Genetic adaptation to high altitude in the Ethiopian highlands

BackgroundGenomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.ResultsWe have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.ConclusionsWe highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.

[1]  M. Wilsona,et al.  Maternal Adaptation to High-altitude Pregnancy : An Experiment of Nature — A Review , 2004 .

[2]  P. Donnelly,et al.  A Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome , 2005, Science.

[3]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[4]  Asan,et al.  Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude , 2010, Science.

[5]  V. Mootha,et al.  MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake , 2010, Nature.

[6]  Jeffrey Ross-Ibarra,et al.  Genetic Data Analysis II. Methods for Discrete Population Genentic Data , 2002 .

[7]  L. Neckers,et al.  Microtubule Disruption Utilizes an NFκB-dependent Pathway to Stabilize HIF-1α Protein* , 2003, The Journal of Biological Chemistry.

[8]  Sunghoon Kim,et al.  Hormonal activity of AIMP1/p43 for glucose homeostasis , 2006, Proceedings of the National Academy of Sciences.

[9]  Megan J. Wilson,et al.  Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[10]  J. Samarut,et al.  Thyroid hormones signaling is getting more complex: STORMs are coming. , 2007, Molecular endocrinology.

[11]  S. Tishkoff,et al.  Living the high life: high-altitude adaptation , 2010, Genome Biology.

[12]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[13]  John D. Welsh,et al.  Vav3 Mediates Receptor Protein Tyrosine Kinase Signaling, Regulates GTPase Activity, Modulates Cell Morphology, and Induces Cell Transformation , 2000, Molecular and Cellular Biology.

[14]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[15]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[16]  D. Heckerman,et al.  Efficient Control of Population Structure in Model Organism Association Mapping , 2008, Genetics.

[17]  David Reich,et al.  Population differentiation as a test for selective sweeps. , 2010, Genome research.

[18]  A. Dombkowski,et al.  Microarray analysis of differentially regulated genes in human neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin. , 2011, Biochemical and biophysical research communications.

[19]  A. I.,et al.  Neural Field Continuum Limits and the Structure–Function Partitioning of Cognitive–Emotional Brain Networks , 2023, Biology.

[20]  Paul Scheet,et al.  A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. , 2006, American journal of human genetics.

[21]  Yiping Shen,et al.  A genome-wide search for signals of high-altitude adaptation in Tibetans. , 2011, Molecular biology and evolution.

[22]  X. Bustelo,et al.  Vav3-deficient Mice Exhibit a Transient Delay in Cerebellar Development , 2010, Molecular biology of the cell.

[23]  Xiaoquan Wen,et al.  Correction: A Map of Recent Positive Selection in the Human Genome , 2006, PLoS Biology.

[24]  Megan J. Wilson,et al.  Identifying positive selection candidate loci for high-altitude adaptation in Andean populations , 2009, Human Genomics.

[25]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[26]  M. Campbell,et al.  PANTHER: a library of protein families and subfamilies indexed by function. , 2003, Genome research.

[27]  K. Campbell,et al.  Ubiquitylation of an Internalized Killer Cell Ig-Like Receptor by Triad3A Disrupts Sustained NF-κB Signaling , 2011, The Journal of Immunology.

[28]  Jinchuan Xing,et al.  Genetic Evidence for High-Altitude Adaptation in Tibet , 2010, Science.

[29]  Rui Mei,et al.  Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data , 2010, PLoS genetics.

[30]  D. Prows,et al.  Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1. , 2011, American journal of respiratory and critical care medicine.

[31]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[32]  Chad Garner,et al.  Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. , 2009, Human molecular genetics.

[33]  Z. Sahnoun,et al.  Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. , 2012, Pathologie-biologie.

[34]  Bruce S. Weir,et al.  Genetic Data Analysis: Methods for Discrete Population Genetic Data. , 1991 .

[35]  G. McVean.  A Genealogical Interpretation of Principal Components Analysis , 2009, PLoS genetics.

[36]  G. Semenza.  Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. , 2011, Biochimica et biophysica acta.

[37]  Mark D Shriver,et al.  The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs , 2004, Human Genomics.

[38]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[39]  G. Semenza,et al.  Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. , 2010, Cardiovascular research.

[40]  L. Neckers,et al.  Microtubule disruption utilizes an NFkappa B-dependent pathway to stabilize HIF-1alpha protein. , 2003, The Journal of biological chemistry.

[41]  R. Elston,et al.  Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  L. Moore.  Human genetic adaptation to high altitude. , 2001, High altitude medicine & biology.

[43]  Sarah L. Nesbeitt.  Ethnologue: Languages of the World , 1999 .

[44]  C. Beall,et al.  An Ethiopian pattern of human adaptation to high-altitude hypoxia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  P. Donnelly,et al.  The Fine-Scale Structure of Recombination Rate Variation in the Human Genome , 2004, Science.

[46]  C. Beall.  Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. , 2006, Integrative and comparative biology.

[47]  Wei Wang,et al.  Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders , 2010, Proceedings of the National Academy of Sciences.

[48]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.