HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans.
HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans.
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HMOX2作为藏族高海拔适应的调节基因
DOI：
10.1002/humu.22935
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Chen Hua
中科院分区：
文献类型：
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作者：
Yang Deying;Peng Yi;Ouzhuluobu;Bianbazhuoma;Cui Chaoying;Bianba;Wang Liangbang;Xiang Kun;He Yaoxi;Zhang Hui;Zhang Xiaoming;Liu Jiewei;Shi Hong;Pan Yongyue;Duojizhuoma;Dejiquzong;Cirenyangji;Baimakangzhuo;Gonggalanzi;Liu Shimin;Gengdeng;Wu Tianyi;Chen Hua
西藏人很好地适应了高海拔环境。在藏族的适应性特征中，相对较低的血红蛋白水平被认为是对低氧挑战的迟钝的红细胞生成反应。以前，EPAS 1和EGLN 1，缺氧途径中的主要上游调节因子，据报道参与藏族血红蛋白的调节。在这项研究中，我们报告了一个下游基因（HMOX 2）参与血红素catalysis，其中窝藏潜在的适应性变异，在藏族。我们首次对西藏人HMOX 2基因组全长（45.6kb）进行了测序，证实了西藏人HMOX 2基因的正选择信号。随后对两个独立的藏族人群（共1,250人）的血红蛋白水平进行的相关分析显示，HMOX 2变体与血红蛋白水平之间存在男性特异性关联。与T等位基因携带者相比，在rs 4786504：T>C处衍生C等位基因的藏族男性显示出较低的血红蛋白水平。此外，我们的体外实验表明，rs 4786504的C等位基因可以增加HMOX 2的表达，可能导致血红素更有效的分解，这可能有助于在高海拔地区保持相对较低的血红蛋白水平。总的来说，我们认为HMOX 2通过调节血红蛋白代谢而促进藏族人的高原适应。
Tibetans are well adapted to high‐altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously,EPAS1andEGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) ofHMOX2in Tibetans, which confirmed the previously suspected signal of positive selection onHMOX2in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male‐specific association between theHMOX2variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression ofHMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose thatHMOX2contributes to high‐altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.