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.