Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2.
Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2.
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DOI：
10.1016/j.cub.2017.04.057
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发表时间：
2017-06-05
期刊：
影响因子：
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通讯作者：
Schoenebeck JJ
中科院分区：
文献类型：
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作者：
Marchant TW;Johnson EJ;McTeir L;Johnson CI;Gow A;Liuti T;Kuehn D;Svenson K;Bermingham ML;Drögemüller M;Nussbaumer M;Davey MG;Argyle DJ;Powell RM;Guilherme S;Lang J;Ter Haar G;Leeb T;Schwarz T;Mellanby RJ;Clements DN;Schoenebeck JJ
在形态学术语中，“形式”用于描述物体的形状和大小。狗的面部形状是惊人的多样化。面部凹陷、吻部近远侧缩短和硬腭增宽是短头犬常见的，是一个福利问题，因为在此类犬中观察到的呼吸窘迫和眼外伤的发生率与其颅骨形状高度相关。面部修复的分子基础的研究进展仅限于在小型短头犬中BMP 3的错义突变。在这里，我们使用来自374个血统和混合品种的狗的头骨等值面的形态测量学解剖头骨形状的遗传学。通过面部形状的反卷积，我们确定了负责犬类面部形状和大小的数量性状基因座。我们的新见解包括认识到，以前与apapricular软骨发育不良相关的FGF4逆转录基因插入，也减少了脑颅的大小。专注于面部形状，我们解决了犬1号染色体上的一个数量性状基因座的188 kb的关键间隔，包括SMOC2。SMOC2内的内含子转座因子促进隐蔽剪接位点的利用，使其并入转录本，并大幅降低短头犬中的SMOC2基因表达。SMOC2破坏以剂量依赖性方式影响面部骨骼。相关的SMOC2单倍型的大小效应是深刻的，占我们测试的狗的面部长度变化的36%。我们的数据通过强调其在人类和兽医学中的临床意义，为SMOC2带来了新的关注。一项需要诊断成像的基于人群的狗遗传学研究解决一个与脸长减少（短头畸形）相关的QTL短头畸形与破坏SMOC2剪接的逆转录转座子的关联SMOC2基因座解释了狗36%的脸长变异揭示狗巨大多样的头骨形状的分子基础需要个体化的形态测量和基因分型方法。使用兽医转诊患者的数据，Marchant et al.揭示了一个大的影响轨迹，是负责脸长度减少（brachycephaly）。
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).