Early Mesozoic Coexistence of Amniotes and Hepadnaviridae

Viruses are not known to leave physical fossil traces, which makes our understanding of their evolutionary prehistory crucially dependent on the detection of endogenous viruses. Ancient endogenous viruses, also known as paleoviruses, are relics of viral genomes or fragments thereof that once infiltrated their host's germline and then remained as molecular “fossils” within the host genome. The massive genome sequencing of recent years has unearthed vast numbers of paleoviruses from various animal genomes, including the first endogenous hepatitis B viruses (eHBVs) in bird genomes. We screened genomes of land vertebrates (amniotes) for the presence of paleoviruses and identified ancient eHBVs in the recently sequenced genomes of crocodilians, snakes, and turtles. We report an eHBV that is >207 million years old, making it the oldest endogenous virus currently known. Furthermore, our results provide direct evidence that the Hepadnaviridae virus family infected birds, crocodilians and turtles during the Mesozoic Era, and suggest a long-lasting coexistence of these viruses and their amniote hosts at least since the Early Mesozoic. We challenge previous views on the origin of the oncogenic X gene and provide an evolutionary explanation as to why only mammalian hepatitis B infection leads to hepatocellular carcinoma.