Abstract
Whether Andean populations are genetically adapted to high altitudes has long been of interest. Initial studies focused on physiological changes in the O2 transport system that occur with acclimatization in newcomers and their comparison with those of long-resident Andeans. These as well as more recent studies indicate that Andeans have somewhat larger lung volumes, narrower alveolar to arterial O2 gradients, slightly less hypoxic pulmonary vasoconstrictor response, greater uterine artery blood flow during pregnancy, and increased cardiac O2 utilization, which overall suggests greater efficiency of O2 transfer and utilization. More recent single nucleotide polymorphism and whole-genome sequencing studies indicate that multiple gene regions have undergone recent positive selection in Andeans. These include genes involved in the regulation of vascular control, metabolic hemostasis, and erythropoiesis. However, fundamental questions remain regarding the functional links between these adaptive genomic signals and the unique physiological attributes of highland Andeans. Well-designed physiological and genome association studies are needed to address such questions. It will be especially important to incorporate the role of epigenetic processes (i.e., non-sequence-based features of the genome) that are vital for transcriptional responses to hypoxia and are potentially heritable across generations. In short, further exploration of the interaction among genetic, epigenetic, and environmental factors in shaping patterns of adaptation to high altitude promises to improve the understanding of the mechanisms underlying human adaptive potential and clarify its implications for human health.
Highlights
Since the early 1900s, anthropologists and physiologists alike have sought to determine if there has been genetic adaptation to high altitude, conventionally defined as above 2500 m or 8250 ft since that is where O2 saturation levels in the arterial blood begin to fall in most persons
Evidence for adaptation was predominantly sought from studies separating short-term physiological responses or those occurring over hours to days or even weeks, termed acclimatization, from those occurring across lifetimes, termed developmental responses, and from those that persisted independent of duration of high-altitude exposure and were inferred to be genetic
Direct evidence for Andean genetic adaptation to high altitude comes from single nucleotide polymorphism (SNP) genome scans and sequencing studies that have identified genomic regions with evidence of recent positive selection (Table 2)
Summary
Since the early 1900s, anthropologists and physiologists alike have sought to determine if there has been genetic adaptation to high altitude, conventionally defined as above 2500 m or 8250 ft since that is where O2 saturation levels in the arterial blood begin to fall in most persons. Evidence for adaptation was predominantly sought from studies separating short-term physiological responses or those occurring over hours to days or even weeks, termed acclimatization, from those occurring across lifetimes, termed developmental responses, and from those that persisted independent of duration of high-altitude exposure and were inferred to be genetic. While multiple studies have shown that Andean and other high-altitude populations have undergone natural selection in several gene regions influencing O2 -sensitive pathways, numerous questions remain regarding the biological processes driving human adaptation to the chronic hypoxia of high altitude and their importance for human health. Studies in Andean residents of high altitude are summarized with respect to the physiological characteristics distinguishing them from acclimatized newcomers and the genomic or genetic factors that are potentially involved. While further study is needed, such studies offer the opportunity to identify the importance of interactions between genomic and epigenomic processes for human adaptation to limited oxygen availability
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