Doctoral Dissertation Improvement: Signatures of Natural Selection Among Populations of the Andean Altiplano and the Tibetan Plateau

这项研究将集中于使用来自不同地理区域的独立的高原种群来确定遗传适应高海拔低氧的基因特异性证据。这包括安第斯山脉的人口(盖丘亚人和艾马拉人)和青藏高原的人口(羌族、哈马族、白马族、藏族)。将讨论三个主要问题：1)青藏高原种群之间是否有基因特异性的自然选择证据？2)安第斯高原种群之间的自然选择是否有基因特异性的证据？3)西藏和安第斯种群是否表现出基因上的相似和/或差异，或者参与高原适应的同一基因在功能上的不同变化？为了回答这些问题，将对研究人群进行各种分子和功能分析。这些措施包括使用单核苷酸多态数据(SNP)筛选候选基因以证明自然选择，然后使用基于测序的方法检测偏离中性的情况，最后进行功能分析以确定特定基因类型之间的生理差异。在过去的二十年中，生物人类学领域采用了分子遗传学技术来更准确地了解人类的生物变异和自然选择在形成这种变异中的作用。尽管使用这些方法有明显的好处，但只进行了一小部分在人类基因组中寻找自然选择特征的研究。这个项目着眼于自然选择在塑造高海拔人群基因组中的作用，超过了之前研究这一进化过程的尝试。这项研究没有关注一个已经适应了高原生活的人类群体，而是考察了两个独立的高海拔群体，并将他们与低海拔群体进行了比较。关注已经适应高海拔生活的两个主要人类群体将增加成功识别候选基因的可能性，并提供一种手段来比较和对比这些群体适应的方式。除了自然选择的基因测试外，我们还将能够测试这些候选基因对特定海拔表型的影响，将生理学研究的力量与数量和进化遗传学相结合。这项研究将有助于识别基因-表型的相关性，并阐明涉及自然选择的变量。今天，高海拔地区，如科罗拉多高原，正在经历人口的大幅增长。目前估计有1.4亿人生活在海拔2500米的高海拔地区。低海拔原住民向高海拔环境的迁移导致与高海拔相关的健康风险上升，如妊娠并发症。这项拟议的研究提供了一个框架来测试在候选基因上发现的变异对特定海拔表型的影响。通过了解高海拔原住民生理适应的遗传基础，我们将更适合于治疗与环境氧分压差异相关的疾病，如先兆子痫(妊娠高血压综合征)。

This research will focus on identifying gene specific evidence for genetic adaptation to high altitude hypoxia using independent, highland populations from distinct geographic regions. This includes the populations of the Andes (Quechua and Aymara) and the populations of the Tibetan Plateau (Qiang, Khama, Baima, Tibetans). Three major questions will be addressed: 1) Is there gene-specific evidence for natural selection among populations of the Tibetan Plateau? 2) Is there gene-specific evidence for natural selection among populations of the Andean Altiplano? 3) Do the Tibetan and Andean populations exhibit similarities and/or differences in genes or functionally different changes in the same genes involved in high altitude adaptation? In order to answer these questions, a variety of molecular and functional assays will be performed on the study populations. These include screening candidate genes for evidence of natural selection using single nucleotide polymorphism data (SNP) followed by detecting departures from neutrality using sequencing-based methods and finally functional assays to determine the physiological differences between particular genotypes.Within the last two decades, the field of biological anthropology has embraced molecular genetic techniques to more precisely understand human biological variation and natural selection's role in shaping this variation. Despite the obvious benefits of using these methods, only a small number of studies looking for signatures of natural selection in the human genome have been conducted. This project, which looks at the role of natural selection in shaping the genomes of high altitude human populations, surpasses previous attempts to study this evolutionary process. Rather than focusing on one human population that has adapted to life at altitude, this research examines two separate high-land groups and compares them to lowland groups. Focusing on two of the major human populations that have adapted to life at high altitude will increase the likelihood of successfully identifying candidate genes and also provide a means to compare and contrast the ways in which these populations have adapted. In addition to genetic tests for natural selection, we will also be able to test for the effects of these candidate genes on particular altitude phenotypes, combining the power of physiological inquiry with quantitative and evolutionary genetics. This research will aid in identifying genotype-phenotype correlations as well as elucidate variables involved in natural selection.Today, areas of high altitude, such as the Colorado highlands, are experiencing heavy population growth. It is currently estimated that 140 million people live at high altitude, defined as 2500 m above sea level. This migration of low altitude natives to high altitude environs has led to a rise in high altitude associated health risks, such as complications with pregnancy. The proposed study provides a framework to test for the effects of variation found at the candidate genes on specific altitude phenotypes. By understanding the genetic bases for the physiological adaptations of high-altitude natives, we will be better suited to treat conditions associated with differences in ambient oxygen tension, such as preeclampsia (pregnancy-induced hypertension).