Worldwide, several human populations may have adapted to high altitude (HA) based on long-term residence in mountainous areas above 3,000 meters. In the Andean region of South America, Quechua natives have lived at altitudes averaging 4,000 meters for at least the past 6,000 years. The specific aim of this project will be to collect genetic and physiological trait data on Quechua (n=600) and to test for association between previously identified genetic markers and high arterial hemoglobin-oxygen saturation (SaO2). The results of this project could provide an answer to the long-standing question of whether Andean populations are genetically adapted to high altitude. The Quechua sample will include sub-samples, born and raised at HA or at sea-level. This will allow evaluation of developmental effects as these may also determine higher SaO2. A sample of n=300 lowlanders will serve as a control group. Six thousand years is a conservative time-depth estimate for Quechua residence at HA and is long enough for Quechua to have experienced natural selection i.e., genetic adaptation. Selection could have favored traits enabling survival under the challenge of chronically low oxygen levels, such as traits related to O2 transport capacity. Apart from genetics, growth and development at HA may exhibit developmental adaptation. For example, lung-size is enhanced in persons born and raised at HA. The current project will test both genetic and developmental hypotheses to explain SaO2 of Peruvian Quechua. The SaO2 is a major determinant of the amount of oxygen in the blood, and Quechua are especially impressive in maintaining high SaO2 during exercise at HA. In previous work, the current research team used a whole-genome approach to identify genomic regions in Quechua that showed strong a priori evidence of natural selection. This genome scan used a dense panel of single nucleotide polymorphism (SNP) genetic markers, and provided evidence of natural selection in several genes of the hypoxia inducible factor (HIF) pathway. HIF is a central regulator that controls downstream genes involved in maintaining cellular oxygen levels. The project is an international collaboration with Peruvian researchers and includes student involvement in both the USA and Peru.