A goal of our research is to characterize genetic organization in the domestic cat and to develop genomic resources facilitating and establishing, Felis catus, as a useful animal model contributing to our understanding of human hereditary disease analogues, neoplasia, genetic factors associated with host response to infectious disease and mammalian genome evolution. In order to map and characterize genes associated with inherited pathologies in the domestic cat which mirror inherited human conditions we have focused on increasing microsatellite density in the genetic map of the cat to increase resolution for mapping of genes associated with inherited and infectious disease.We are completing our third and last genetic linkage map of the domestic cat. The linkage map is being generated in a large multi-generational domestic cat pedigree maintained by the Nestle-Purina Pet Care Company (n=483 informative meioses). Previous first and second generation maps of the cat were generated in an interspecies pedigree between the domestic cat and the Asian leopard cat. Whereas, this gave us the opportunity to map and integrate Type I (coding loci) and Type II (polymorphic microsatellites) loci, the current map will allow us to address whether the hybrid nature of the previous pedigree had an impact on recombination values. The third generation map is composed entirely of microsatellite loci. Approximately 625 loci will be ordered in the current map. Linkage groups have been assembled and ordering of loci within the linkage groups is currently in progress. The current map demonstrates considerable improvement over previous maps. All of the cats' 18 autosomes are now spanned by single linkage groups; marker density is more than doubled, providing a 5 cM resolution. There is also greatly expanded cover of the X chromosome, with some 75 microsatellite loci. The pseudoautosomal (PAR) and nonPAR regions of the X-chromosome are spanned by separate linkage groups. Approximately 85% of the markers contained in the genetic linkage map are also mapped in the most current radiation hybrid (RH) map of the cat. This provides critical reference and integration with coding (Type I) loci. Whereas the third generation map is composed entirely of microsatellite loci, the access to extended genomic regions flanking the repeat motif, enabled by the recent cat 2X whole genome sequence, and the whole genome sequence (WGS) of the dog have enabled us to obtain identifiable orthologues in the canine and human genome sequences for over 95% of the microsatellites. Essentially, practically every microsatellite acts as a """"""""virtual"""""""" Type 1 locus. Combined with the cat RH map, these genomic tools provide us with the comparative reference to other mammalian genomes which is critical for linkage and association mapping.Mapping and Characterization of Genes Associated with Inherited Disease Pathology in Cat Pedigrees with Homology to Human Hereditary Disease:1. Autosomal recessive retinitis pigmentosa (arRP): A genetically and clinically heterogeneous and progressive degenerative disorder of the retina, leading usually to severe visual handicap in adulthood. Our collaborator, Dr. Kristina Narfstrom at the Missouri College of Veterinary Medicine, maintains a colony of Abyssinian cats with progressive retinal atrophy (rdAc), a slowly progressive degeneration process of the rod and cone systems with similarities to classical human RP. The Abyssinian cat has the potential of becoming a new and important animal model in the study of hereditary visual cell disease processes. Over 32 candidate genes or genomic regions linked to human RP were genotyped in the rdAc pedigree with highly polymorphic microsatellites and failed to detect linkage to a disease locus. Subsequently, we conducted a full genome screen of the rdAc pedigree with randomly selected polymorphic microsatellites. Linkage was established to a genomic region with a high LOD score (>15) at a theta of 0.
