Abstract
The natural hypoxic experiments performed on native human populations residing the highlands provide an excellent opportunity to learn how environmental challenges reform human genetic architecture. In this chapter, we give a broad overview of current evidence for physiological and genetic adaptations based on three renowned highland groups from the Qinghai-Tibet Plateau, the Andes Altiplano, and the Ethiopian Plateau. We summarize several well-recognized adaptive signals strongly suggested by early studies and highlight recent findings accumulating rapidly and broadly with whole-genome sequencing and multi-omics approaches. These studies offer a glimpse into the complex driving forces and mechanisms of adaptive evolution and imply the genetic predisposition of relevant diseases and possible therapeutic strategies.
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References
Aldenderfer M (2003) Moving up in the world: archaeologists seek to understand how and when people came to occupy the Andean and Tibetan plateaus. Am Sci 91:542–549
Aldenderfer M (2011) Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol 12:141–147. https://doi.org/10.1089/ham.2010.1094
Alkorta-Aranburu G et al (2012) The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet 8:e1003110. https://doi.org/10.1371/journal.pgen.1003110
Altundag A et al (2014) The effect of high altitude on olfactory functions. Eur Arch Otorhinolaryngol 271:615–618. https://doi.org/10.1007/s00405-013-2823-3
Appelhoff RJ et al (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279:38458–38465. https://doi.org/10.1074/jbc.M406026200
Arciero E et al (2018) Demographic history and genetic adaptation in the Himalayan region inferred from genome-wide SNP genotypes of 49 populations. Mol Biol Evol 35:1916–1933. https://doi.org/10.1093/molbev/msy094
Arsenault PR et al (2013) A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism. J Biol Chem 288:33571–33584. https://doi.org/10.1074/jbc.M113.482364
Bartsch P, Saltin B (2008) General introduction to altitude adaptation and mountain sickness. Scand J Med Sci Sports 18(Suppl 1):1–10. https://doi.org/10.1111/j.1600-0838.2008.00827.x
Beall CM (2006) Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol 46:18–24. https://doi.org/10.1093/icb/icj004
Beall CM, Goldstein MC (1987) Hemoglobin concentration of pastoral nomads permanently resident at 4,850-5,450 meters in Tibet. Am J Phys Anthropol 73:433–438. https://doi.org/10.1002/ajpa.1330730404
Beall CM, Reichsman AB (1984) Hemoglobin levels in a Himalayan high altitude population. Am J Phys Anthropol 63:301–306. https://doi.org/10.1002/ajpa.1330630306
Beall CM et al (1997) Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives. Am J Phys Anthropol 104:427–447. https://doi.org/10.1002/(SICI)1096-8644(199712)104:4<427::AID-AJPA1>3.0.CO;2-P
Beall CM et al (1998) Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106:385–400. https://doi.org/10.1002/(SICI)1096-8644(199807)106:3<385::AID-AJPA10>3.0.CO;2-X
Beall CM et al (2002) An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci U S A 99:17215–17218. https://doi.org/10.1073/pnas.252649199
Beall CM et al (2010) Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A 107:11459–11464. https://doi.org/10.1073/pnas.1002443107
Berra E et al (2003a) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 22:4082–4090. https://doi.org/10.1093/emboj/cdg392
Berra E et al (2003b) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 22:4082–4090. https://doi.org/10.1093/emboj/cdg392
Bigham AW, Lee FS (2014) Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev 28:2189–2204. https://doi.org/10.1101/gad.250167.114
Bigham AW et al (2009) Identifying positive selection candidate loci for high-altitude adaptation in Andean populations. Hum Genomics 4:79–90. https://doi.org/10.1186/1479-7364-4-2-79
Bigham A et al (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6:e1001116. https://doi.org/10.1371/journal.pgen.1001116
Bigham AW et al (2013) Andean and Tibetan patterns of adaptation to high altitude. Am J Hum Biol 25:190–197. https://doi.org/10.1002/ajhb.22358
Bigham AW et al (2014) Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude. Physiol Genomics 46:687–697. https://doi.org/10.1152/physiolgenomics.00063.2014
Bishop T et al (2013) Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol 591:3565–3577. https://doi.org/10.1113/jphysiol.2012.247254
Brutsaert TD, Soria R, Caceres E, Spielvogel H, Haas JD (1999) Effect of developmental and ancestral high altitude exposure on chest morphology and pulmonary function in Andean and European/North American natives. Am J Hum Biol 11:383–395. https://doi.org/10.1002/(SICI)1520-6300(1999)11:3<383::AID-AJHB9>3.0.CO;2-X
Brutsaert TD et al (2003) Spanish genetic admixture is associated with larger V(O2) max decrement from sea level to 4338 m in Peruvian Quechua. J Appl Physiol 95:519–528
Brutsaert TD et al (2005) Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives. Am J Physiol Regul Integr Comp Physiol 289:R225–R234. https://doi.org/10.1152/ajpregu.00105.2005
Brutsaert TD et al (2019) Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. Proc Natl Acad Sci 116:24006. https://doi.org/10.1073/pnas.1906171116
Cavalli-Sforza L, Menozzi P, Piazza A (1995) Genetics and the origin of human “races”. Russ J Genet 54:853–867
Center for International Earth Science Information Network, C. C. U (2012) NASA socioeconomic data and applications center. SEDAC, Palisades
Chen FH et al (2015) Agriculture facilitated permanent human occupation of the Tibetan Plateau after 3600 BP. Science 347:248–250. https://doi.org/10.1126/science.1259172
Chen F et al (2019) A late middle pleistocene denisovan mandible from the Tibetan plateau. Nature 569:409–412. https://doi.org/10.1038/s41586-019-1139-x
Chen L, Wolf AB, Fu W, Li L, Akey JM (2020) Identifying and interpreting apparent Neanderthal ancestry in African individuals. Cell 180:677–687. https://doi.org/10.1016/j.cell.2020.01.012
Cheviron ZA, Bachman GC, Connaty AD, McClelland GB, Storz JF (2012) Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice. Proc Natl Acad Sci U S A 109:8635–8640. https://doi.org/10.1073/pnas.1120523109
Chiang C et al (2017) The impact of structural variation on human gene expression. Nat Genet 49:692–699. https://doi.org/10.1038/ng.3834
Childebayeva A et al (2019) LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure. Epigenetics 14:1–15. https://doi.org/10.1080/15592294.2018.1561117
Crocker ME et al (2020) Effects of high altitude on respiratory rate and oxygen saturation reference values in healthy infants and children younger than 2 years in four countries: a cross-sectional study. Lancet Glob Health 8:e362–e373. https://doi.org/10.1016/S2214-109X(19)30543-1
Dannemann M, Kelso J (2017) The contribution of Neanderthals to phenotypic variation in modern humans. Am J Hum Genet 101:578–589. https://doi.org/10.1016/j.ajhg.2017.09.010
Deng L et al (2019) Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders. Natl Sci Rev 6:1201–1222. https://doi.org/10.1093/nsr/nwz108
Dillehay TD, Collins MB (1988) Early cultural evidence from Monte-Verde in Chile. Nature 332:150–152. https://doi.org/10.1038/332150a0
Ding Q, Hu Y, Xu S, Wang J, Jin L (2014) Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians. Mol Biol Evol 31:683–695. https://doi.org/10.1093/molbev/mst260
Durvasula A, Sankararaman S (2020) Recovering signals of ghost archaic introgression in African populations. Sci Adv 6:eaax5097. https://doi.org/10.1126/sciadv.aax5097
Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463. https://doi.org/10.1038/nature02625
Eichstaedt CA et al (2014) The Andean adaptive toolkit to counteract high altitude maladaptation: genome-wide and phenotypic analysis of the Collas. PLoS One 9:e93314. https://doi.org/10.1371/journal.pone.0093314
Eichstaedt CA et al (2017) Evidence of early-stage selection on EPAS1 and GPR126 genes in Andean high altitude populations. Sci Rep 7:13042. https://doi.org/10.1038/s41598-017-13382-4
Elks CE et al (2012) Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol 3:29. https://doi.org/10.3389/fendo.2012.00029
Enard D, Petrov D (2018) Evidence that RNA viruses drove adaptive introgression between Neanderthals and modern humans. Cell 175:360–371. https://doi.org/10.1016/j.cell.2018.08.034
Erzurum SC et al (2007) Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc Natl Acad Sci 104:17593. https://doi.org/10.1073/pnas.0707462104
Fan S, Hansen ME, Lo Y, Tishkoff SA (2016) Going global by adapting local: A review of recent human adaptation. Science 354:54–59. https://doi.org/10.1126/science.aaf5098
Fehren-Schmitz L et al (2011) Diachronic investigations of mitochondrial and Y-chromosomal genetic markers in pre-Columbian Andean highlanders from South Peru. Ann Hum Genet 75:266–283. https://doi.org/10.1111/j.1469-1809.2010.00620.x
Ferezou J et al (1993) Reduction of postprandial lipemia after acute exposure to high altitude hypoxia. Int J Sports Med 14:78–85. https://doi.org/10.1055/s-2007-1021150
Foll M, Gaggiotti OE, Daub JT, Vatsiou A, Excoffier L (2014) Widespread signals of convergent adaptation to high altitude in Asia and america. Am J Hum Genet 95:394–407. https://doi.org/10.1016/j.ajhg.2014.09.002
Forsman A (2015) Rethinking phenotypic plasticity and its consequences for individuals, populations and species. Heredity 115:276–284. https://doi.org/10.1038/hdy.2014.92
Furrow RE (2014) Epigenetic inheritance, epimutation, and the response to selection. PLoS One 9:e101559. https://doi.org/10.1371/journal.pone.0101559
Fuselli S et al (2003) Mitochondrial DNA diversity in south America and the genetic history of Andean highlanders. Mol Biol Evol 20:1682–1691. https://doi.org/10.1093/molbev/msg188
Gaur P et al (2020) Comparative analysis of high altitude hypoxia induced erythropoiesis and iron homeostasis in Indian and Kyrgyz lowlander males. Curr Res Biotechnol 2:120–130. https://doi.org/10.1016/j.crbiot.2020.10.001
Ge RL et al (2012) Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. Mol Genet Metab 106:244–247
Ghosh S et al (2019) Exhaled nitric oxide in ethnically diverse high-altitude native populations: a comparative study. Am J Phys Anthropol 170:451–458. https://doi.org/10.1002/ajpa.23915
Gou X et al (2014) Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia. Genome Res 24(8):1308–1315
Gouy A, Excoffier L (2020) Polygenic patterns of adaptive introgression in modern humans are mainly shaped by response to pathogens. Mol Biol Evol 37:1420–1433. https://doi.org/10.1093/molbev/msz306
Graham AM, McCracken KG (2019) Convergent evolution on the hypoxia-inducible factor (HIF) pathway genes EGLN1 and EPAS1 in high-altitude ducks. Heredity 122:819–832. https://doi.org/10.1038/s41437-018-0173-z
Green RE et al (2010) A draft sequence of the Neandertal genome. Science 328:710–722. https://doi.org/10.1126/science.1188021
Grossman SR et al (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327:883–886. https://doi.org/10.1126/science.1183863
Groves BM et al (1993) Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J Appl Physiol 74:312–318. https://doi.org/10.1152/jappl.1993.74.1.312
Gurung PD, Upadhyay AK, Bhardwaj PK, Sowdhamini R, Ramakrishnan U (2019) Transcriptome analysis reveals plasticity in gene regulation due to environmental cues in Primula sikkimensis, a high altitude plant species. BMC Genomics 20:989. https://doi.org/10.1186/s12864-019-6354-1
Hall JE, Lawrence ES, Simonson TS, Fox K (2020) Seqing higher ground: functional investigation of adaptive variation associated with high-altitude adaptation. Front Genet 11:471. https://doi.org/10.3389/fgene.2020.00471
Hammer MF, Woerner AE, Mendez FL, Watkins JC, Wall JD (2011) Genetic evidence for archaic admixture in Africa. Proc Natl Acad Sci U S A 108:15123–15128. https://doi.org/10.1073/pnas.1109300108
Hao Y et al (2019) Comparative transcriptomics of 3 high-altitude passerine birds and their low-altitude relatives. Proc Natl Acad Sci 116:11851. https://doi.org/10.1073/pnas.1819657116
Hassen M (1990) The oromo of Ethiopia: a history, 1570–1860. Cambridge University Press, Cambridge
Hawks J, Wang ET, Cochran GM, Harpending HC, Moyzis RK (2007) Recent acceleration of human adaptive evolution. Proc Natl Acad Sci U S A 104:20753–20758. https://doi.org/10.1073/pnas.0707650104
Haygood R, Babbitt CC, Fedrigo O, Wray GA (2010) Contrasts between adaptive coding and noncoding changes during human evolution. Proc Natl Acad Sci 107:7853. https://doi.org/10.1073/pnas.0911249107
He Y et al (2018) Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia. Natl Sci Rev 5:516–529. https://doi.org/10.1093/nsr/nwy037
Heinrich EC et al (2019) Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans. Ann Hum Genet 83:171–176. https://doi.org/10.1111/ahg.12299
Ho JJ, Man HS, Marsden PA (2012) Nitric oxide signaling in hypoxia. J Mol Med 90:217–231. https://doi.org/10.1007/s00109-012-0880-5
Hochachka PW, Rupert JL (2003) Fine tuning the HIF-1 ‘global’ O2 sensor for hypobaric hypoxia in Andean high-altitude natives. Bioessays 25:515–519. https://doi.org/10.1002/bies.10261
Horikoshi M et al (2016) Genome-wide associations for birth weight and correlations with adult disease. Nature 538:248–252. https://doi.org/10.1038/nature19806
Horscroft JA et al (2017) Metabolic basis to Sherpa altitude adaptation. Proc Natl Acad Sci U S A 114:6382–6387. https://doi.org/10.1073/pnas.1700527114
Hu H et al (2017) Evolutionary history of Tibetans inferred from whole-genome sequencing. PLoS Genet 13:e1006675. https://doi.org/10.1371/journal.pgen.1006675
Huang SY, Ning XH, Zhou ZN, Gu ZZ, Hu ST (1984) Ventilatory function in adaptation to high altitude: studies in Tibet. Springer, New York
Hubisz MJ, Williams AL, Siepel A (2020) Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph. PLoS Genet 16:e1008895. https://doi.org/10.1371/journal.pgen.1008895
Huerta-Sanchez E et al (2013) Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations. Mol Biol Evol 30:1877–1888. https://doi.org/10.1093/molbev/mst089
Huerta-Sanchez E et al (2014) Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 512:194–197. https://doi.org/10.1038/nature13408
Huerta-Sánchez E et al (2014) Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 512:194–197. https://doi.org/10.1038/nature13408
Hurles ME, Dermitzakis ET, Tyler-Smith C (2008) The functional impact of structural variation in humans. Trends Genet 24:238–245. https://doi.org/10.1016/j.tig.2008.03.001
Irizarry RA et al (2008) Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res 18:780–790. https://doi.org/10.1101/gr.7301508
Ivan M et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468. https://doi.org/10.1126/science.1059817
Jaakkola P et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472. https://doi.org/10.1126/science.1059796
Jagoda E et al (2018) Disentangling immediate adaptive introgression from selection on standing introgressed variation in humans. Mol Biol Evol 35:623–630. https://doi.org/10.1093/molbev/msx314
Jeong C et al (2014) Admixture facilitates genetic adaptations to high altitude in Tibet. Nat Commun 5:3281. https://doi.org/10.1038/ncomms4281
Julian C (2017) Epigenomics and human adaptation to high altitude. J Appl Physiol 123:1362–1370. https://doi.org/10.1152/japplphysiol.00351.2017
Julian CG, Moore LG (2019) Human genetic adaptation to high altitude: evidence from the Andes. Gene 10:10020150. https://doi.org/10.3390/genes10020150
Julian CG et al (2009) Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth. Am J Physiol Regul Integr Comp Physiol 296:R1564–R1575. https://doi.org/10.1152/ajpregu.90945.2008
Keith B, Johnson RS, Simon MC (2011) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183
Kelly SA, Panhuis TM, Stoehr AM (2012) Phenotypic plasticity: molecular mechanisms and adaptive significance. Compr Physiol 2:1417–1439. https://doi.org/10.1002/cphy.c110008
Khrameeva EE et al (2014) Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans. Nat Commun 5:3584. https://doi.org/10.1038/ncomms4584
Kronholm I, Collins S (2016) Epigenetic mutations can both help and hinder adaptive evolution. Mol Ecol 25:1856–1868. https://doi.org/10.1111/mec.13296
Lachance G et al (2014) DNMT3a epigenetic program regulates the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. Proc Natl Acad Sci U S A 111:7783–7788. https://doi.org/10.1073/pnas.1322909111
Lawrence ES, Heinrich EC, Wu L, Villafuerte FC, Simonson TS (2018) Genetic missense variants at the EGLN1 Locus associated with high-altitude adaptation in Tibetans are rare in Andeans. FASEB J 32:lb478. https://doi.org/10.1096/fasebj.2018.32.1_supplement.lb478
Lee FS, Percy MJ (2011) The HIF pathway and erythrocytosis. Annu Rev Pathol 6:165–192. https://doi.org/10.1146/annurev-pathol-011110-130321
Leon-Velarde F, Mejia O (2008) Gene expression in chronic high altitude diseases. High Alt Med Biol 9:130–139. https://doi.org/10.1089/ham.2007.1077
Leon-Velarde F et al (2005) Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol 6:147–157. https://doi.org/10.1089/ham.2005.6.147
Levett DZ et al The role of nitrogen oxides in human adaptation to hypoxia. Sci Rep 1(109):109
Lewis H (1966) The origins of the Galla and Somali. J Afr Hist 7:27–46. https://doi.org/10.1017/S0021853700006058
Li Y et al (2014) Population variation revealed high-altitude adaptation of Tibetan Mastiffs. Mol Biol Evol 31:1200–1205
Li S, Li D, Zhao X, Wang Y, Zhu Q (2017) A non-synonymous SNP with the allele frequency correlated with the altitude may contribute to the hypoxia adaptation of Tibetan chicken. PLoS One 12:e0172211
Li JT et al (2018) Comparative genomic investigation of high-elevation adaptation in ectothermic snakes. Proc Natl Acad Sci U S A 26:21
Li YC et al (2019) Neolithic millet farmers contributed to the permanent settlement of the Tibetan Plateau by adopting barley agriculture. Natl Sci Rev 6:1005–1013. https://doi.org/10.1093/nsr/nwz080
Lindo J et al (2018) The genetic prehistory of the Andean highlands 7000 years BP though European contact. Sci Adv 4:eaau4921. https://doi.org/10.1126/sciadv.aau4921
Lisy K, Peet DJ (2008) Turn me on: regulating HIF transcriptional activity. Cell Death Differ 15:642–649. https://doi.org/10.1038/sj.cdd.4402315
Liu KX, Sun XC, Wang SW, Hu B (2007) Association of polymorphisms of 1772 (C-->T) and 1790 (G-->A) in HIF1A gene with hypoxia adaptation in high altitude in Sherpas. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 24:230–232
Liu X et al (2019) EPAS1 gain-of-function mutation contributes to high-altitude adaptation in Tibetan Horses. Mol Biol Evol 36:2591–2603. https://doi.org/10.1093/molbev/msz158
Liu Y et al (2020) De novo transcriptomic and metabolomic analyses reveal the ecological adaptation of high-altitude Bombus pyrosoma. Insects 11:090631. https://doi.org/10.3390/insects11090631
Llamas B et al (2016) Ancient mitochondrial DNA provides high-resolution time scale of the peopling of the Americas. Sci Adv 2:e1501385. https://doi.org/10.1126/sciadv.1501385
Locke AE et al (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197–206
Loenarz C et al (2011) The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO Rep 12:63–70. https://doi.org/10.1038/embor.2010.170
Long K et al (2019) Small non-coding RNA transcriptome of four high-altitude vertebrates and their low-altitude relatives. Sci Data 6:192. https://doi.org/10.1038/s41597-019-0204-5
Lorenzo FR et al (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46:951–956. https://doi.org/10.1038/ng.3067
Lotterhos KE, Whitlock MC (2015) The relative power of genome scans to detect local adaptation depends on sampling design and statistical method. Mol Ecol 24:1031–1046. https://doi.org/10.1111/mec.13100
Lou H et al (2015) A 3.4-kb copy-number deletion near EPAS1 is significantly enriched in high-altitude Tibetans but absent from the Denisovan sequence. Am J Hum Genet 97:54–66. https://doi.org/10.1016/j.ajhg.2015.05.005
Lu D et al (2016) Ancestral origins and genetic history of Tibetan highlanders. Am J Hum Genet 99:580–594. https://doi.org/10.1016/j.ajhg.2016.07.002
Lynch TF, Kennedy KAR (1970) Early human cultural and skeletal remains from Guitarrero Cave, Northern Peru. Science 169:1307. https://doi.org/10.1126/science.169.3952.1307
MacInnis MJ, Rupert JL (2011) Ome on the Range: altitude adaptation, positive selection, and Himalayan genomics. High Alt Med Biol 12:133–139. https://doi.org/10.1089/ham.2010.1090
Martin D, Windsor J (2008) From mountain to bedside: understanding the clinical relevance of human acclimatisation to high-altitude hypoxia. Postgrad Med J 84:622–627. https://doi.org/10.1136/pgmj.2008.068296
Mendez FL, Watkins JC, Hammer MF (2012) A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea. Am J Hum Genet 91:265–274. https://doi.org/10.1016/j.ajhg.2012.06.015
Meyer M et al (2012) A high-coverage genome sequence from an archaic denisovan individual. Science 338:222–226. https://doi.org/10.1126/science.1224344
Meyer MC et al (2017) Permanent human occupation of the central Tibetan Plateau in the early Holocene. Science 355:64–67. https://doi.org/10.1126/science.aag0357
Miao B, Wang Z, Li Y (2017) Genomic analysis reveals hypoxia adaptation in the Tibetan Mastiff by introgression of the gray wolf from the Tibetan Plateau. Mol Biol Evol 34:734–743. https://doi.org/10.1093/molbev/msw274
Mondal M et al (2016) Genomic analysis of Andamanese provides insights into ancient human migration into Asia and adaptation. Nat Genet 48:1066–1070. https://doi.org/10.1038/ng.3621
Moore LG (2017) Human genetic adaptation to high altitudes: Current status and future prospects. Quat Int 461:4–13. https://doi.org/10.1016/j.quaint.2016.09.045
Moore LG et al (2004) Maternal adaptation to high-altitude pregnancy: an experiment of nature--a review. Placenta 25(Suppl A):60–71. https://doi.org/10.1016/j.placenta.2004.01.008
Moreno-Mayar JV et al (2018) Early human dispersals within the Americas. Science 362:eaav2621. https://doi.org/10.1126/science.aav2621
Munroe DJ, Harris TJR (2010) Third-generation sequencing fireworks at Marco Island. Nat Biotechnol 28:426–428. https://doi.org/10.1038/nbt0510-426
Naeije R (2010) Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis 52:456–466. https://doi.org/10.1016/j.pcad.2010.03.004
Nakatsuka N et al (2020) A paleogenomic reconstruction of the deep population history of the Andes. Cell 181:1131–1145. https://doi.org/10.1016/j.cell.2020.04.015
Niermeyer S, Andrade Mollinedo P, Huicho L (2009) Child health and living at high altitude. Arch Dis Child 94:806–811. https://doi.org/10.1136/adc.2008.141838
Ou LC, Leiter JC (2004) Effects of exposure to a simulated altitude of 5500 m on energy metabolic pathways in rats. Respir Physiol Neurobiol 141:59–71. https://doi.org/10.1016/j.resp.2004.04.001
Ouzhuluobu et al (2020) De novo assembly of a Tibetan genome and identification of novel structural variants associated with high-altitude adaptation. Natl Sci Rev 7:391–402. https://doi.org/10.1093/nsr/nwz160
Pagani L et al (2012a) Ethiopian genetic diversity reveals linguistic stratification and complex influences on the Ethiopian gene pool. Am J Hum Genet 91:83–96. https://doi.org/10.1016/j.ajhg.2012.05.015
Pagani L et al (2012b) High altitude adaptation in Daghestani populations from the Caucasus. Hum Genet 131:423–433. https://doi.org/10.1007/s00439-011-1084-8
Pamenter ME, Hall JE, Tanabe Y, Simonson TS (2020) Cross-species insights into genomic adaptations to hypoxia. Front Genet 11:00743. https://doi.org/10.3389/fgene.2020.00743
Pan H et al (2018) Mutations in EPAS1 in congenital heart disease in Tibetans. Biosci Rep 38:1389. https://doi.org/10.1042/bsr20181389
Peng Y et al (2011) Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol 28:1075–1081. https://doi.org/10.1093/molbev/msq290
Peng Y et al (2017) Down-regulation of EPAS1 transcription and genetic adaptation of Tibetans to high-altitude hypoxia. Mol Biol Evol 34:818–830. https://doi.org/10.1093/molbev/msw280
Petr M, Paabo S, Kelso J, Vernot B (2019) Limits of long-term selection against Neandertal introgression. Proc Natl Acad Sci U S A 116:1639–1644. https://doi.org/10.1073/pnas.1814338116
Piperno A et al (2011) Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project. Blood 117:2953–2959. https://doi.org/10.1182/blood-2010-08-299859
Pleurdeau D (2005) Human technical behavior in the African middle stone age: the lithic assemblage of Porc-Epic Cave (Dire Dawa, Ethiopia). Afr Archaeol Rev 22:177–197. https://doi.org/10.1007/s10437-006-9000-7
Posth C et al (2018) Reconstructing the deep population history of Central and South America. Cell 175:1185–1197. https://doi.org/10.1016/j.cell.2018.10.027
Prabhakar NR (2020) 2019 nobel prize in physiology or medicine. Physiology 35:81–83. https://doi.org/10.1152/physiol.00001.2020
Prior SJ et al (2003) Sequence variation in hypoxia-inducible factor 1alpha (HIF1A): association with maximal oxygen consumption. Physiol Genomics 15:20–26. https://doi.org/10.1152/physiolgenomics.00061.2003
Prufer K et al (2014) The complete genome sequence of a Neanderthal from the Altai mountains. Nature 505:43–49. https://doi.org/10.1038/nature12886
Prufer K et al (2017) A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358:655–658. https://doi.org/10.1126/science.aao1887
Qi X et al (2013) Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau. Mol Biol Evol 30:1761–1778. https://doi.org/10.1093/molbev/mst093
Qi X et al (2019) The transcriptomic landscape of Yaks reveals molecular pathways for high altitude adaptation. Genome Biol Evol 11:72–85. https://doi.org/10.1093/gbe/evy264
Qin ZD et al (2010) A mitochondrial revelation of early human migrations to the Tibetan Plateau before and after the last glacial maximum. Am J Phys Anthropol 143:555–569. https://doi.org/10.1002/ajpa.21350
Quan, C. et al. (2020). Characterization of structural variation in Tibetans reveals new evidence of high-altitude adaptation and introgression. bioRxiv, 2020.2012.2001.401174. https://doi.org/10.1101/2020.12.01.401174
Rademaker K et al (2014) Paleoindian settlement of the high-altitude Peruvian Andes. Science 346:466–469. https://doi.org/10.1126/science.1258260
Rawluszko-Wieczorek AA, Horbacka K, Krokowicz P, Misztal M, Jagodzinski PP (2014) Prognostic potential of DNA methylation and transcript levels of HIF1A and EPAS1 in colorectal cancer. Mol Cancer Res 12:1112–1127. https://doi.org/10.1158/1541-7786.MCR-14-0054
Richards EJ (2006) Inherited epigenetic variation--revisiting soft inheritance. Nat Rev Genet 7:395–401. https://doi.org/10.1038/nrg1834
Rothhammer F, Santoro CM (2001) El Desarrollo Cultural En El Valle De Azapa, Extremo Norte De Chile Y Su Vinculación Con Los Desplazamientos Poblacionales Altiplánicos. Lat Am Antiq 12:59–66. https://doi.org/10.2307/971757
Rothhammer F, Silva C (1989) Peopling of Andean South America. Am J Phys Anthropol 78:403–410. https://doi.org/10.1002/ajpa.1330780308
Rupert JL, Hochachka PW (2001) Genetic approaches to understanding human adaptation to altitude in the Andes. J Exp Biol 204:3151–3160
Sabeti PC et al (2006) Positive natural selection in the human lineage. Science 312:1614–1620. https://doi.org/10.1126/science.1124309
Sabeti PC et al (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449:913–918. https://doi.org/10.1038/nature06250
Sackton TB, Clark N (2019) Convergent evolution in the genomics era: new insights and directions. Philos Trans R Soc B 374:20190102. https://doi.org/10.1098/rstb.2019.0102
Sandoval JR et al (2013) The genetic history of indigenous populations of the Peruvian and Bolivian Altiplano: the legacy of the Uros. PLoS One 8:e73006. https://doi.org/10.1371/journal.pone.0073006
Sandweiss DH et al (1998) Quebrada jaguay: early south American maritime adaptations. Science 281:1830–1832. https://doi.org/10.1126/science.281.5384.1830
Sankararaman S et al (2014) The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507:354–357. https://doi.org/10.1038/nature12961
Sargent C et al (2013) The impact of altitude on the sleep of young elite soccer players (ISA3600). Br J Sports Med 47(Suppl 1):i86–i92. https://doi.org/10.1136/bjsports-2013-092829
Scheinfeldt LB, Tishkoff SA (2010) Living the high life: high-altitude adaptation. Genome Biol 11:133. https://doi.org/10.1186/gb-2010-11-9-133
Scheinfeldt LB et al (2012) Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 13:R1. https://doi.org/10.1186/gb-2012-13-1-r1
Schneider MP, Boesen EI, Pollock DM (2007) Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol 47:731–759. https://doi.org/10.1146/annurev.pharmtox.47.120505.105134
Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354. https://doi.org/10.1038/nrm1366
Schumacker PT et al (2014) High altitude: human adaptation to hypoxia. Springer, New York
Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578. https://doi.org/10.1146/annurev.cellbio.15.1.551
Semenza GL (2004) Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19:176–182. https://doi.org/10.1152/physiol.00001.2004
Seo JS et al (2016) De novo assembly and phasing of a Korean human genome. Nature 538:243–247. https://doi.org/10.1038/nature20098
Shao Y et al (2015) Genetic adaptations of the plateau zokor in high-elevation burrows. Sci Rep 5:17262. https://doi.org/10.1038/srep17262
Shi L et al (2016) Long-read sequencing and de novo assembly of a Chinese genome. Nat Commun 7:12065. https://doi.org/10.1038/ncomms12065
Silventoinen K et al (2003) Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res 6:399–408. https://doi.org/10.1375/136905203770326402
Simonson TS et al (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329:72. https://doi.org/10.1126/science.1189406
Song S et al (2016) Exome sequencing reveals genetic differentiation due to high-altitude adaptation in the Tibetan cashmere goat (Capra hircus). BMC Genomics 17:122. https://doi.org/10.1186/s12864-016-2449-0.
Steinmann K, Richter AM, Dammann RH (2011) Epigenetic silencing of erythropoietin in human cancers. Genes Cancer 2:65–73. https://doi.org/10.1177/1947601911405043
Stobdan T et al (2015) Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice. Proc Natl Acad Sci U S A 112:10425–10430. https://doi.org/10.1073/pnas.1507486112
Storz JF, Scott GR, Cheviron ZA (2010) Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J Exp Biol 213:4125–4136. https://doi.org/10.1242/jeb.048181
Suzuki K et al (2003) Genetic variation in hypoxia-inducible factor 1alpha and its possible association with high altitude adaptation in Sherpas. Med Hypotheses 61:385–389. https://doi.org/10.1016/s0306-9877(03)00178-6
Szpak M et al (2018) FineMAV: prioritizing candidate genetic variants driving local adaptations in human populations. Genome Biol 19:5. https://doi.org/10.1186/s13059-017-1380-2
Tarazona-Santos E et al (2001) Genetic differentiation in South Amerindians is related to environmental and cultural diversity: evidence from the Y chromosome. Am J Hum Genet 68:1485–1496. https://doi.org/10.1086/320601
Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82. https://doi.org/10.1101/gad.11.1.72
Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (1998) The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12:3320–3324. https://doi.org/10.1101/gad.12.21.3320
Tucci S et al (2018) Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia. Science 361:511–516. https://doi.org/10.1126/science.aar8486
Udpa N et al (2014) Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol 15:R36. https://doi.org/10.1186/gb-2014-15-2-r36
Velotta JP, Ivy CM, Wolf CJ, Scott GR, Cheviron ZA (2018) Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution 72:2712–2727. https://doi.org/10.1111/evo.13626
Vernot B, Akey JM (2014) Resurrecting surviving Neandertal lineages from modern human genomes. Science 343:1017–1021. https://doi.org/10.1126/science.1245938
Virues-Ortega J, Garrido E, Javierre C, Kloezeman KC (2006) Human behaviour and development under high-altitude conditions. Dev Sci 9:400–410. https://doi.org/10.1111/j.1467-7687.2006.00505.x
Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72. https://doi.org/10.1371/journal.pbio.0040072
Vuckovic D et al (2020) The polygenic and monogenic basis of blood traits and diseases. Cell 182:1214–1231. https://doi.org/10.1016/j.cell.2020.08.008
Wang B et al (2011) On the origin of Tibetans and their genetic basis in adapting high-altitude environments. PLoS One 6:e17002. https://doi.org/10.1371/journal.pone.0017002
Wang G-D et al (2014) Genetic convergence in the adaptation of dogs and humans to the high-altitude environment of the tibetan plateau. Genome Biol Evol 6:2122–2128. https://doi.org/10.1093/gbe/evu162
Weir BS, Hill WG (2002) Estimating F-statistics. Annu Rev Genet 36:721–750. https://doi.org/10.1146/annurev.genet.36.050802.093940
Weitz CA, Garruto RM, Chin CT (2016) Larger FVC and FEV1 among Tibetans compared to Han born and raised at high altitude. Am J Phys Anthropol 159:244–255. https://doi.org/10.1002/ajpa.22873
Wenger RH, Stiehl DP, Camenisch G (2005) Integration of oxygen signaling at the consensus HRE. Sci STKE 2005:re12. https://doi.org/10.1126/stke.3062005re12
West JB (1982) Respiratory and circulatory control at high altitudes. J Exp Biol 100:147
Witt KE, Huerta-Sanchez E (2019) Convergent evolution in human and domesticate adaptation to high-altitude environments. Philos Trans R Soc Lond Ser B Biol Sci 374:20180235. https://doi.org/10.1098/rstb.2018.0235
Wu TY et al (2005) Hemoglobin levels in Tibet: different effect of age and gender for Tibetans vs Han. Comp Clin Pathol 14:25–35. https://doi.org/10.1007/s00580-005-0550-x
Wu DD et al (2018) Pervasive introgression facilitated domestication and adaptation in the Bos species complex. Nat Ecol Evol 2:1139–1145. https://doi.org/10.1038/s41559-018-0562-y
Wuren T et al (2014) Shared and unique signals of high-altitude adaptation in geographically distinct Tibetan populations. PLoS One 9:e88252. https://doi.org/10.1371/journal.pone.0088252
Xiang K et al (2013) Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Mol Biol Evol 30:1889–1898. https://doi.org/10.1093/molbev/mst090
Xin J et al (2020) Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation. Nat Commun 11:4928. https://doi.org/10.1038/s41467-020-18638-8
Xu S et al (2010) A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol 28:1003–1011
Xu X-H et al (2014) Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. Sci Rep 4:7465–7465. https://doi.org/10.1038/srep07465
Xu J et al (2015) Association between genetic polymorphisms of EDNRA gene and high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau. Zhonghua Yi Xue Za Zhi 95:1382–1385
Yang D et al (2016) HMOX2 functions as a modifier gene for high-altitude adaptation in Tibetans. Hum Mutat 37:216–223. https://doi.org/10.1002/humu.22935
Yang J et al (2017) Genetic signatures of high-altitude adaptation in Tibetans. Proc Natl Acad Sci U S A 114:4189–4194. https://doi.org/10.1073/pnas.1617042114
Yasukochi Y, Nishimura T, Motoi M, Watanuki S (2018) Association of EGLN1 genetic polymorphisms with SpO2 responses to acute hypobaric hypoxia in a Japanese cohort. J Physiol Anthropol 37:9. https://doi.org/10.1186/s40101-018-0169-7
Yi X et al (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:75–78. https://doi.org/10.1126/science.1190371
Yip G, Heinrich EC, Villafuerte FC, Simonson TS (2018) Heme-oxygenase 2 (HMOX2) variants associated with evolutionary adaptation and hemoglobin concentration in Tibetans are common in Andean Highlanders. FASEB J 32:lb413
Yu G, Wang L-G, Han Y, He Q-Y (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16:284–287. https://doi.org/10.1089/omi.2011.0118
Yuan Y, Chung CY, Chan TF (2020) Advances in optical mapping for genomic research. Comput Struct Biotechnol J 18:2051–2062. https://doi.org/10.1016/j.csbj.2020.07.018
Yun Sung Cho LH, Hou H, Lee H, Jiaohui X, Kwon S, Sukhun O, Kim H-M, Jho S, Kim S, Shin Y-A, Kim BC, Kim H, Kim C-U, Luo S-J, Johnson WE, Koepfli K-P, Schmidt-Küntzel A, Turner JA, Marker L, Harper C, Miller SM, Jacobs W, Bertola LD, Kim TH, Lee S, Zhou Q, Jung H-J, Xiao X, Gadhvi P, Pengwei X, Xiong Y, Luo Y, Pan S, Gou C, Chu X, Zhang J, Liu S, He J, Chen Y, Yang L, Yang Y, He J, Liu S, Wang J, Kim CH, Kwak H, Kim J-S, Hwang S, Ko J, Kim C-B, Kim S, Bayarlkhagva D, Paek WK, Kim S-J, O'Brien SJ, Wang J, Bhak J (2013) The tiger genome and comparative analysis with lion and snow leopard genomes. Nat Commun 4:2433
Zhang W et al (2014) Hypoxia adaptations in the grey wolf (Canis lupus chanco) from Qinghai-Tibet Plateau. PLoS Genet 10:e1004466. https://doi.org/10.1371/journal.pgen.1004466.
Zhang Q et al (2016) The expression plasticity of hypoxia related genes in high altitude and plains Nanorana parkeri populations. Asian Herpetol Res 7:21–27. https://doi.org/10.16373/j.cnki.ahr.150056.
Zhang C et al (2017a) Differentiated demographic histories and local adaptations between Sherpas and Tibetans. Genome Biol 18:1242. https://doi.org/10.1186/s13059-017-1242-y
Zhang H et al (2017b) Cross-altitude analysis suggests a turning point at the elevation of 4,500 m for polycythemia prevalence in Tibetans. Am J Hematol 92:E552–E554. https://doi.org/10.1002/ajh.24809
Zhang XL et al (2018) The earliest human occupation of the high-altitude Tibetan Plateau 40 thousand to 30 thousand years ago. Science 362:1049–1051
Zhang Q, Yan Q, Yang H, Wei W (2019) Oxygen sensing and adaptability won the 2019 nobel prize in physiology or medicine. Genes Dis 6:328–332. https://doi.org/10.1016/j.gendis.2019.10.006
Zhang D et al (2020) Denisovan DNA in late pleistocene sediments from baishiya karst cave on the Tibetan Plateau. Science 370:584–587. https://doi.org/10.1126/science.abb6320
Zhou D et al (2013) Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. Am J Hum Genet 93:452–462. https://doi.org/10.1016/j.ajhg.2013.07.011
Zhuang J et al (1993) Hypoxic ventilatory responsiveness in Tibetan compared with Han residents of 3,658 m. J Appl Physiol 74:303–311. https://doi.org/10.1152/jappl.1993.74.1.303
Acknowledgements
This study was supported by the National Science Fund for Distinguished Young Scholars (31525014), the National Natural Science Foundation of China (NSFC) (31771388, 91731303, 32030020, 31961130380, and 32041008), the Strategic Priority Research Program (XDB38000000) and Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) of the Chinese Academy of Sciences (CAS), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the National Key Research and Development Program (2016YFC0906403), and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Deng, L., Xu, S. (2021). Population Genomics of High-Altitude Adaptation. In: Saitou, N. (eds) Evolution of the Human Genome II. Evolutionary Studies. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56904-6_3
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