藏族群体是研究高海拔极端低氧环境遗传适应机制的一个良好范本。藏族群体进化出了很多重要的应对低氧环境的适应性性状，如较低的血红蛋白含量，较高的通气量水平，较高的血氧饱和度以及较少发生的低氧下肺血管收缩和婴儿出生体重的减少。这些特异性遗传性状的产生是由于藏族人群在高海拔环境下长时间受自然选择，从而引起全基因组上基因发生遗传变化。之前的研究工作中，通过比较生活在高海拔的藏族群体和低海拔的汉族群体，人们已经发现了很多存在明显等位基因频率差异的候选基因。其中，EPAS1和EGLN1这两个基因是位于低氧代谢通路上游的关键调控基因，它们可能在藏族的高原适应中起着关键作用。EPAS1和EGLN1这两个基因都跟藏族群体较低的血红蛋白含量相关，它们可能是通过调控促红细胞生成素(EPO)的转录来调节血红蛋白含量。然而，是否存在其它可以调节血红蛋白代谢的基因参与藏族的适应还需要进一步的探究。在我们的研究中，我们发现了一个可以调节血红素代谢的下游基因HMOX2，它在藏族人群中存在适应性的序列变异。HMOX2基因属于血红素加氧酶家族(HO)。血红素加氧酶是血红素代谢的关键限速酶，可以将血红素代谢为一氧化碳、亚铁离子和胆绿素，胆绿素接下来快速地被胆绿素还原酶转化成胆红素，从而实现将体内多余的血红素代谢掉。HMOX2是血红素加氧酶家族的组成性表达亚型，在体内很多器官中都高表达。但是，HMOX2基因的突变位点是否对藏族人群的高原低氧环境适应性有贡献还不清楚。我们首先对全长为45.6kb的HMOX2基因进行了重测序，发现该基因在藏族群体中存在正选择信号。接下来在两个独立的藏族群体（共1250个个体）中对HMOX2基因相关性分析的结果表明，序列多态位点rs4786504在藏族男性群体中存在与血红蛋白浓度的相关性。在这个位点中携带突变型C的个体比祖先型T个体的携带者有更低的血红蛋白含量。我们的体外实验进一步地表明，当多态位点rs4786504为C时，对应的HMOX2表达量增加，从而可能加速体内多余血红素的代谢，在高海拔条件下保持较低的血红蛋白含量。综合这些证据，我们认为HMOX2作为一个修饰基因可以低氧代谢通路的下游调节血红蛋白的代谢，实现藏族人群对高原低氧环境遗传适应。; Tibetans are a well-known example of successful adaptation to the hypoxic environments at high altitude. They have acquired several key adaptive traits to cope with the low-oxygen condition, such as reduced hemoglobin (Hb) levels, increased resting ventilation, better levels of blood oxygen saturation, low hypoxic pulmonary vasoconstriction and lower incidence of reduced birth weight. These heritable traits are likely caused by genetic modifications of genes in the genome due to long-term natural selection at high altitude.Previous studies have reported a set of candidate genes exhibiting unusually large allelic divergence between Tibetan highlanders and Han Chinese lowlanders. In particular, two upstream regulators of the hypoxic pathway (EPAS1 and EGLN1) possess Tibetan-specific mutations that may contribute to the adaptive traits in Tibetans. Both EPAS1 and EGLN1 were shown to be associated with the low hemoglobin levels in Tibetans, likely through their transcriptional regulation of EPO, a glycoprotein hormone that controls erythropoiesis, or red blood cell production. However, whether there are other genes involved in the control of hemoglobin metabolism in Tibetans need to be investigated.In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. It belongs to the heme oxygenase (HO) family. The HO enzymes are responsible for heme catabolism, acting as rate-limiting enzymes in the heme degradation pathway, which produces equimolar quantities of carbon monoxide (CO), iron, and biliverdin. Biliverdin is rapidly converted to bilirubin by biliverdin reductase. HMOX2 is the constitutively expressed isoform of HO with high levels of expression in many organs. However, whether there are HMOX2 variants contributing to high-altitude adaptation in Tibetans remains unclear.We first re-sequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504 displayed lower hemoglobin level as compared to the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.
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