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Newmarket, United Kingdom

Karlsson E.K.,The Broad Institute of MIT and Harvard | Karlsson E.K.,Harvard University | Sigurdsson S.,The Broad Institute of MIT and Harvard | Sigurdsson S.,Uppsala University | And 31 more authors.
Genome Biology | Year: 2013

Background: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.Results: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.Conclusions: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease. © 2013 Karlsson et al.; licensee BioMed Central Ltd. Source

Ricketts S.L.,Canine Genetics Research Group | Pettitt L.,Canine Genetics Research Group | McLaughlin B.,Canine Genetics Research Group | Jenkins C.A.,Canine Genetics Research Group | Mellersh C.S.,Canine Genetics Research Group
Mammalian Genome | Year: 2015

Hereditary cataract is a common ocular disorder in the purebred dog population and is a leading cause of visual impairment and blindness in dogs. Despite this, little is known to date about the genetics underlying this condition. We have used a genome-wide association study and targeted resequencing approach to identify a novel locus for cataracts in the Australian Shepherd breed of dog, using dogs that are clear of an HSF4 mutation, previously identified as the major susceptibility locus in this breed. Cataract cases were defined as dogs with bilateral posterior cataracts, or bilateral nuclear cataracts. Controls were at least 8 years of age with no evidence of cataracts or other ocular abnormality. Using 15 bilateral posterior polar cataract cases and 68 controls, we identified a genome-wide statistical association for cataracts in the Australian Shepherd on canine chromosome 13 at 46.4 Mb (P value: 1.5 × 10−7). We sequenced the 14.16 Mb associated region in ten Australian Shepherds to search for possible causal variants underlying the association signal and conducted additional fine-mapping of the region by genotyping 28 intronic variants that segregated correctly in our ten sequenced dogs. From this analysis, the strongest associated variants were located in intron 5 of the SCFD2 gene. Further study will require analysis of additional cases and controls and ocular tissue from dogs affected with bilateral cataracts that are free of the HSF4 mutation. © 2015, Springer Science+Business Media New York. Source

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