Indeed much of the variation between laboratory mouse strains is thought to be due to variation in the number and location of ERVs they possess 5. In addition, the consequences of retroviral germline infection, where proviruses in the germline (particularly gammaretroviruses) are subject to Mendelian inheritance and are potentially active in every cell of an individual, have been extensively studied in inbred and wild-derived laboratory mouse strains 5. The negative effects of exogenous retroviral infection of somatic cells have been well characterised 3, 4. The proviruses will also undergo mutations which can ultimately render them inactive. The ongoing conflict between virus and host (sometimes termed a retroviral “invasion” of the host germline), unfolds over millions of years, during which time proviruses can frequently reintegrate in the host genome causing further germline mutations (de facto natural mutagenesis). This makes the transition from a newly endogenised, active retrovirus to a genomically fixed ERV a complex and dynamic evolutionary process. Retroviruses are insertional mutagens, affecting the host in multiple potentially deleterious ways, including the disruption or alteration of gene expression 2. Since most mammalian ERVs derive from germline infections that occurred millions of years ago, the early and most critical stages of host–pathogen accommodation, including the immediate effects on host health, remain unclear. They originate when exogenous retroviruses infect the host germline and are subsequently inherited by offspring as endogenous retroviruses (ERVs), some of which eventually reach fixation. Retrovirus-like elements are abundant in vertebrate genomes 1, comprising 8% of the human genome. Our data provide insights into the tremendous mutational load suffered by the host during active retroviral germline invasion, a process repeatedly experienced and overcome during the evolution of vertebrate lineages. We detect dysregulation of genes containing IS and identify a highly-expressed transduced oncogene. We find that tumours accumulate novel IS, with proximate genes over-represented for cancer associations. We characterise KoRV integration sites (IS) in tumour and healthy tissues from 10 koalas, detecting 1002 unique IS, with hotspots of integration occurring in the vicinity of known cancer genes. Here we examine retroviral endogenisation during its earliest stages in the koala ( Phascolarctos cinereus), a species undergoing germline invasion by koala retrovirus (KoRV) and affected by high cancer prevalence. However, millions of years of evolution obscure many of the immediate repercussions of retroviral endogenisation on host health. Repeated retroviral infections of vertebrate germlines have made endogenous retroviruses ubiquitous features of mammalian genomes.
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