ICCFGG 2022
#10 Genetic control of gene expression for trait mapping in the dog Reuben M. Buckley , D. Thad Whitaker, and Elaine A. Ostrander reuben.buckley@nih.gov Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA The translation of dog genotype-phenotype associations into humans can be limited by incorrectly identifying target genes in association analyses. To address this limitation, we have begun to move beyond genome-wide association studies (GWAS) and instead use transcriptomics to untangle the complex circuitry mediating genotype-phenotype relationships. Here we present the develop- ment of a domestic dog expression quantitative trait loci (eQTL) dataset. We used bulk RNA-seq to measure gene expression in the testes of 47 neutered dogs. In addition, we used single cell expression profiles from human testes to perform bulk RNA-seq deconvolution. To determine the suitability of using the dog for eQTL analysis we characterized the impact of body size alleles at the well characterized IGF1 locus on the expression of IGF1 itself. Previous analyses have demonstrat- ed differences in IGF1 levels in serum associate with the body-size genotypes, however the effect has not been demonstrated using bulk RNA-seq data. Our results show that by correcting for cell type heterogeneity, IGF1 gene expression patters replicates observations in serum. Next, we used a permutation approach to perform eQTL analysis across our entire dataset and identified eight significant eGene and eQTL pairs. For all significant associations there was no bias between dog breed, predicted developmental stage, and dog age, indicating the robustness of our methods to detect eQTLs despite changes in testis gene expression throughout development. As this resource matures, it will facilitate the accurate detection of target genes in GWAS and provide a framework for comparing genetic architecture across species. #11 Genomic Characterization of somatic alterations in canine Histiocytic Sarcoma leads to the development of therapeutic options and diagnostic tools Benoit Hédan 1 , Stéphanie Mottier 1 , Armel Houel 1 , Jérôme Alexandre Denis 2 , Edouard Cadieu 1 , Jérôme Abadie 3 , Nadine Botherel 1 , Catherine André 1 , Thomas Derrien 1 benoit.hedan@univ-rennes1.fr 1 Institut Génétique et Développement de Rennes, CNRS-UMR6290, Université Rennes 1 , Rennes, France, 2 Sorbonne Université ; Service de Biochimie Endocrinienne et Oncologique, UF Oncobiologie Cellulaire et Moléculaire, APHP, Hôpitaux Universitaires Pitié Salpêtrière, Paris, France, 3 ONIRIS, AMaROC, Ecole Nationale Vétérinaire, Agroalimentaire et de l’Alimentation Nantes Atlantique, Nantes, France Dog is a unique and original model to decipher the genetic mechanisms involved in cancer. We focused on canine histiocytic sarcoma (HS) which presents striking breed specificity: HS mainly affects Bernese Mountain dogs, Rottweilers and Retrievers, while in Humans, HS is extremely rare and poorly understood. Though RNAseq of 3 cases, we identified in canine and human HS the same mutations in PTPN11, a gene belonging to the MAPK pathway. Moreover, the particular clinical presentation of HS with respect to canine breed predispositions allowed us to highlight that PTPN11 mutations are driver events for a specific subtype of human and canine HS: the visceral disseminated form (Hedan et al. 2020).
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