9–11 The “Out of Africa” hypothesis would be supported if global HBV genotype distributions

matched these anatomically modern human (Homo sapiens) migrations. Crucially, HBV sequences sampled from several isolated indigenous populations belong to separate subgenotypes.12–16 In some cases, such as the Indonesian archipelago, the distribution of HBV genotypes/subgenotypes is associated with Deforolimus cost the ethnic origin of the populations.12 These geographical patterns indicate that HBV diversity might be associated with early waves of human migration, although HBV phylogeny does not match perfectly the evolutionary history of human populations or primates.5 We investigated the controversy about the origin of HBV in humans and systematically searched for patterns in HBV phylogeny related

to modern human history. Based on evidence supporting the coincidence of HBV and human migrations, we investigated the timescale of global HBV dispersal and tested the hypothesis of co-divergence of the virus with modern humans using phylodynamic selleck inhibitor and phylogeographic methods. We also propose a model for the origin of HBV in Old World primates. We suggest, based on multiple lines of evidence, that the “Out of Africa” hypothesis is far more likely than the alternative hypotheses about the HBV origin in humans. HBV, hepatitis B virus; 95% HPD, 95% higher posterior density; ka, thousand years ago; tMRCA, time to most recent common ancestor. If HBV co-diverged with human populations,

we should be able to find distinct patterns relating to ancient human population movements. We systematically searched the literature of HBV epidemiology using the keywords “Amerindians,” “Pacific,” “Aborigines,” “Indigenous,” AND “HBV.” We also downloaded nucleotide sequences isolated from populations using these keywords. The search was completed in August 2010 and updated in May 2012 (Supporting Information). We tested for HBV-human co-divergence using a stepwise calibration-test approach. Briefly, we checked whether the coalescence times of the Amerindian population (13.0-20.0 ka BP), MCE when used to calibrate the ages of the Amerindian-specific genotypes on the HBV tree, were able to estimate the co-migration of HBV and humans in Polynesia. These dates are based on genetic and archaeological evidence for the dispersal times of modern humans in the Americas.17 We then incorporated the Polynesian and the Haitian calibration dates in our molecular clock analyses (6.6 ± 1.5 ka and no earlier than 500 years ago, respectively) to incorporate dates that covered a larger part of the HBV genetic diversity. If HBV had only appeared in the human population a few thousand years ago, we would not expect early and late coalescent dates in the human phylogeny to match with those in the phylogeny of their HBV isolates. We also tested whether historical human population sizes correlated with the inferred effective population sizes of HBV.