century mummies and two recent studies, which detected HBV from ancient DNA samples, ranging in age from approximately 800 to 4,500 years (Mühlemann et al, 2018) and 1,000 to 7,000 years ago (Krause-Kyora et al, 2018), showed that the HBV infections were present for at least 7,000 years (Patterson Ross et al, 2018; Kahila Bar-Gal et al, 2012). As the major genotypes have probably originated before and during the onset of Neolithic and the subgenotypes during the later Neolithic period, the majority of HBV diversity has been accumulated as a result of dispersals following the antecedent ‘Out of Africa’ population migrations, which hosted and conveyed the parental HBV strains (Kramvis, 2014; Locarnini et al, 2013; Zehender et al, 2014).…”

“…The putative origin of genotype A was probably in the Middle East/Central Asia and thereafter followed two distinct routes of dispersal, one within Africa and a second to Western Europe. The hypothesis that the putative origin of genotype A was in the Middle East/Central Asia was further supported by the recent analysis of HBV ancestral genotype A sequences in ancient samples (Mühlemann et al, 2018). Specifically, the location of two HBV sequences, which clustered at the root of the genotype A and sampled 4,000 years ago, was in Central Asia (data not shown) (Mühlemann et al, 2018).…”

“…The hypothesis that the putative origin of genotype A was in the Middle East/Central Asia was further supported by the recent analysis of HBV ancestral genotype A sequences in ancient samples (Mühlemann et al, 2018). Specifically, the location of two HBV sequences, which clustered at the root of the genotype A and sampled 4,000 years ago, was in Central Asia (data not shown) (Mühlemann et al, 2018). Supporting the results of our previous study, where we analysed subgenomic preS/S region, HBV-A strains from sub-Saharan Africa were the source for Caribbean, Latin America and South Asia following recent human mobility, as a result of the historical forced migration of the slave trade in the 16th – 19th centuries (Kramvis and Paraskevis, 2013).…”