Ancient Gene Capture and Recent Gene Loss Shape the Evolution of Orthopoxvirus-Host Interaction Genes

The survival of viruses depends on their ability to resist host defenses and, of all animal virus families, the poxviruses have the most antidefense genes. Orthopoxviruses (ORPV), a genus within the subfamily Chordopoxvirinae, infect diverse mammals and include one of the most devastating human pathogens, the now eradicated smallpox virus. ORPV encode ∼200 genes, of which roughly half are directly involved in virus genome replication and expression as well as virion morphogenesis. The remaining ∼100 "accessory" genes are responsible for virus-host interactions, particularly counter-defense of innate immunity. Complete sequences are currently available for several hundred ORPV genomes isolated from a variety of mammalian hosts, providing a rich resource for comparative genomics and reconstruction of ORPV evolution. To identify the provenance and evolutionary trends of the ORPV accessory genes, we constructed clusters including the orthologs of these genes from all chordopoxviruses. Most of the accessory genes were captured in three major waves early in chordopoxvirus evolution, prior to the divergence of ORPV and the sister genus Centapoxvirus from their common ancestor. The capture of these genes from the host was followed by extensive gene duplication, yielding several paralogous gene families. In addition, nine genes were gained during the evolution of ORPV themselves. In contrast, nearly every accessory gene was lost, some on multiple, independent occasions in numerous lineages of ORPV, so that no ORPV retains them all. A variety of functional interactions could be inferred from examination of pairs of ORPV accessory genes that were either often or rarely lost concurrently. IMPORTANCE Orthopoxviruses (ORPV) include smallpox (variola) virus, one of the most devastating human pathogens, and vaccinia virus, comprising the vaccine used for smallpox eradication. Among roughly 200 ORPV genes, about half are essential for genome replication and expression as well as virion morphogenesis, whereas the remaining half consists of accessory genes counteracting the host immune response. We reannotated the accessory genes of ORPV, predicting the functions of uncharacterized genes, and reconstructed the history of their gain and loss during the evolution of ORPV. Most of the accessory genes were acquired in three major waves antedating the origin of ORPV from chordopoxviruses. The evolution of ORPV themselves was dominated by gene loss, with numerous genes lost at the base of each major group of ORPV. Examination of pairs of ORPV accessory genes that were either often or rarely lost concurrently during ORPV evolution allows prediction of different types of functional interactions.