title: Reliable timescale inference of HBV genotype A origin and phylodynamics.
abstract: The worldwide distributed Hepatitis B virus (HBV) genotype A is classified into three subgenotypes, and one quasi-subgenotype. The majority of HBV-A subgenotypes are widespread in Africa and in ethnic groups that have relatively recently emigrated from African countries, whereas HBV-A2 is highly prevalent among subjects at high risk for sexual exposure to HBV in north-western Europe and the USA. The aim of this study was to reconstruct the origin and dispersion of HBV-A subgenotypes on a reliable timescale using short-term calibration based on heterochronous sampling for HBV-A2, and long-term calibration based on historical data for the other subgenotypes. To this aim, we analysed 113 newly characterised HBV-A isolates with 247 reference sequences retrieved from a public database. The phylodynamic reconstruction was performed by a Bayesian framework. The common ancestor of the currently circulating A subgenotypes was placed in west-central Africa a mean 1057 years ago. The genotype diverged into two main clades at the beginning of the 13th century: one including all of the west-central African quasi-subgenotypes and the other corresponding to subgenotype A1, originating in east Africa and further segregating into two main subclades: an "African" and a "cosmopolitan" clade. It is likely that the slave trade was the main source the spread of cosmopolitan HBV-A1, which was exported to Asia in the 17th century as a result of Arab or Portuguese trade, and to Latin America in the 18th centuries through the trans-Atlantic slave trade. The origin of the currently circulating A2 strains dates back to the first decades of the 20th century, and the evolutionary demography analysis suggests an exponential growth of infections, between 1970s and the mid-1990s. In conclusion, the very different epidemiological and evolutionary histories of HBV-A subgenotypes justify the use of different calibration approaches to reconstruct their reciprocal phylodynamics.
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy. Electronic address: gianguglielmo.zehender@unimi.it.
authors.forename: Gianguglielmo
authors.initials: G
authors.lastname: Zehender
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gabanelli
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Ebranati
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Veo
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, National Institute of Health, 00161 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lo Presti
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, National Institute of Health, 00161 Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cella
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, National Institute of Health, 00161 Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Giovanetti
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Bussini
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Salpini
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lai
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, 20157 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tanzi
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy.
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.affiliation: L. Sacco Department of Biomedical and Clinical Science, University of Milan, 20157 Milan Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Galli
authors.affiliation: Department of Infectious, Parasitic and Immunomediated Diseases, National Institute of Health, 00161 Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ciccozzi
mesh_terms: D000349:Africa; D001208:Asia; D002138:Calibration; D002874:Chromosome Mapping; D005060:Europe; D019143:Evolution, Molecular; D005814:Genes, Viral; D014644:Genetic Variation; D005838:Genotype; D006509:Hepatitis B / Q000821:virology; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics*; D006801:Humans; D010802:Phylogeny; D058974:Phylogeography; D017422:Sequence Analysis, DNA
keywords: HBV genotype A; HBV subgenotype A1; HBV subgenotype A2; Hepatitis B virus; Molecular clock calibration; Phylogeography