Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses

Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras. [Display omitted] •Nackednaviruses are non-enveloped fish viruses related to hepadnaviruses•Both virus families separated from a common ancestor >400 million years ago•The envelope protein gene of hepadnaviruses emerged through two distinct processes•Hepadnaviruses mainly co-evolve with hosts while nackednaviruses jump between hosts Hepatitis B viruses are enveloped viruses of global medical importance. Lauber et al. report the discovery of nackednaviruses, a non-enveloped sister family to hepatitis B viruses in fish. Both lineages separated >400 million years ago. The envelope gene of hepatitis B viruses emerged de novo, followed by virus-host co-evolution over geologic eras.