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.
Highlights
Identifying gene regions showing signatures of natural selection in the human genome offers a window into our recent evolutionary past, as well as a deeper understanding of how this evolutionary force has shaped extant patterns of variation
We selected these complementary methods because each statistic possesses a varying degree of efficacy for identifying signatures of natural selection depending on the allelic background of the populations used in the analysis, the strength of selection and the length of time elapsed since the start of the selective event
Given the aspects of genetic variation summarised by these statistics, it is not expected that the results of tests will overlap
Summary
Identifying gene regions showing signatures of natural selection in the human genome offers a window into our recent evolutionary past, as well as a deeper understanding of how this evolutionary force has shaped extant patterns of variation. Detect signatures of selection in three major continental groups: West Africans, East Asians and Northern Europeans.[1,2,3,4,5,6] To date, only a few studies have focused on identifying candidate genes under selection with reference to a specific selective pressure.[7,8] Here, we use high-density SNP data to search for candidate genes for altitude adaptation in Andean populations. By expanding the populations of study to the Americas and targeting a specific selective pressure, hypobaric hypoxia, we can produce a more detailed and nuanced understanding of this evolutionary process
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