Domesticated dogs show unparalleled diversity in body size across breeds, but within breeds variation is limited by selective breeding. Many heritable diseases of dogs are found among breeds of similar sizes, suggesting that as in humans, alleles governing growth have pleiotropic effects. Here, we conducted independent genome-wide association studies in the small Shetland Sheepdog breed and discovered a locus on chromosome 9 that is associated with a dental abnormality called maxillary canine-tooth mesioversion (MCM) (P = 1.53 × 10⁻⁷) as well as two body size traits: height (P = 1.67 × 10⁻⁵) and weight (P = 1.16 × 10⁻⁷). Using whole-genome resequencing data, we identified variants in two proximal genes: FTSJ3, encoding an RNA methyltransferase, and GH1, encoding growth hormone. A substitution in FTSJ3 and a splice donor insertion in GH1 are strongly associated with MCM and reduced body size in Shetland Sheepdogs. We demonstrated in vitro that the GH1 variant leads to exon 3 skipping, predicting a mutant protein known to cause human pituitary dwarfism. Statistical modeling, however, indicates that the FTSJ3 variant is the stronger predictor of MCM and that each derived allele reduces body size by about 1 inch and 5 pounds. In a survey of 224 breeds, both FTSJ3 and GH1 variants are frequent among very small “toy” breeds and absent from larger breeds. Our findings indicate that a chromosome 9 locus harboring tightly linked variants in FTSJ3 and GH1 reduces growth in the Shetland Sheepdog and toy breed dogs and confers risk for MCM through vertical pleiotropy.

驯养的犬在各个犬种上均显示出无与伦比的体型多样性，但在犬种内，变异受选择性育种的限制。在大小相似的犬种中发现了许多犬类遗传病，这表明与人类一样，支配生长的等位基因具有多效性效应。在这里，我们对设得兰群岛牧羊犬小品种进行了全基因组关联研究，发现了9号染色体上的一个位点，该位点也与称为上颌犬齿变位（MCM）的牙齿异常有关（P = 1.53×10 ^-7）作为两个身体大小特征：身高（P = 1.67×10 ^-5）和体重（P = 1.16×10 ^-7）。使用全基因组重测序数据，我们确定了两个近端基因的变异：编码RNA甲基转移酶的FTSJ3和编码生长激素的GH1。FTSJ3的取代和GH1的剪接供体插入与MCM和设得兰群岛牧羊犬的体型减小密切相关。我们在体外证明了GH1变异导致外显子3跳跃，预示着已知会导致人垂体矮化的突变蛋白。然而，统计模型表明，FTSJ3变体是MCM的更强预测因子，并且每个衍生的等位基因均使体型减少了约1英寸和5磅。在对224个品种的调查中，FTSJ3和GH1变体在很小的“玩具”品种中很常见，而在较大的品种中却不存在。我们的发现表明，在FTSJ3和GH1中包含紧密连接的变异体的9号染色体位点会降低设得兰群岛牧羊犬和玩具犬的生长，并通过垂直多效性赋予MCM风险。