Genetics and genomics of myxomatous mitral valve disease in dogs

• Main Author: O'Brien, Mitchell John
• Format: Thesis
• Language: English
• Published: The University of Sydney 2022
• Subjects: genetics; genomics; canine; dog; complex trait; disease; Cavalier; Canis lupus
• Online Access: https://hdl.handle.net/2123/27483

As a result of its unique evolutionary history, the modern dog (Canis lupus familiaris) has a simplified genetic landscape that makes it a strong model for investigating the genetic basis of breed specific traits and diseases. This thesis applies genomic methodologies to a complex disease, myxomatous mitral valve disease (MMVD), with the primary aim of improving our understanding of its genetic basis. MMVD is an acquired disease of the dog that causes valvular dysfunction and may result in the development of congestive heart failure (CHF). In dogs, MMVD is the most frequent cause of cardiovascular morbidity and mortality, and despite a thorough understanding of the clinical aspects, the genetic mechanisms that drive disease onset and progression are uncertain. Current MMVD research supports a polygenic mode of inheritance and exemplifies the difficulty in identifying disease risk variants in complex traits. In this thesis, genomic workflows are used to investigate MMVD in an Australian population of Cavalier King Charles Spaniels (CKCS), a breed disproportionately affected by the trait. I first assessed the strength of MMVD phenotypes for use in comparative genomic studies. Then, through bioinformatic approaches, I investigated the genetic landscape of the disease in this breed. Using genomic tools developed for the dog and a combined approach of objective phenotyping, I was able to thoroughly explore the genetics and genomics of MMVD in the CKCS using different types of genomic analyses. In doing so, I was able to demonstrate the utility of pedigreed breeds in the investigation of complex traits and the versatility of genomic datasets. Throughout this thesis MMVD associated loci, candidate genes and putative functional variants are reported.