Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece. firstname.lastname@example.org.
The origin of hepatitis B virus (HBV) infection in humans and other apes remains largely unresolved.Understanding the origin of HBV is crucial because it provides a frameworkfor studying the burden, and subsequently the evolution, of HBV pathogenicity with respect to changes in human population size and life expectancy.To investigate this controversy,we examined the relationship between HBV phylogeny and genetic diversity of modern humans,investigated the timescale of global HBV dispersal andtested the hypothesis of HBV-human co-divergence. We find that the globaldistribution of HBV genotypes and subgenotypes are consistent with the major prehistoric modern human migrations.Wecalibrate the HBV molecular clock usingthe divergencetimesofdifferent indigenous human populations based on archaeological and genetic evidence,and showthatHBVjumped into humans around 33,600; 95% Higher Posterior Density: 22,000-47,100 years ago (estimated substitution rate: 2.2?10(-6) ; 95% Higher Posterior Density: 1.5-3.0?10(-6) substitutions/site/year). This coincides with the origin of modern non-African humans. Crucially, the most pronounced increase in the HBV pandemic correlates with the global population increase over the last 5,000 years. We also show that the non-human HBV clades inorang-utans and gibbonsresulted from cross-species transmission events from humansthat occurred no earlier than 6,100 years agoConclusion: Our study provides, for the first time, an estimated timescale for the HBV epidemicthat closely coincides withdates of human dispersals, supporting the hypothesis that HBV has been co-expanding and co-migrating with human populations for the last 40,000 years.