Canine Population Structure: Assessment and Impact of Intra-Breed Stratification on SNP-Based Association Studies

BackgroundIn canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions.Methodology/Principal FindingsIn this report, we address the magnitude and impact of genetic diversity among common breeds sampled in the U.S. and Europe. The breeds selected, including the Rottweiler, Bernese mountain dog, flat-coated retriever, and golden retriever, share susceptibility to a class of soft tissue cancers typified by malignant histiocytosis in the Bernese mountain dog. We genotyped 722 SNPs at four unlinked loci (between 95 and 271 per locus) on canine chromosome 1 (CFA1). We showed that each population is characterized by distinct genetic diversity that can be correlated with breed history. When the breed studied has a reduced intra-breed diversity, the combination of dogs from international locations does not increase the rate of false positives and potentially increases the power of association studies. However, over-sampling cases from one geographic location is more likely to lead to false positive results in breeds with significant genetic diversity.ConclusionsThese data provide new guidelines for association studies using purebred dogs that take into account population structure.背景 在犬类遗传学领域，群体结构对全基因组关联研究的影响通常通过从单一犬种（通常来自同一国家或地理区域）中选取数量大致相等的病例组与对照组样本开展分析。然而，提升遗传学研究效力的一种可行方案是选取同一犬种但不同地理区域的个体，其核心假设为独立减数分裂事件会以不同方式缩短突变位点周围的推定祖先单倍型。不过，目前对于来自不同地理区域的同一犬种犬只之间的遗传变异，相关研究仍较为匮乏。 材料与方法/主要结果 本研究针对美国与欧洲采集的常见犬种群体间遗传多样性的程度及其影响展开探究。本次选取的研究对象包括罗威纳犬、伯恩山犬、平毛寻回犬以及金毛寻回犬，上述犬种均对一类以伯恩山犬恶性组织细胞增生症为典型代表的软组织癌症具有易感性。我们对犬1号染色体（CFA1）上4个不连锁位点的722个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）位点进行了基因分型，每个位点包含95至271个SNP。研究结果显示，各群体均具备独特的遗传多样性特征，且该特征可与对应犬种的繁育历史建立关联。当所研究的犬种种内多样性较低时，整合不同地理区域的犬只样本并不会提升假阳性率，反而有可能提升关联研究的效力。但对于遗传多样性较高的犬种，仅过度采样单一地理区域的病例样本则更易引发假阳性结果。 结论 本研究数据为基于纯种犬的全基因组关联研究提供了新的指导原则，该原则充分考虑了群体结构因素。