13,20 Moreover, F sequences sampled from sporadic cases among the non-Amerindian population appear as nested clades within the “Amerindian” genotype F radiation.3 Genotype H, which has been isolated from Amerindians in North and Central America, displays a close phylogenetic relationship with genotype F.21,22 This suggests an ancient introduction of the F/H ancestral strains to the Americas, certainly occurring before the recent European colonization. HBV sequences sampled from several isolated indigenous populations, such as the Canadian Arctic, Indonesian tribes, Papua Indonesia, and Pacific islands, form distinct subgenotypes (B6 for Canadian Arctic, C3 for Pacific,

C3 and C5-C10 for Indonesia). This pattern suggests that HBV genotypes and subgenotypes were shaped by different waves of human AZD3965 molecular weight migration across the continents.12,23–26 This hypothesis is further supported by the observed gradient of nucleotide and amino acid diversity from west to east, as well as the clustering of HBV sequences from three Polynesian islands, which is in accordance with archeological and linguistic evidence for the initial west-to-east settlement of Polynesia.19 Crucially, analyses of the Y chromosome and the mitochondrial DNA (mtDNA) markers revealed a dual genetic origin of Polynesians (Remote Oceania) from Near Oceania (Melanesia) and Asia

(see Supporting Information).19 The detection of two autochthonous subgenotypes (C3 and D4) in Remote Oceania is consistent with mTOR inhibitor the dual genetic origin of this population.19 Phylogenetic analyses of the HBV sequences isolated from Haiti revealed that a proportion of them formed a monophyletic clade within subgenotype A5 from Africa. The latter finding

suggests that the particular strains spread as the result of a founder effect that occurred during the period of the slave transport from Africa to Haiti between the 16th and 19th centuries. The fact that the nested “Haitian” A5 clade originated 200-500 years in the past suggests that the subgenotypes within see more A have been circulating in Africa for several centuries, well before the start of slave migration from Africa to the Caribbean. To test the co-divergence of HBV with humans, we examined whether the tMRCA of HBV lineages from particular regions correlated with previous estimates of divergence times of isolated human populations. Briefly, we employed a stepwise calibration of the HBV molecular clock. We initially tested whether the oldest calibration points (i.e., the migration into the Americas and Oceania) were reciprocally concordant. We then added a series of younger calibration points (see Materials and Methods and Supporting Information), allowing us to cover a larger part of the HBV history.