Date of Award

8-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics and Biochemistry

Committee Member

Dr. Leigh Anne Clark, Commmittee Chair

Committee Member

Dr. Miriam Konkel

Committee Member

Dr. Stephen Kresovich

Committee Member

Dr. Margaret Ptacek

Committee Member

Dr. Rajandeep Sekhon

Abstract

The unique population structure of dog breeds, arising from their domestication from gray wolves and subsequent breed formation, and the similarity of their inherited diseases to human disorders make them an ideal comparative genetics model. Herein the genetic basis of three canine muscle diseases, each a model for human disease, is investigated using genome-wide approaches. Nemaline rod myopathy (NM) is one of the most common congenital myopathies in people and is characterized by rod bodies in the muscle fibers, muscle weakness, and reduced muscle tone. We characterized the first large animal model of autosomal recessive NM in a family of American bulldogs and, through a combination of genome-wide SNP profiling and whole exome sequencing, identified a nonsense mutation in NEB. Limb girdle muscular dystrophy (LGMD) affects the hip and shoulder muscles and may cause respiratory and cardiac muscle degeneration. We determined that a muscular dystrophy in a family of Boston terriers is a sarcoglycanopathy, a type of LGMD caused by mutations in one of six sarcoglycan genes, and identified a 2 bp deletion in SGCD through direct whole exome sequencing. Further, an unrelated Boston terrier having LGMD harbors a 19.4 kb deletion, omitting exons 7 and 8 of SGCD. The NEB and SGCD mutations are present only in the affected families. Juvenile dermatomyositis (JDM) is an autoimmune disease with a complex mode of inheritance and an environmental trigger, affecting children ages 2 to 17. In dogs, dermatomyositis (DMS) affects collies and Shetland sheepdogs and causes skin lesions and muscle weakness. We conducted genome-wide association studies in both breeds and identified linkage disequilibrium with SNPs on chromosomes 10 and 31. Through whole genome and transcriptome sequencing, we found mutations in two novel genes, PAN2 (chr10) and MAP3K7CL (chr31). Additionally, we identified an association with a haplotype of the major histocompatibility complex class II genes on chromosome 12, alleles of which are also associated with JDM. When variants at all three loci are considered together, genotypes confer low, moderate, or high risk for DMS, with moderate- and high-risk genotypes explaining 93% of cases.

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