Sequencing of Fifty Human Exomes Reveals Adaptation to High Altitude

By X. Yi, Y. Liang, E. Huerta-Sánchez, Xin Jin, Z. Cuo, J. Pool, Xun Xu, Hui Jiang, N. Vinckenbosch, Thorfinn Sand Korneliussen and 60 more. Science, 2010

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No Genetic Vertigo Peoples living in high altitudes have adapted to their situation (see the Perspective by Storz). To identify gene regions that might have contributed to high-altitude adaptation in Tibetans, Simonson et al. (p. 72, published online 13 May) conducted a genome scan of nucleotide polymorphism comparing Tibetans, Han Chinese, and Japanese, while Yi et al. (p. 75) performed comparable analyses on the coding regions of all genes—their exomes. Both studies converged on a gene, endothelial Per-Arnt-Sim domain protein 1 (also known as hypoxia-inducible factor 2α), which has been linked to the regulation of red blood cell production. Other genes identified that were potentially under selection included adult and fetal hemoglobin and two functional candidate loci that were correlated with low hemoglobin concentration in Tibetans. Future detailed functional studies will now be required to examine the mechanistic underpinnings of physiological adaptation to high altitudes. Sequencing coding regions identified genetic changes that were likely involved in adaptation to hypoxia. Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18× per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

Subfields: Cancer Research, Genetics, Physiology

View Paper: https://www.semanticscholar.org/paper/210e24e9efc2ddfba6131b33880e044e662255a6

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Citations in the corpus

Genetic adaptation to high altitude in the Ethiopian highlands (2012, background): “Previous genomic studies involving high-altitude residents of Asia and South America have identified three candidate genes (EPAS1, EGLN1, and PPARA) that exhibit patterns of SNP variation consistent with recent positive selection [8-13].”
Infant and child death in the human environment of evolutionary adaptation (2013, background): “However, it is important to note that recent theories suggest that the last 10,000 years have played a significant role as a source of evolutionary adaptations and are hence part of the human EEA (Cochran & Harpending, 2009; Hartl & Clark, 1997; Irons, 1998; Yi et al., 2010; Tishkoff et al., 2007).”
A genomic history of Aboriginal Australia (2016, methodology): “To identify any selection specific to Aboriginal Australians, we used two different methods based on the identification of SNPs with high allele frequency differences between Aboriginal Australians and other groups, similar to the often used Population-Branch Statistics 79 (PBS, S16).”
Robust Identification of Local Adaptation from Allele Frequencies (2012, background): “Outlook The population genomic comparison of closely related populations that differ strongly in environmental variables has already yielded many great candidate loci (see for example, altitude adaptation in Tibetans, Beall et al., 2010; Simonson et al., 2010; Yi et al., 2010).”
ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, background): “Genome-wide analysis of Tibetans by two independent groups revealed a high correlation between the presence of single-nucleotide polymorphisms at the EPAS1 locus (which encodes HIF-2 ) and nonelevated hemoglobin concentrations in this population (11, 367).”
Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder (2011, methodology): “The genotyping assay and base-calling procedures were performed as previously describe”
Demographic history and rare allele sharing among human populations (2011, methodology): “We developmethods to precisely estimate SFSs from high-throughput sequencing data and use this information to estimate demographic parameters for a detailed Out-of-Africa demographic model by using ∂a∂i (6), a software package that uses diffusion approximation to calculate expected SFSs across multi”
Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “The basis for this remarkable evolutionary adaptation appears to have involved the selection of genetic variants at multiple loci encoding components of the oxygen-sensing system, particularly HIF-2a (Beall et al., 2010; Simonson et al., 2010; Yi et al., 2010).”