Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Institute of Marine Research, Bergen, Norway.
Nat Commun. 2024 Aug 29;15(1):7510. doi: 10.1038/s41467-024-51898-2.
The Greying with age phenotype in horses involves loss of hair pigmentation whereas skin pigmentation is not reduced, and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence in Syntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only). Our direct pedigree-based observation of the origin of a G2 allele from a G3 allele by copy number contraction demonstrates the dynamic evolution of this locus and provides the ultimate evidence for causality of the copy number variation of the 4.6 kb intronic sequence.
马的衰老表型涉及毛发色素沉着的丧失，而皮肤色素沉着没有减少，并且易患黑色素瘤。最初报道的致病突变是Syntaxin 17 内含子 4.6kb 序列的重复。Grey 马的灰色化速度差异很大。在这里，我们证明了存在两种不同的 Grey 等位基因，G2 携带重复序列的两个串联拷贝，G3 携带三个。后者是迄今为止最常见的等位基因，可能是由于对明显的白色表型的强烈选择。我们的研究结果揭示了一个显著的剂量效应，即 G3 等位基因与快速灰色化和黑色素瘤高发相关，而 G2 与缓慢灰色化和黑色素瘤低发相关。拷贝数扩张将弱增强子转变为强黑素细胞特异性增强子，这是毛发灰色化（G2 和 G3）和黑色素瘤风险显著升高（仅 G3）的基础。我们通过拷贝数收缩直接基于系谱观察到 G2 等位基因源自 G3 等位基因，证明了该基因座的动态进化，并为 4.6kb 内含子序列拷贝数变异的因果关系提供了最终证据。
