Hepatitis B Virus: Alternative phylogenetic hypotheses and its impact on molecular evolution inferences

Characterizing molecular evolution patterns of the Hepatitis B Virus (HBV) is important for a better understanding of the natural history of this infection. However, several molecular evolution estimates are conditioned on tree topology. There is no consensus about the phylogenetic relationships of HBV genotypes, and different studies often find alternative topologies. While most studies consider HBV genotypes F and H as sister to all other human genotypes, a recent study suggested an alternative HBV phylogeny that indicates an accelerated substitution rate for HBV-F/H partially driven by positive selection. In this study, we evaluate the impact of alternative HBV topologies on inferences of HBV phylogeny, rate acceleration, and positive selection on the HBV-F/H branch. Our results indicate that under certain methodological approaches alternative HBV topologies are equally likely. Considering phylogenetic uncertainty, there is no evidence that HBV-F/H had an accelerated substitution rate, even though inferences of positive selection are robust to alternative background topologies. Our results further suggest that, under reasonable assumptions, HBV-F/H most likely represents the sister lineage to all other human/ape HBV genotypes. Understanding the full range of likely topologies will be crucial for elaborating, testing, and refining hypothesis about the evolutionary HBV origins in our species.