Date of Award

5-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics and Biochemistry

Committee Chair/Advisor

Dr. Leigh Anne Clark

Committee Member

Dr. Miriam Konkel

Committee Member

Dr. Trudy Mackay

Committee Member

Dr. Margaret Ptacek

Abstract

Dogs provide an excellent model for human hereditary disease research; thus, the development of canine genomic tools has been prioritized in recent years. Today, SNP arrays, multiple genome assemblies, and multi-breed reference panels containing whole genome resequencing (WGS) data from hundreds of canids are available to facilitate genome-wide genotyping in the dog. Herein, a variety of genome-wide techniques are employed to identify the genetic factors underlying congenital idiopathic megaesophagus (CIM) in two breeds, German shepherd dogs (GSDs) and Great Danes, and startle disease in Spanish greyhounds.

CIM is a complex canine esophageal motility disorder characterized by ineffective peristalsis and esophageal dilation, which prevent normal food transport into the stomach. In the GSD, we discovered a sex bias in CIM independent of body size wherein males are twice as likely to be affected as females, suggesting that females may possess protective endogenous factors. Using genome-wide SNP genotypes, we conducted a genome-wide association study (GWAS) for CIM and uncovered a major locus on chromosome 12. WGS data revealed that the associated region harbors a 33 bp variable number tandem repeat (VNTR) in MCHR2. Sex and the VNTR are the first genetic factors identified in CIM, and, together, predict disease state in the GSD with greater than 75% accuracy.

In Great Danes, we employed a novel phenotype mapping strategy to identify variants underlying CIM. We generated low-pass WGS data for affected and healthy individuals, imputed to whole genome level, and validated the utility of our data set for GWAS by mapping loci known to cause coat colors/patterns. A GWAS for CIM identified a major locus on chromosome 1 comprised of variants best associated with the disorder in Great Danes.

Startle disease is a neurological disorder wherein glycinergic neurotransmission is dysfunctional, causing an exaggerated startle reflex. We characterized the second dog model for startle disease in a family of Spanish greyhounds, and, through WGS, identified a frameshift mutation predicted to truncate the presynaptic glycine transporter, SLC6A5. Genotyping of a larger cohort indicated that the mutation is private to the family, and a genetic test is now available to prevent dissemination of the pathogenic allele.

Available for download on Friday, May 12, 2023

Included in

Genetics Commons

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