Genomic diversity and lymphoma predisposition in bullmastiffs

Abstract

Lymphoma, cancer of the lymphocytes, is one of the most common malignancies seen in dogs. Studies have reported a high incidence of lymphoma in particular breeds suggesting a genetic component to the disease. The aim of this thesis was to investigate genetic factors influencing lymphoma predisposition in Bullmastiffs, one of the most at risk breeds, and assess the level of genetic diversity in the breed. Analysis of gene expression data from resting and stimulated lymphocytes in dogs characterized genes, and potential biomarkers, involved in the early response of T-cells to activation in dogs. Genealogical and molecular methods were used to assess the level of diversity in the Bullmastiff population. The small effective population size, popular sire use and presence of subpopulations highlight the need to maintain diversity and monitor use of breeding individuals. The application of NetView, a population analysis pipeline, in dogs was also trialed in German shepherd dogs, validating the pipelines ability to provide a more easily interpretable visualisation of the fine scale population structure. A genome-wide association analysis and fine-scale mapping detected an association between a 1.2Mb region on CFA13 containing five risk haplotypes and four candidate genes (MYC, miR-1204, miR-1205 and miR-1206) and early onset lymphoma in Bullmastiffs. A difference in haplotype frequency and homozygosity across two risk haplotypes was identified between high and low risk breeds, highlighting these two regions as candidates. Additional sources of variation in the Bullmastiff were identified from genotype and whole genome sequence data using copy number variant detection and variant discovery algorithms. Together this information has expanded understanding of the genomic factors influencing lymphoma risk in dogs and may be used by breeders to develop breeding strategies to reduce the incidence of lymphoma in the Bullmastiff population whilst maintaining diversity.