ClarkJessica_MSThesis_Final.pdf

With the discovery and treatment of any disease comes the important question of its genetic prevalence. This is especially important for animals under strict breeding control, such as dogs, because this can provide essential information regarding breeding pair decisions. Thus, the focus of this thesis is to investigate the genetic prevalence of three different diseases: 1) Factor VII Deficiency (FVIID), 2) Collie Eye Anomaly (CEA), and 3) Progressive Rod-Cone Degeneration-Progressive Retinal Atrophy (prcd-PRA). Factor VII Deficiency (FVIID) is a clotting disorder observed in both humans and dogs, characterized by impeded function of the Factor VII protein. In dogs, FVIID is caused by a single nucleotide substitution (c.407G>A) in the F7 gene. This mutation, identified in a colony of research Beagles, is also present in dogs with a wide variety of distantly-related breed backgrounds and in mixed-breed dogs, suggesting an ancient, ancestral origin. Given the relatively common presence of this variant, it was hypothesized that this genetic mutation could be contributing to excessive bleeding in canine autopsy cases that could not be attributed to typical causes. DNA from formalin-fixed paraffin-embedded tissues (n = 67 cases) were Sanger sequenced for the FVIID c.407G>A mutation, and all were determined to be homozygous wild-type. Therefore, the tested variant is not associated with the unexplained bleeding in these cases, and it is not a logical diagnostic test to apply to similar cases in the future.

CEA and prcd-PRA are ophthalmic genetic diseases of concern often included in commercial genetic testing panels. A large dataset spanning 15+ years provided by a commercial partner company (OptiGen/Wisdom Panel, Kinship) encompassed dogs tested for the CEA-associated NHEJ1 deletion (n = 33,834 dogs) and the prcd-PRA causal mutation in PRCD (n = 86,667 dogs). Disease trends were observed graphically and analyzed with Chi-square goodness-of-fit testing and regression modeling for disease status and genotype classification. Both diseases had a statistically significant change in genotype frequencies from the first year of data to the last; both diseases also had a negative association between progression of time and overall probability of a dog being disease-positive or a carrier/heterozygous. This suggests that genetic testing results are being incorporated into breeding decisions, although affected dogs were still being identified by the end of this study. Different breeds, AKC groups, FCI groups, genetic clades, and geography were also investigated to determine impact on overall disease trend.