Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data

Abstract

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.

Graduated effects of high-altitude hypoxia and highland ancestry on birth size

“…Such findings not only support genetically determined protective mechanisms, but they also suggest differences according to genetic imprinting, in which maternally transmitted genes restrict but paternally transmitted genes enhance fetal growth. Multiple independent groups have also shown that (31). It is also known that high altitude impairs the pregnancy-associated increase in uterine blood flow, but this defect is significantly diminished in highland native pregnancies (18).…”

A review of inter- and intraspecific variation in the eutherian placenta

“…EGLN1 encodes hypoxia-inducible factor prolyl hydroxylase 2, a protein that regulates the expression of HIF-1a, the transcription factor responsible for the hypoxic response [90]. EGLN1 shows evidence for positive selection at 25 SNPs in Andeans and 28 SNPs in Tibetans [89]. This finding suggests there is a genetic basis for the adaptation to hypoxia in these populations, and future work should test how these positively selected SNPs affect the oxygen exchange between the mother and fetus via the placenta.…”

Domiciliary Oxygen: Facts and fallacies

“…The strongest evidence for selection was found at the locus encoding HIF-2α [64][65][66]. Selection of loci encoding PHD2, FIH-1 and target HIF genes has also been reported [67]. As the selected genetic variants alter the function of these proteins is not known.…”