Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Current biology, 2017-06, Vol.27 (11), p.1573-1584.e6

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 to 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 utilization 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. •A population-based genetics study of dogs that required diagnostic imaging•Resolution of a QTL associated with face length reduction (brachycephaly)•Association of brachycephaly with a retrotransposon that disrupts SMOC2 splicing•The SMOC2 locus explains up to 36% of face length variation in dogs Uncovering the molecular basis of dogs’ vastly diverse skull shapes requires individualized approaches to morphometrics and genotyping. Using data from veterinary referral patients, Marchant et al. shed light on a large effect locus that is responsible for face length reduction (brachycephaly).