ICCFGG 2022
#21 A TUBA1B Retrogene Insertion is associated with dwarfism in Great Pyrenees dogs KM Minor 1 , JR Mickelson 1 , S Cook 2 , and KJ Ekenstedt 2 kje0003@purdue.edu 1 Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Minneso- ta, St. Paul, MN, USA, 2 Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA Dwarfism in Great Pyrenees dogs is a heritable recessive chondrodysplastic disorder in which radiographic abnormalities, restricted to the metaphyses of long bones and vertebrae, result in a mature dog half the height of a non-dwarf Great Pyrenees. Sporadic cases of dwarf Great Pyrenees are also deaf, and infertility has been noted for some cases. Here we report a genome-wide association analysis accompanied by whole genome sequencing that identified a TUBA1B retrogene insertion (parent gene located on canine chromosome 27) into the RABL3 gene on canine chromosome 33. This retrogene insertion is perfectly associated with dwarfism in the breed. RNAseq performed with peripheral blood RNA indicates splicing of RABL3 is likely significantly altered, and experiments are ongoing to further evaluate TUBA1B expression; these results may provide a link between the genotype and phenotype. A genetic mechanism for chondrodysplasia and dwarfism resulting from either a TUBA1B retrogene or RABL3 function has not yet been reported in any species. #22 The Canine Diabetes Genetics Partnership: whole genome and targeted sequencing of dog breeds at high and low risk of diabetes mellitus Marsha D. Wallace 1,2 , A. Denyer 1 , S. Falcone 2 , C. Mellersh 3 , K. Hughes 4 , D. Xia 1 , A. Psifidi 1 , E. Schofield 3 , S. Ricketts 3 , P.J. Watson 4 , I.K. Ramsey 4 , L.J. Kennedy 5 , G. Williams 6 , N. Zimmerman 6 , M.E. Herrtage 4 , C.A. O’Callaghan 2 , B. Catchpole 1 , L.J. Davison 1,2 mwallace@well.ox.ac.uk 1 Royal Veterinary College, University of London, UK; 2 Wellcome Centre for Human Genetics, University of Oxford, UK; 3 Kennel Club Genetics Centre, University of Cambridge, UK; 4 Department of Veterinary Medicine, University of Cambridge, UK; 5 School of Veterinary Medicine, University of Glasgow, UK; 6 University of Manchester, UK; 7 Dechra Veterinary Products. Diabetes mellitus affects 1 in 300 dogs and is fatal without insulin therapy. As an unintention- al result of selective breeding, diabetes risk is variable among breeds e.g. high risk Samoyed, moderate risk Labrador retriever, low risk Boxer. The Canine Diabetes Genetics Partnership has undertaken breed-comparative whole genome sequencing (WGS) to discover genetic variants contributing to differential diabetes risk in Samoyeds, Labrador retrievers, and Boxers, using samples from the UK Canine Diabetes Database and Archive. Discordance analysis identified >3.5 million genetic variants differing among these breeds. An evidence-based bioinformatics workflow was developed to rank and prioritize candidate variants based on within-breed and across-breed diabetes association statistics, allele frequencies in canine databases, and gene annotations. Annotations included incorporation of human GWAS data, pathway information, gene ontology, UK Biobank data, and RefSeq gene summaries to weight plausible roles in diabetes pathogenesis. Targeted follow-up sequencing of several thousand prioritized variants was performed in the same
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