Massey University Manawatu, Private Bag 11 222, Palmerston North, 4442, New Zealand.
Livestock Improvement Corporation (LIC), 605 Ruakura Rd, Newstead, 3286, New Zealand.
Genet Sel Evol. 2019 Nov 8;51(1):62. doi: 10.1186/s12711-019-0506-2.
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.
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性状。它是荷斯坦-弗里森牛的标志，先前的几项研究已经检测到具有荷斯坦-弗里森牛血统的动物的白色斑点的主要遗传位点。在这里，我们的目的是通过迄今为止对该性状进行的最大规模的牛遗传作图研究，更好地了解白色斑点的潜在遗传和分子机制。
使用已导入的全基因组序列数据，我们在 2973 头杂种奶牛和公牛中进行了全基因组关联分析。在第 6 和第 22 号染色体上发现了高度显著的数量性状位点（QTL），突出了众所周知的毛色基因 KIT 和 MITF 可能是这些效应的原因。这些结果与先前的研究基本一致，尽管我们还报告了第 2 号染色体上的第三个显著 QTL，该 QTL 似乎是新的。该信号紧邻 PAX3 基因映射，该基因编码已知的转录因子，该因子控制 MITF 的表达，并且是马中白色斑点的因果基因。对这些基因座的更详细检查显示了 PAX3 基因中的一个候选因果突变（p.Thr424Met），以及在皮肤中表达的 MITF 转录本的内含子 2 中的保守元件内的另一个候选突变（rs209784468）。这些分析还揭示了 6 号染色体基因座的机制模糊性，其中高度分散的关联信号表明该区域的 KIT 和/或其他基因存在多个或多等位基因 QTL。
我们的研究结果扩展了先前报道 KIT 可能是白色斑点的原因的研究结果，并报告了 MITF 和 PAX3 基因中候选因果突变之间的新关联。这些 QTL 的效应大小相当大，可以根据所需的特征，用于选择毛色更深或更白的动物。
