Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk.
Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk.
复制标题
DOI：
10.1038/ng.3911
复制
发表时间：
2017-08
期刊：
影响因子：
30.8
通讯作者：
Kingsley DM
中科院分区：
文献类型：
--
作者：
Capellini TD;Chen H;Cao J;Doxey AC;Kiapour AM;Schoor M;Kingsley DM
GDF5的变异与人类关节炎和身高降低有关，但因果突变仍然未知。我们在转基因小鼠中调查了GDF5的调控区域，并精细绘制了控制关节和长骨生长端表达的单独增强子。一个大的下游调控区含有一种新的生长促进因子（GROW1），这是骨骼发育末端正常GDF5表达和体内正常骨长度所必需的。人类GROW1包含一个共同的碱基对变化，降低增强子活性，并与人类正选择的峰值共定位。这种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身上也有发现。我们的研究表明，在北方环境中，GROW1的一种古老的调节变异被反复选择，过去对生长表型的选择解释了GDF5单倍型的高频率，这种单倍型也增加了许多人群的关节炎易感性。在尼安德特人和现代人中，GDF5基因座上的一个常见调控变异改变了一种生长促进子的功能。
Variants in GDF5 are associated with human arthritis and height reduction, but the causal mutations are still unknown. We surveyed GDF5 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 harbors 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 reduces enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa, but common in Eurasia and found in Neandertals and Denisovans. Our studies 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. One Sentence Summary: A common regulatory variant at the GDF5 locus alters the function of a growth enhancer in Neandertals and modern humans.
登录
查看更多内容
影响因子：
30.8
作者：
Guenther CA;Tasic B;Luo L;Bedell MA;Kingsley DM
通讯作者：
Kingsley DM
生长分化因子 5 的单核苷酸多态性与先天性髋关节发育不良的关联：病例对照研究。
影响因子：
4.9
作者：
Dai, Jin;Shi, Dongquan;Zhu, Pengsheng;Qin, Jianghui;Ni, Haijian;Xu, Yong;Yao, Chen;Zhu, Lunqing;Zhu, Hongtao;Zhao, Baocheng;Wei, Jia;Liu, Baorui;Ikegawa, Shiro;Jiang, Qing;Ding, Yitao
通讯作者：
Ding, Yitao
影响因子：
2
作者：
HAMILTON, WD
通讯作者：
HAMILTON, WD
影响因子：
2.8
作者：
Betti, Lia;Lycett, Stephen J.;Pearson, Osbjorn M.
通讯作者：
Pearson, Osbjorn M.
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D