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.

Figure 1

The geography of human adaptation to high altitude. Geographic locations where humans have adapted to life at high altitude are indicated in grey and include the Andean Altiplano of South America, the Tibetan Plateau of Central Asia and the Semien Plateau of Ethiopia. The inset indicates the sampling locations of the four Native American population samples. The populations include Peruvian Quechua, Bolivian Aymara, Nahua, Mixtec and Tlapanec speakers from Guerrero, Mexico, and Maya from the Yucatan Peninsula, Mexico.

Figure 2

Empirical distribution of LSBL across three populations: Andeans, Mesoamericans and East Asians. The inset shows LSBLs above 0.3 for Andeans and Mesoamericans. These two populations have fewer LSBLs above 0.15 compared with the East Asians, which is expected, given their more recent common ancestry. LSBL = Locus-specific branch length.