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

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; ... (2017). Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2. Current Biology, 27(11), 1573-1584.e6. Cell Press 10.1016/j.cub.2017.04.057

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Radiology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Drögemüller, Michaela; Lang, Johann and Leeb, Tosso

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

0960-9822

Publisher:

Cell Press

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

11 Sep 2017 10:43

Last Modified:

13 Jun 2018 11:11

Publisher DOI:

10.1016/j.cub.2017.04.057

PubMed ID:

28552356

Uncontrolled Keywords:

GWAS QTL SMOC2 brachycephaly craniofacial dog morphology retrotransposon selection whole-genome sequencing

BORIS DOI:

10.7892/boris.101165

URI:

https://boris.unibe.ch/id/eprint/101165

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