Variants in GDF5 are associated with human arthritis and decreased height, but the causal mutations are still unknown. We surveyed the Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at ends of developing bones and for normal bone lengths in vivo. Human GROW1 contains a common base-pair change that decreases enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa but common in Eurasia and is found in Neandertals and Denisovans. Our results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations.

中文翻译：

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GDF5增强子的衍生等位基因的古老选择会影响人的生长和骨关节炎的风险。

GDF5的​​变异与人类关节炎和身高下降有关，但因果突变仍然未知。我们调查了Gdf5基因座中转基因小鼠的调控区域，并绘制了精细映射的单独增强子，控制着关节与长骨生长端之间的表达。较大的下游调节区域包含新型生长促进剂（GROW1），这是发育中的骨骼末端正常Gdf5表达和体内正常骨骼长度所必需的。人类GROW1包含一个常见的碱基对变化，该变化会降低增强子活性，并与人类中阳性选择的峰共定位。衍生的等位基因在非洲很少见，但在欧亚大陆很常见，在尼安德特人和丹尼索瓦人中都发现。