GENETIC MAPPING OF NOVEL LOCI AFFECTING CLINICAL PHENOTYPES OF THE DOMESTIC DOG AND CAT
White, Michelle Elizabeth
Domestic dogs and cats present a unique opportunity for research in precision medicine: they receive comparable medical surveillance, share our environment, and have similar resources available for genetic analysis. The complete blood count (CBC) and clinical chemistry panel (CCP) are routine for screening and diagnosing disease in both human and veterinary medicine. Variations in these parameters are known to have a strong heritability component in humans, mice, dogs and cats. Using a GWAS of 353 dogs of various breeds and mixed breeds, we detected nine significant QTL for blood phenotypes. One, an allele on chromosome 13 associated with decreased alanine aminotransferase activity, may have implications for screening for hepatic injury and thus provides an opportunity for precision medicine with the use of genotype to personalize reference intervals by patient when interpreting diagnostic blood values. In a similar GWAS of 146 cats from both pet and feral populations, two loci achieved significance for association with mean corpuscular hemoglobin concentration (MCHC) and alkaline phosphatase activity. An additional GWAS was performed to detect expression quantitative trait loci (eQTL). We found hundreds of significant eQTL in 129 cats, with affected genes enriched for gene ontology categories of binding and protein binding, consistent with the regulation of gene expression using transcription factors. Precision medicine is also important for targeting cancer treatments based on specific tumor mutations. We identified variants in 71 matched tumor-normal samples from dogs with canine lymphoma and associated them with clinical outcomes. The gene FBXW7 was mutated in tumors of 13% of dogs, and these dogs had significantly shorter survival time. With validation, genotyping dogs for FBXW7 mutations could help make treatment decisions and better inform prognosis for these dogs while simultaneously allowing them to act as translational models for human lymphoma for which FBXW7 mutations are also common. We have detected several clinically actionable genetic variants for precision medicine in the dog and cat. The phenotypes associated with these variants are all of significance in human medicine, making our results relevant for both veterinary and translational applications.
Genetics; Canine genomics; Canine lymphoma; Feline genomics; Personalized medicine; Precision medicine; Translational medicine; Translation studies; Medicine
Boyko, Adam R.
Schimenti, John C.; Altier, Craig; Danko, Charles G.
Biomedical and Biological Sciences
Ph.D., Biomedical and Biological Sciences
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International