Deciphering the Origin and Evolution of Hepatitis B Viruses

Hepatitis B viruses constitute the family Hepadnaviridae, enveloped viruses with reverse‐transcribed DNA genomes. An outstanding feature is their streamlined genome organization with extensive gene overlap. Remarkably, the ~1,100 bp long open reading frame (ORF) coding for 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 hepatitis B viruses including genome replication via protein‐primed reverse‐transcription and utilization of structurally related capsids. Phylogenetic reconstruction revealed that both virus families separated more than 400 million years ago before the rise of tetrapods. We show that hepatitis B viruses 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 life‐style, followed by co‐evolution with their hosts over geologic eras.