Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
PLoS One. 2010 Mar 10;5(3):e9632. doi: 10.1371/journal.pone.0009632.
The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.
家犬（Canis familiaris）表现出深刻的表型多样性，是遗传解析简单和复杂特征的理想模式生物。然而，一些最有趣的表型是在特定品种中固定的，因此使用基于经典分离的映射方法对其进行遗传分析就不太可行。我们使用中等密度 SNP 阵列、经过精心挑选的少量动物和品种实施了一种跨品种映射方法，这些动物和品种具有感兴趣的表型，旨在确定负责品种定义特征的遗传变异。在使用三个先前定义的基因座（高尿酸血症、白色斑点和软骨发育不全）进行的概念验证实验中，使用来自多个品种的少量受影响（10-30）和对照（20-60）样本，正确地确定了染色体分配。以狗中最引人注目的形态特征之一：短头颅类型为例，以类似的方式进行了全基因组关联。尽管已经在小鼠和人类中使用基于类似表型的候选基因方法对此特征进行了研究，但使用这种方法仍然难以确定其致病基因。来自九个受影响品种和十三个对照品种的样本在 Cfa1 上确定了短头颅类型的强烈全基因组关联。两个独立的数据集确定了相同的基因组区域。相关区域的相对杂合度水平表明它已受到选择压力的影响，这与其作为品种定义的形态特征一致。对该区域中的其他狗进行基因分型证实了这种关联。迄今为止，犬种的遗传结构主要用于分离特征的全基因组关联。这些结果表明，在强烈选择下的非分离特征同样可以通过使用少量样本进行遗传分析来解决。
