Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

Abstract

Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

Inbreeding depression causes reduced fecundity in Golden Retrievers

“…Unfortunately, Golden Retrievers are also overrepresented in neoplasia cases, with more documented mortalities due to cancer than nearly any other breed (Kent et al, 2018;Dobson et al, 2014). And while some genetic variants have been associated with increased risk for certain cancers (Arendt et al, 2015), other major genetic contributors to Golden Retriever lifespan and fitness remain unidentified.…”

Heteroplasmic Mutations and Polymorphisms in the Cyb Gene of Mitochondrial DNA in Canine Mast Cell Tumours

“…In turn, polymorphism in m.14972 in vivo 33: 57-63 (2019) 60 Table III. Polymorphisms in the mitochondrial cytochrome b (Cyb) gene in blood in cases of canine mast cell tumour (dogs was found only in three male dogs (2,31,33) (Table III). Tumour grade-specific polymorphisms according to the classification proposed by Kiupel et al (15) were also noted.…”

“…In our previous and available studies on mitochondrial genomics in dogs, there was no relation between polymorphism and breed susceptibility (14)(15)(16)(17)(18)(19). However, interesting results of molecular analyses of nuclear genes were obtained in Golden Retriever dogs: polymorphisms in the G protein subunit alpha i2 gene (Gnai2) and hyaluronidase genes have been associated with the risk of MCT development (33).…”

The canine era: the rise of a biomedical model

“…) and cancer (Arendt et al . ). Unique population history and breed structure have resulted in a genetic architecture that facilitates the exploration of the genetic basis of simple and complex disorders (Ostrander & Kruglyak ).…”

“…By genotyping cases from Golden Retrievers originating from different populations, distinct chromosomal regions associated with mast cell tumours could be identified (Arendt et al . ). Sequence capture of the different associated regions and the subsequent sequencing identified a SNP in GNAI2 .…”