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

这项研究将侧重于确定基因特异性证据的遗传适应高海拔缺氧使用独立的，高原人口从不同的地理区域。 这包括安第斯山脉的人口（克丘亚人和艾马拉人）和青藏高原的人口（羌族、卡马族、白马族、藏族）。 三个主要问题将被解决：1）是否有基因特异性的证据，自然选择种群之间的青藏高原？ 2)是否有基因特异性的证据，自然选择之间的人口安第斯高原？3)西藏人和安第斯人是否在基因上表现出相似性和/或差异，或者在涉及高海拔适应的相同基因中表现出功能上的不同变化？为了回答这些问题，将对研究人群进行各种分子和功能测定。 这些包括使用单核苷酸多态性数据（SNP）筛选候选基因以获得自然选择的证据，然后使用基于测序的方法检测偏离中性的情况，最后通过功能测定来确定特定基因型之间的生理差异。生物人类学领域已经接受了分子遗传技术，以更精确地了解人类的生物变异和自然选择在形成这种变化中的作用。 尽管使用这些方法有明显的好处，但只有少数研究在人类基因组中寻找自然选择的特征。 该项目着眼于自然选择在塑造高海拔人群基因组中的作用，超越了以前研究这一进化过程的尝试。 这项研究并没有集中在一个已经适应了高海拔生活的人群上，而是考察了两个独立的高地群体，并将它们与低地群体进行了比较。 将重点放在两个主要的人类群体，已经适应了高海拔生活将增加成功地确定候选基因的可能性，也提供了一种手段来比较和对比这些人群的适应方式。 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，将生理调查的力量与定量和进化遗传学相结合。 这项研究将有助于确定基因型-表型的相关性，以及阐明参与自然选择的变量。今天，高海拔地区，如科罗拉多高地，正在经历人口的大量增长。 目前估计有1.4亿人生活在高海拔地区，即海拔2500米。 这种低海拔土著人向高海拔环境的迁移导致了与高海拔相关的健康风险的增加，例如怀孕并发症。 这项研究提供了一个框架，以测试在特定的海拔表型的候选基因的变化的影响。 通过了解高海拔当地人生理适应的遗传基础，我们将更适合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）。

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).