Canine Brachycephaly is Associated with a Retrotransposon-Mediated Missplicing of SMOC2

Thomas Marchant, Edward J Johnson, Lynn McTeir, Craig Johnson, Adam Gow, Tiziana Liuti, Dana Kuehn, Karen L Svenson, Mairead Bermingham, Michaela Drögemüller, Marc Nussbaumer, Megan Davey, David Argyle, Roger M Powell, Sérgio Guilherme, Johann Lang, Gert Ter Haar, Tosso Leeb, Tobias Schwarz, Richard MellanbyDylan Clements, Jeffrey Schoenebeck

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

In morphological terms, “form” is used to describe an object’s shape and size. In dogs, facial form is stunningly diverse. Facial retrusion, the proximodistal shortening of the snout and widening of the hard palate is common to brachycephalic dogs and is a welfare concern, as the incidence of respiratory distress and ocular trauma observed in this class of dogs is highly correlated with their skull form. Progress to identify the molecular underpinnings of facial retrusion is limited with association of a missense mutation in BMP3 among small brachycephalic dogs. Here, we used morphometrics of skull isosurfaces derived from 374 pedigree and mixed breed dogs to dissect the genetics of skull form. Through deconvolution of facial forms, we identified quantitative trait loci that are responsible for canine facial shapes and sizes. Our novel insights include recognition that the FGF4 retrogene insertion, previously associated with appendicular chondrodysplasia, also reduces neurocranium size. Focusing on facial shape, we resolved a quantitative trait locus on canine chromosome 1 to a 188 kb critical interval that encompasses SMOC2. An intronic, transposable element within SMOC2 promotes the utilisation of cryptic splice sites, causing its incorporation into transcripts and drastically reduces SMOC2 gene expression in brachycephalic dogs. SMOC2 disruption affects the facial skeleton in a dose-dependent manner. The size effects of the associated SMOC2 haplotype are profound, accounting for 36% of facial length variation in the dogs we tested. Our data bring new focus to SMOC2 by highlighting its clinical implications in both human and veterinary medicine.
Original languageEnglish
Pages (from-to)1573-1584
Number of pages19
JournalCurrent Biology
Issue number11
Early online date25 May 2017
Publication statusPublished - 5 Jun 2017


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