Identifying positive selection candidate loci for high-altitude adaptation in Andean populations

Abstract

High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Widespread signals of convergent adaptation to high altitude in Asia and America

“…With this procedure, 362 SNPs (31%) were found under convergent adaptation, whereas 611 SNPs (53%) were found under selection only in Asia, and 186 SNPs (16%) only under selection in South America. These results suggest that convergent adaptation is more common than previously thought 5,24,57 even at the SNP level, but consistent with results of a recent literature meta-analysis over several species 5 .…”

“…Several candidate genes for adaptation to altitude have nevertheless been clearly identified 21,22 , the most prominent ones being involved in the hypoxia inducible factor (HIF) pathway, which plays a major role in response to hypoxia 23 . In Andeans, VEGFA (vascular endothelial growth factor A, MIM 192240), PRKAA1 (protein kinase, AMP-activated, alpha 1 catalytic subunit, MIM 602739) and NOS2A (nitric oxide synthase 2A, MIM 163730) are the best-supported candidates, as well as EGLN1 (egl-9 family hypoxia-inducible factor 1, MIM 606425), a down regulator of some HIF targets 12,24 . In Tibetans 10,11,13,14,16,25 , the HIF pathway gene EPAS1 (endothelial PAS domain protein 1, MIM 603349) and EGLN1 have been repeatedly identified 22 .…”

Genodynamics: A New Biophysical Approach to Modeling Adaptation in Human Populations

“…Our program found a functional correlation between two SNPs in intron 1 of the egl-9 family hypoxia inducible factor 1 (EGLN1) gene and the environmental parameter UV exposure. Though EGLN1's involvement in high altitude adaptation is more well, several studies have shown that the variation present in this gene has strong signatures of positive selection with regard to altitude in both Tibetan and Andean populations [15][16][17][18][19]. However, our study did not corroborate this finding which could be due to the lack of Tibetan and Andean genotype data for which we have plans to rectify in future studies.…”

Diurnal changes of arterial oxygen saturation and erythropoietin concentration in male and female highlanders

“…The [Epo] increase was also small or absent at 2600 m in Bogot a (B€ oning et al 2001Schmidt et al 2002;Cristancho et al 2007). In contrast to Tibetans, genetic adaptation of HIFa probably does not play a role in Epo secretion among Andean natives (Bigham et al 2009). There are, however, changes in HIF-targeted genes important for metabolism in an oxygen-deprived cellular environment and for microcirculation.…”