Closest relatives of poxviruses are spread in the gut of humans and animals worldwide: the egoviruses

Abstract Large and giant double-stranded DNA viruses within the phylum Nucleocytoviricota are diverse and prevalent in the environment where they substantially affect the ecology and evolution of eukaryotes 1–4 . Until now, these viruses were only sporadically found in the digestive system of vertebrates 5–7 . Here, we present the discovery of a diversified group of Nucleocytoviricota viruses dubbed egoviruses that almost exclusively occur in the digestive system of vertebrates worldwide. Egoviruses are most closely related to poxviruses and represent a third order within the class Pokkesviricetes 8 . They contain large linear genomes that include genes linked to multilayered icosahedral capsids only observed in asfuviruses. The widespread occurrence of egovirus genes in genomes of metamonads (with signal particularly enriched among Trichomonas and Tritrichomonas ), and their co-existence in human fecal samples as demonstrated by our metagenomic survey point towards a preferential infection of unicellular eukaryotes known to prevail, often as symbionts or pathogens, in the gut of vertebrates worldwide 9 . Notably, the numerous Egovirales genes found throughout Trichomonas vaginalis genomes (>3% of their gene pools) designate this prominent sexually transmitted human pathogen as a likely vector to the spread of egoviruses. Notably, one egovirus clade is human-specific, evolutionarily constrained, and spread across continents, demonstrating a long-term association with the human population at a global scale. Egoviruses represent the only diverse, widespread, and abundant group of double-stranded DNA viruses infecting eukaryotes in the digestive system of vertebrates, with implications for human health, capsid evolution and the origin of poxviruses.