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

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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).