White spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein–Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein–Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date. Using imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region. Our findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics.

中文翻译：

---

全基因组关联分析揭示了与牛白斑相关的 QTL 和候选突变

皮毛上的白色斑点是包括牛和其他哺乳动物在内的各种家养物种的特征。这是荷斯坦-弗里斯兰牛的一个标志，之前的几项研究已经检测到对荷斯坦-弗里斯兰血统动物中白斑有重大影响的基因位点。在这里，我们的目标是通过对牛的这一性状进行迄今为止最大规模的绘图研究，更好地了解白斑病的潜在遗传和分子机制。使用估算的全基因组序列数据，我们对 2973 头混种奶牛和公牛进行了全基因组关联分析。在 6 号和 22 号染色体上发现了高度显着的数量性状基因座 (QTL)，突出显示了公认的毛色基因 KIT 和 MITF 可能是造成这些影响的原因。这些结果与之前的研究基本一致，尽管我们还报告了 2 号染色体上的第三个显着 QTL，该 QTL 似乎是新颖的。该信号紧邻 PAX3 基因，该基因编码一种控制 MITF 表达的已知转录因子，并且是马白斑的致病基因座。对这些基因座的更详细检查揭示了 PAX3 (p.Thr424Met) 中的候选因果突变，以及皮肤中表达的 MITF 转录物内含子 2 的保守元件内的另一个候选突变 (rs209784468)。这些分析还揭示了 6 号染色体位点的机制模糊性，其中高度分散的关联信号表明涉及该区域 KIT 和/或其他基因的多个或多等位基因 QTL。我们的研究结果扩展了之前报道 KIT 可能是白斑致病基因的研究，并报告了 MITF 和 PAX3 基因候选因果突变之间的新关联。这些QTL的影响大小是显着的，并且可用于根据所需的特征来选择具有较深或相反较白皮毛的动物。