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.

从形态学术语而言，“形态”用于描述物体的外形与尺寸。犬类的面部形态多样性尤为惊人。面部后缩（facial retrusion）指吻部近远端缩短且硬腭加宽，这一特征常见于短头犬（brachycephalic dogs），并会引发动物福利问题——此类犬出现呼吸窘迫与眼部损伤的概率与其颅骨形态高度相关。目前针对面部后缩的分子机制研究进展有限，仅在小型短头犬中发现BMP3基因的错义突变与其存在关联。本研究对374只纯种系谱犬及混血犬的颅骨等值面开展形态测量分析，以解析颅骨形态的遗传基础。通过面部形态的解卷积分析，我们鉴定出了调控犬面部形态与尺寸的数量性状基因座（quantitative trait loci）。本研究的新发现包括：此前被报道与肢体软骨发育不良相关的FGF4逆转录基因插入（FGF4 retrogene insertion），同样可减小神经颅的尺寸。针对面部形态的聚焦分析中，我们将犬1号染色体上的数量性状基因座精细定位至一段包含SMOC2基因的188-kb关键区间内。SMOC2基因内含子中的转座元件会促进隐蔽剪接位点的利用，导致该元件被整合进转录本中，并大幅降低短头犬体内SMOC2基因的表达水平。SMOC2基因的功能缺失会以剂量依赖的方式影响面部骨骼发育。所鉴定的SMOC2单倍型对表型的影响极为显著，在本次受试的犬群中，其可解释36%的面部长度变异。本研究数据为SMOC2基因带来了新的研究焦点，同时凸显了其在人类医学与兽医学中的临床意义。