Data from: Canine brachycephaly is associated with a retrotransposon-mediated missplicing of SMOC2

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.