Endogenous retroviruses [ERVs] are relicts of infectious retroviruses that have infected and integrated the viral genome into a germ cell, essentially creating a new host gene. The history of retrovirus epizootics in a population is therefore reflected by ERVs. The genomes of all mammalian species contain ERVs but most of these derive from retroviral colonization events that occurred in the ancient history of a contemporary species. We identified a new family of ERV in mule deer, CrERV, which has repeatedly colonized the host genome over the last 200,000 years up to present time and retains transcriptional activity in all animals. While ERVs clearly have a fundamental role in host genome evolution and contemporary phenotypes, they also have an enigmatic association with disease. It is particularly intriguing that an active ERV is present in mule deer because the prion disease - chronic wasting disease [CWD]- occurs naturally in this species; elevated retroviral transcripts have been detected in experimental CWD infection in several species. The aim of our research is to determine if the CrERV colonization histories differ in mule deer from states with endemic (Wyoming) and absent (Montana and Oregon) CWD because differences in the distribution of full length retroviruses among deer genomes can affect genome structure and function. We have developed new empirical, computational, and statistical tools and a draft of the mule deer genome to comprehensively assess the genomic location and estimate the population frequency and evolutionary history of each CrERV in all sampled animals. Our results demonstrate that mule deer in Montana and Oregon share a similar CrERV colonization history that is very different from that experienced in Wyoming deer. These data suggest that the genomic landscape shaped in part by an endogenous retrovirus may contribute to the natural susceptibility or resistance of mule deer to CWD.