POSTER ABSTRACTS
the robustness and scalability of our prior work by genotyping full-length canine MHC genes in a large cohort of canids. We conducted long-range sequencing of three class II (DLA-DQA1, DLA-DQB1, DLA-DRB1) and four class I (DLA-12, DLA-64, DLA-79, DLA-88) genes in 95 canids. Haplotype phasing was achieved at the locus-level and concordance with traditional Sanger-based genotyping was assessed. In addition to resolving haplotypes in traditionally under-investigated loci, the predicted functional impact of variants observed outside of the polymorphic exons was interrogated. Our results demonstrate the feasibility and economic viability of genotyping the canine MHC at a larger scale than previously attempted using long-range sequencing of the entire loci. Furthermore, our containerized and publicly available pipeline enables more robust analyses between MHC haplotypes and autoimmune disease in an automated and scalable fashion. #25 Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs Jonas Donner1 , Jamie Freyer2, Stephen Davison3, Heidi Anderson1, Matthew Blades3, Leena Honkanen1, Laura Inman2, Casey A. Brookhart-Knox2, Annette Louviere2, Oliver P Forman3, Rebecca Chodroff Foran2 jonas.donner@kinship.co 1Wisdom Panel Research Team, Wisdom Panel, Kinship, Helsinki, Finland, 2Wisdom Panel Research Team, Wisdom Panel, Kinship, Portland, OR, USA, 3Wisdom Panel Research Team, Wisdom Panel, Kinship, Leicestershire, UK Hundreds of Mendelian disease variants have been characterized in dogs to date, and commer- cial screening is being offered for most of them worldwide. There typically remains a paucity of information regarding the broader population frequency of newly discovered variants, as well as uncertainty regarding their functional and clinical impact on additional genomic ancestry back- grounds beyond the discovery breed. Panel screening of disease variants in direct-to-consumer and veterinary clinic settings provides an opportunity to establish large-scale cohorts with both genotype and phenotype data available to address open questions related to variant prevalence, dis- tribution, and relevance. We screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of more than three million dogs; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries and territories) for 250 genetic disease-associated variants. Electronic medical records were available for 43.5% of the genotyped dogs, enabling follow up on the clinical impact of variants. We provide frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-linked variant. We provide evidence of full penetrance of several variants on diverse breed ancestry backgrounds, and plausible evidence for the clinical significance of several variants across a variety of additional breeds. We further assess genome-wide heterozygosity levels in over 100 breeds and show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease load. This data has the potential to guide discussions on disease variant and genetic test relevance by breed.
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