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Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data


High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.


Vyšlo v časopise: Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001116
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001116

Souhrn

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.


Zdroje

1. AldenderferM

2003 Moving up in the world. American Scientist 91 542 549

2. ZhaoM

KongQP

WangHW

PengMS

XieXD

2009 Mitochondrial genome evidence reveals successful Late Paleolithic settlement on the Tibetan Plateau. Proc Natl Acad Sci U S A 106 21230 21235

3. NiermeyerS

ZamdioS

MooreLG

2001 The People.

HTaSRB

High Altitude: An exploration of Human Adaptation New York Marcel Dekker, Inc

4. MooreLG

2001 Human genetic adaptation to high altitude. High Alt Med Biol 2 257 279

5. BeallCM

BrittenhamGM

StrohlKP

BlangeroJ

Williams-BlangeroS

1998 Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106 385 400

6. BeallCM

GoldsteinMC

1987 Hemoglobin concentration of pastoral nomads permanently resident at 4,850–5,450 meters in Tibet. Am J Phys Anthropol 73 433 438

7. WinslowRM

ChapmanKW

GibsonCC

SamajaM

MongeCC

1989 Different hematologic responses to hypoxia in Sherpas and Quechua Indians. J Appl Physiol 66 1561 1569

8. ZhuangJ

DromaT

SunS

JanesC

McCulloughRE

1993 Hypoxic ventilatory responsiveness in Tibetan compared with Han residents of 3,658 m. J Appl Physiol 74 303 311

9. GrovesBM

DromaT

SuttonJR

McCulloughRG

McCulloughRE

1993 Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J Appl Physiol 74 312 318

10. BeallCM

BlangeroJ

Williams-BlangeroS

GoldsteinMC

1994 Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders. Am J Phys Anthropol 95 271 276

11. BeallCM

StrohlKP

BlangeroJ

Williams-BlangeroS

DeckerMJ

1997 Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders. Hum Biol 69 597 604

12. BeallCM

2000 Tibetan and Andean contrasts in adaptation to high-altitude hypoxia. Adv Exp Med Biol 475 63 74

13. BeallCM

2000 Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72 201 228

14. ShriverMD

MeiR

BighamA

MaoX

BrutsaertTD

2006 Finding the genes underlying adaptation to hypoxia using genomic scans for genetic adaptation and admixture mapping. Adv Exp Med Biol 588 89 100

15. TishkoffSA

ReedFA

RanciaroA

VoightBF

BabbittCC

2007 Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39 31 40

16. NortonHL

KittlesRA

ParraE

McKeigueP

MaoX

2007 Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol Biol Evol 24 710 722

17. McEvoyB

BelezaS

ShriverMD

2006 The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model. Hum Mol Genet 15 Spec No 2 R176 181

18. FlintJ

HardingRM

BoyceAJ

CleggJB

1993 The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 6 215 262

19. WeatherallDJ

2001 Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet 2 245 255

20. KwiatkowskiDP

2005 How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77 171 192

21. GesangL

LiuG

CenW

QiuC

ZhuomaC

2002 Angiotensin-converting enzyme gene polymorphism and its association with essential hypertension in a Tibetan population. Hypertens Res 25 481 485

22. HottaJ

HanaokaM

DromaY

KatsuyamaY

OtaM

2004 Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 126 825 830

23. BighamAW

KiyamuM

Leon-VelardeF

ParraEJ

Rivera-ChM

2008 Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt Med Biol 9 167 178

24. HopflG

OgunsholaO

GassmannM

2003 Hypoxia and high altitude. The molecular response. Adv Exp Med Biol 543 89 115

25. BighamA

MaoX

BrutsaertT

WilsonM

JulianCG

2010 Identifying Positive Selection Candidate Loci for High-Altitude Adaptation in Andean Populations. Human Genomics 4 in press

26. MooreLG

ShriverM

BemisL

VargasE

2006 An evolutionary model for identifying genetic adaptation to high altitude. Adv Exp Med Biol 588 101 118

27. BarrettJC

FryB

MallerJ

DalyMJ

2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265

28. Lopez HerraezD

BauchetM

TangK

TheunertC

PugachI

2009 Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs. PLoS ONE 4 e7888

29. PattersonN

PriceAL

ReichD

2006 Population structure and eigenanalysis. PLoS Genet 2 e190

30. TangH

QuertermousT

RodriguezB

KardiaSL

ZhuX

2005 Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 76 268 275

31. TajimaF

1989 Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123 585 595

32. ZhangC

BaileyDK

AwadT

LiuG

XingG

2006 A whole genome long-range haplotype (WGLRH) test for detecting imprints of positive selection in human populations. Bioinformatics 22 2122 2128

33. ShriverM

KennedyGC

ParraEJ

LawsonHA

HuangJ

2004 The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs. Human Genomics 1 274 286

34. StorzJF

PayseurBA

NachmanMW

2004 Genome scans of DNA variability in humans reveal evidence for selective sweeps outside of Africa. Mol Biol Evol 21 1800 1811

35. PickrellJK

CoopG

NovembreJ

KudaravalliS

LiJZ

2009 Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19 826 837

36. MooreLG

ZamudioS

ZhuangJ

DromaT

ShohetRV

2002 Analysis of the myoglobin gene in Tibetans living at high altitude. High Alt Med Biol 3 39 47

37. RedonR

IshikawaS

FitchKR

FeukL

PerryGH

2006 Global variation in copy number in the human genome. Nature 444 444 454

38. PintoD

MarshallC

FeukL

SchererSW

2007 Copy-number variation in control population cohorts. Hum Mol Genet 16 Spec No. 2 R168 173

39. ConradDF

PintoD

RedonR

FeukL

GokcumenO

2009 Origins and functional impact of copy number variation in the human genome. Nature 464 704 712

40. BeaumontM

NicholsR

1996 Evaluating loci for use in the genetic analysis of population structure. Proceedings of the Royal Society of London in B Biological Sciences 263 1619 1626

41. BowcockAM

KiddJR

MountainJL

HebertJM

CarotenutoL

1991 Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. Proc Natl Acad Sci U S A 88 839 843

42. LewontinRC

KrakauerJ

1973 Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics 156 439 447

43. AkeyJM

ZhangG

ZhangK

JinL

ShriverMD

2002 Interrogating a high-density SNP map for signatures of natural selection. Genome Res 12 1805 1814

44. WangGL

JiangBH

RueEA

SemenzaGL

1995 Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92 5510 5514

45. EpsteinAC

GleadleJM

McNeillLA

HewitsonKS

O'RourkeJ

2001 C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107 43 54

46. BunnHF

PoytonRO

1996 Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76 839 885

47. HirsilaM

KoivunenP

GunzlerV

KivirikkoKI

MyllyharjuJ

2003 Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 278 30772 30780

48. MaxwellPH

WiesenerMS

ChangGW

CliffordSC

VauxEC

1999 The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399 271 275

49. JaakkolaP

MoleDR

TianYM

WilsonMI

GielbertJ

2001 Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292 468 472

50. IvanM

KondoK

YangH

KimW

ValiandoJ

2001 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292 464 468

51. ErzurumSC

GhoshS

JanochaAJ

XuW

BauerS

2007 Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc Natl Acad Sci U S A 104 17593 17598

52. JulianCG

WilsonMJ

LopezM

YamashiroH

TellezW

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

53. MooreLG

ZamudioS

ZhuangJ

SunS

DromaT

2001 Oxygen transport in tibetan women during pregnancy at 3,658 m. Am J Phys Anthropol 114 42 53

54. WilsonMJ

LopezM

VargasM

JulianC

TellezW

2007 Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents. Am J Physiol Regul Integr Comp Physiol 293 R1313 1324

55. LorenzoVF

YangY

SimonsonTS

NussenzveigR

JordeLB

2009 Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three-generation Han Chinese family. Blood Cells Mol Dis 43 221 225

56. MooreLG

2011 Uterine blood flow as a determinant of feto-placental development.

BurtonGJ

BarkerDJP

The Placenta and Fetal Programming Cambridge Cambridge University Press In press

57. McCarrollSA

KuruvillaFG

KornJM

CawleyS

NemeshJ

2008 Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40 1166 1174

58. BrutsaertTD

ParraEJ

ShriverMD

GamboaA

PalaciosJA

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

59. TorroniA

MillerJA

MooreLG

ZamudioS

ZhuangJ

1994 Mitochondrial DNA analysis in Tibet: implications for the origin of the Tibetan population and its adaptation to high altitude. Am J Phys Anthropol 93 189 199

60. ShriverMD

ParraEJ

DiosS

BonillaC

NortonH

2003 Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112 387 399

61. BonillaC

ShriverMD

ParraEJ

JonesA

FernandezJR

2004 Ancestral proportions and their association with skin pigmentation and bone mineral density in Puerto Rican women from New York city. Hum Genet 115 57 68

62. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

63. PurcellS

http://pngu.mgh.harvard.edu/purcell/plink/. v1.05 ed

64. BenjaminiY

HochbergY

1995 Controlling the flase discovery rate: a practical and powerful approach to mulitple testing. Jounral of the Royal Statistical Society 57 289 300

65. WrightS

1950 Genetical structure of populations. Nature 166 247 249

66. WeirBS

CockerhamCC

1984 Estimating F-statistics for the analysis of population structure. Evolution 38 951 953

67. KauerMO

DieringerD

SchlottererC

2003 A microsatellite variability screen for positive selection associated with the “out of Africa” habitat expansion of Drosophila melanogaster. Genetics 165 1137 1148

68. SchlottererC

2002 A microsatellite-based multilocus screen for the identification of local selective sweeps. Genetics 160 753 763

69. VoightBF

KudaravalliS

WenX

PritchardJK

2006 A map of recent positive selection in the human genome. PLoS Biol 4 e72

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Genetika Reprodukčná medicína

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