Closest relatives of poxviruses replicate in the digestive system of humans and animals worldwide

Large and giant double-stranded DNA viruses are diverse and highly prevalent in the environment where they substantially affect the ecology and evolution of eukaryotes ^1–4 . Until now, they were only sporadically found in the digestive system of vertebrates ^5–7 . Here, we present the discovery of a diversified group of DNA viruses with large linear genomes dubbed egoviruses that comprise a putative viral order most closely related to animal-infecting poxviruses. Egoviruses are found worldwide, almost exclusively in the digestive system of humans, livestock and wild animals. One egovirus is human-specific, evolutionarily constrained, and spread across continents, demonstrating a long-term association between egoviruses and the human population. Analysis of eukaryotic homologs of egovirus core genes suggests that these viruses primarily infect Trichostomatia (Ciliates), which play a central role in ruminant digestive processes ⁸ , and Parabasalia (Metamonada), which directly influence animal immunity and gut microbiome ecology ⁹ . Egoviruses also contributed to the genetic makeup of polintons, endogenous viruses that proliferated in genomes of Trichomonas vaginalis ¹⁰ and its close relatives among the Parabasalia . Unlike poxviruses that form brick-shaped virions, egoviruses are predicted to form multilayered icosahedral capsids resembling those of asfuviruses and likely representing the ancestral virion structure. Egoviruses currently are the only known clade of eukaryotic DNA viruses abundant in the animal digestive system. Phylogenomic analysis suggests an evolutionary scenario whereby egovirus-like ancestors of poxviruses infected anaerobic unicellular eukaryotes inside the gut of ancestral animals, before transitioning to animal cell infection which was accompanied by the virion metamorphosis.