Genes and the fertility of Tibetan Women at High Altitude in Nepal

西藏人在海拔3000米（约10，000 '）以上的地方生活了至少10，000年，因此具有独特的生物学特征，包括携带氧气的血红蛋白水平出乎意料地低。 解释这种血红蛋白水平的基因最近被发现，并且在西藏人中以独特的高频率出现。这种高频率的可能机制是这些基因的低血红蛋白形式的人的生育率和儿童存活率较高。这项研究将验证这样一个假设，即在尼泊尔高海拔地区，携带低血红蛋白基因变体的藏族妇女比携带其他变体的妇女有更多的存活子女。 1350名居住在海拔3000米或更高的藏族妇女将提供DNA，用于对EPAS 1、EGLN 1和HIF 1alpha基因进行分型，这些基因以前被发现可以调节对缺氧（低氧可用性）的反应，例如发生在高海拔地区的反应。 此外，还将收集血红蛋白浓度和血红蛋白氧饱和度的测量结果，以及有关这些妇女生育史和子女存活率的信息。 预测的结果是，具有藏人中最常见的基因形式的妇女将具有较低的血红蛋白浓度，较高的血红蛋白氧饱和度，以及更多的存活子女。 这些结果将把严重的环境压力与生物和遗传变异以及生殖成功联系起来，为自然选择在人类中的作用建立一个案例，并提高我们对适应新环境过程的理解。 这个美国-尼泊尔的合作研究对所有海拔高度的健康都有影响，因为这些基因是子宫内发育所必需的，它们在骨关节炎和类风湿性关节炎、心力衰竭和癌症等多种疾病的生物学中发挥着核心作用。

Tibetans have lived at altitudes above 3000m (~10,000') for at least 10,000 years and consequently have distinctive biological traits, including unexpectedly low levels of hemoglobin, the molecule that carries oxygen. Genes accounting for such hemoglobin levels were recently identified and occur at uniquely high frequency among Tibetans. The likely mechanism for this high frequency is higher fertility and child survival for those people with the low-hemoglobin forms of those genes. This research will test the hypothesis that Tibetan women at high altitude in Nepal with the low-hemoglobin variants of the genes have more surviving children than those with the other variants. 1350 women of Tibetan ethnicity residing at 3000m or higher who have completed their reproductive careers will provide DNA for typing the genes called EPAS1, EGLN1 and HIF1alpha that were previously found to regulate the response to hypoxia (low oxygen availability), such as that occurring at high altitudes. In addition, measurements of hemoglobin concentration and oxygen saturation of hemoglobin, as well as information on these women's fertility history and the survival of their children, will be collected. The predicted outcome is that women with the forms of the genes that are most frequent among Tibetans will have lower hemoglobin concentration, higher oxygen saturation of hemoglobin, and more surviving children. Those results will connect a severe environmental stress to biological and genetic variation and reproductive success, building a case for natural selection operating in a human population and improving our understanding of the processes of adapting to new environments. This U.S.-Nepalese collaborative research has health implications at all altitudes because these genes are necessary for intrauterine development, and they play central roles in the biology of diseases as diverse as osteo- and rheumatoid arthritis, heart failure, and cancer.