Genetic analysis of the domestic cat in the United Kingdom; populations and diseases

The domestic cat is one of the most popular pets in the world. It is estimated that 89–92% of domestic cats in the UK are non-pedigree Domestic shorthair (DSH), Domestic longhair (DLH), or Domestic semi-longhair cats (DSLH). Despite their popularity, little is known of the UK non-pedigree cats’ population structure and disease genetics, with the majority of feline genetics research focussing on pedigree cats. This thesis utilised a custom designed feline biobank and a custom designed single nucleotide variant (SNV) array, to investigate the population genetics of 1,344 UK cats before investigating the genetic associations for three of the most common complex diseases in domestic cats, diabetes mellitus, hyperthyroidism, and chronic kidney disease. Principal components analysis and fastSTRUCTURE analysis verified that the UK’s DSH, DLH, and DSLH cats are random-bred, rather than admixed, mixed breed, or crossbreed cats. In contrast to pedigree cats, the linkage disequilibrium of these random-bred cats was least extensive and decayed rapidly. Homozygosity by descent (HBD) analysis showed the majority of non-pedigree cats had proportionally less of their genome in HBD segments compared to pedigree cats, and that these segments were older. Together, these findings suggest that the DSH, DLH, and DSLH cats should be considered as a population of random-bred cats rather than a crossbreed or pedigree-admixed cat. This thesis undertook one of the largest feline genome wide association studies (GWAS) to date for diabetes mellitus, chronic kidney disease and hyperthyroidism. These studies were conducted using three different tiers of control cats to address the issue of collecting healthy geriatric control cats. GWAS identified significant associations for all three of these complex diseases in domestic cats. In order to provide a comprehensive genetic analysis across UK cat populations this thesis performed whole genome sequencing (WGS) for the rare disease anal atresia (AA) type II in a pedigree British shorthair kitten, a scenario when genotyping using a SNV array would not be considered suitable. This is the first study to examine the genetic associations for AA in a domestic cat. This study utilised a trio based WGS approach where the unaffected queen and sire of the affected cat are also resequenced. After filtering variants in an autosomal recessive manner, comparison with the sequences of three further relatives and the 99 lives cat genome sequence database, 14 variants predicted to have a high impact were identified. Of interest were 2 homozygous deletion variants located within the Lysine-specific methyltransferase 2D (KMT2D) gene. Further analysis for structural variants also identified a 9-base pair insertion in KMT2D. KMT2D is put forward as a candidate gene for AA type II in cats and is supported by evidence of KMT2D association with both syndromic and non-syndromic ano-rectal malformation in humans. Collectively the results of this thesis give a comprehensive look into the genetics of population and disease in both random-bred and pedigree cats in the UK. These results clarify the population structure of the DSH, DLH and DSLH cats in the UK and provide genomic locations for variant discovery in 3 of the most common complex diseases in domestic cats. This thesis has also identified a candidate gene for the rare disease AA, a disease not previously investigated in the domestic cat.