PRESENTATION ABSTRACTS
To gain more insights into the genetic bases of HS, we investigated somatic mutations through whole exome sequencing of 38 tumour and matching control paired samples in three predisposed breeds. We performed a comprehensive somatic analysis based on state-of-the-art bioinformatic tools (Mutect2 and GATK_CNV), using conservative criteria to identify mutations, short InDels and Copy Number Variations. We confirmed the importance of the MAPK pathway in HS development and we demonstrated the sensitivity of 13 HS cell lines to drug targeting this pathway. Finally, we showed that these somatic mutations could be use for an earlier diagnosis of HS. In this study, we showed the strengths of the dog model with breed predisposition to identify pathways involved in HS and its subtypes that lead to advances in translational medicine both benefiting to dogs and humans. #12 A common canine loss-of-function variant in MC3R delays puberty and reduces both body weight and adiposity Alyce McClellan 1 , Natalie Wallis 1 , Eloise Cross 2 , Jacek Mokrosinski 2 , Sadaf Farooqi 2 , Eleanor Raffan 1 er311@cam.ac.uk 1 Department of Physiology Development and Neuroscience, University of Cambridge, UK 2 Wellcome-MRC Institute of Metabolic Science, University of Cambridge, UK Melanocortin signalling has a central role in energy homeostasis. Melanocortin 4 receptors (MC4R) regulate eating behaviour and energy expenditure. Melanocortin 3 receptor (MC3R) is involved in disposition of energy to lean mass, growth and reproduction with damaging variants reducing/ delaying all three. However, there is uncertainty about its role in obesity due to low population frequency. In dogs, population bottlenecks mean some disease variants occur at high frequency within breeds, including the variant MC3R p.M320I. We capitalised on this to further elucidate MC3R’s role in energy balance. In vitro, we showed MC3R p.M320I severely impairs receptor signalling. It occurs frequently in 26 dog breeds; Labrador retrievers, which have minor allele frequency 48%, were further analysed. Adiposity was assessed using body condition score (BCS), an ordinal 9-point scale of adiposity. The variant was associated with lower BCS (p=0.001, effect size (β)= -0.21) and body weight (p=0.00037, β= -1.2kg) but has no effect on food motivation. The onset of puberty in female Labradors was delayed with first pro-oestrus occurring 1 month later per copy of p.M320I from the wildtype mean of 9 months (p=0.01, β= 1.07 months). In conclusion, Labradors homozygous for MC3R p.M320I have reduced adiposity and weight and delayed female puberty which means we have identified a major modifier of these important physi- ological variables. This supports data from other species about MC3R role in controlling disposition of energy to growth and reproduction. Notably, our data clarifies previously contradictory evidence from mice and men by showing loss of MC3R function does not increase adiposity.
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