Linkage Disequilibrium and Recombination in the Domestic Cat (Felis silvestris catus): Applications to Genome-wide Association and Linkage Studies

The unique evolutionary and breeding histories of domestic cats, as well as cats' hereditary and infectious diseases that resemble those in humans make it an interesting subject for genetic studies. This dissertation investigates linkage disequilibrium (LD) and recombination in the domestic cat, Felis silvestris catus, applying these concepts to the localization of an inherited form of blindness. The dissertation is composed of three independent studies. The first study explored the extent of LD within 18 breeds and two random bred populations of cats. Using single nucleotide polymorphisms (SNPs) genotyped via a custom illumina GoldenGate Assay (1536 loci over 10 regions), LD was estimated by (i) by calculating the squared correlation coefficient (r2) between the SNPs in each region and within each population independently, (ii) by modeling the decay of all pair-wise estimates as a function of distance, and (iii) by using the point of 50% decay of r2 to compare the extent of LD between breeds. The longest extent of LD was observed in the Burmese breed (~380 kb) and the shortest extent of LD was found in the Siberian breed (~17 kb). The LD of cat breeds largely reflected the breeds' population history and breeding strategies. The second study investigated population recombination rate and aimed to identify and characterize recombination hotspots in selected regions. The genotype data for 701 SNP loci in a single random bred population were used for recombination inference using the program inferRho. The ten regions included in the analysis exhibited variable population recombination rates and four decisive recombination hotspots were identified on cat chromosomes A2, D1, and E2 regions. Fifty-two spots were identified as "warm-spots", which are areas with lower recombination intensity. No correlation was detected between the GC content and the locality of recombination spots. The hot and warm-spots were found to enclose L2 LINE elements and MIR and tRNA-Lys SINE elements in agreement with hotspots found in other mammals. The third study utilized LD and recombination based methods to localize the chromosome region of a hereditary eye condition characterized by an autosomal recessive retinal degeneration specific to Persian cats. A multi-generation pedigree segregating for the disease was genotyped using a 63K SNP array and analyzed via genome-wide linkage and association analyses. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (LOD ≈ 14) with complete linkage on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently showed significant associations within the same region on chromosome E1. Using haplotype analysis, a ~1.3 Mb region was identified to be highly associated for progressive retinal atrophy in Persian cats. Several genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.