During a retroviral infection, a DNA copy of the viral genome is integrated into the host genome as a provirus that contains all the necessary viral genes and regulatory sequences for replication. Thus, infection of germ tissues may lead to a provirus that is transmitted vertically to offspring in Mendelian fashion. This element is referred to as an endogenous retrovirus (ERV) and may, over time, reach a polymorphic state or fixation within a given population. Endogenous retroviral elements have contributed to considerable portions of mammalian genomes and are recognized as mediators of genomic variation and disease. In humans, ERVs are associated with several diseases, including cancer, based on the presence of retrovirus-like particles, RNAs, and enzyme activities in tumor and disease-associated tissues. While the relationship of human ERV expression to disease is not fully understood, it is clear from animal models of human disease that replicative activity and proteins derived from related ERVs are able to affect aberrant cellular proliferation, to drive tumorigenesis, and to incite immune responses. Thus, animal models are uniquely opportune to improve our understanding of connections between ERVs and their effects to the host, and essential to establish links between closely related HERV groups and disease. In the canine, ERV lineages are unstudied and considered to be extinct based on low genomic repeat content and a seeming lack of infectious retroviruses. However, retroviral particles and enzyme activity have been detected in canine lymphomas and canine cell lines support retrovirus replication from several host species including human. The canine ERV ?Fc1? belongs to a recombinant ERV sublineage derived from ERVs most related to the conserved human ERV-W and ERV-Fc elements that are associated with several diseases, whose emergence involved transmission between human/canid ancestors. Our data show the Fc1 group includes many new members with intact ORFs and LTRs, raising the possibility of Fc1 activity and consequences to the host. Such ERVs in new contexts are likely to interfere with genome function and display retained viral functions, raising the possibility for replication capacity. The objective of this proposal is to characterize ERV-Fc1 properties in the canine model to obtain a more complete view of potential role(s) in disease and to human ERVs. We will examine this expanded ERV group by 1) characterizing Fc1 loci from an extended panel of breeds and outbred canines, 2) determining the population distribution and evolution of Fc1 amplification, and 3) determining Fc1 properties and prevalence in disease. This work has significance to advance basic and clinical research fronts in ERV activities, functions, and pathogenicity in the canine model and will present an important variant resource for application to future human genomics comparative analyses.
The role of de-regulated expression of endogenous retroviruses (ERVs) in human disease is only partially understood, illustrating the need for alternative models to obtain a complete view of dynamics and host effects of these elements. In animals, relatives of human ERVs drive spontaneous cancers via replication or expression of oncogenic proteins. We present the first evidence of recent activity from a novel endogenous retroviral lineage in the canine most closely related to a subset of human ERVs that are de-regulated in several diseases and cancers. This research will characterize the activities and disease-association of this lineage as a model to improve our understanding of the basis of closely related human ERVs in disease.
