Dating the origin of hepatitis B virus reveals higher substitution rate and adaptation on the branch leading to F/H genotypes.

The evolution of hepatitis B virus (HBV), particularly its origins and evolutionary timescale, has been the subject of debate. Three major scenarios have been proposed, variously placing the origin of HBV in humans and great apes from some million years to only a few thousand years ago (ka). To compare these scenarios, we analyzed 105 full-length HBV genome sequences from all major genotypes sampled globally. We found a high correlation between the demographic histories of HBV and humans, as well as coincidence in the times of origin of specific subgenotypes with human migrations giving rise to their host indigenous populations. Together with phylogenetic evidence, this suggests that HBV has co-expanded with modern humans. Based on the co-expansion, we conducted a Bayesian dating analysis to estimate a precise evolutionary timescale for HBV. Five calibrations were used at the origins of F/H genotypes, D4, C3 and B6 from respective indigenous populations in the Pacific and Arctic and A5 from Haiti. The estimated time for the origin of HBV was 34.1ka (95% highest posterior density interval 27.6-41.3ka), coinciding with the dispersal of modern non-African humans. Our study, the first to use full-length HBV sequences, places a precise timescale on the HBV epidemic and also shows that the "branching paradox" of the more divergent genotypes F/H from Amerindians is due to an accelerated substitution rate, probably driven by positive selection. This may explain previously observed differences in the natural history of HBV between genotypes F1 and A2, B1, and D.