Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians

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Deedu (DU) Mongolians, who migrated from the Mongolian steppes to the Qinghai-Tibetan Plateau approximately 500 years ago, are challenged by environmental conditions similar to native Tibetan highlanders. Identification of adaptive genetic factors in this population could provide insight into coordinated physiological responses to this environment. Here we examine genomic and phenotypic variation in this unique population and present the first complete analysis of a Mongolian whole-genome sequence. High-density SNP array data demonstrate that DU Mongolians share genetic ancestry with other Mongolian as well as Tibetan populations, specifically in genomic regions related with adaptation to high altitude. Several selection candidate genes identified in DU Mongolians are shared with other Asian groups (e.g., EDAR), neighboring Tibetan populations (including high-altitude candidates EPAS1, PKLR, and CYP2E1), as well as genes previously hypothesized to be associated with metabolic adaptation (e.g., PPARG). Hemoglobin concentration, a trait associated with high-altitude adaptation in Tibetans, is at an intermediate level in DU Mongolians compared to Tibetans and Han Chinese at comparable altitude. Whole-genome sequence from a DU Mongolian (Tianjiao1) shows that about 2% of the genomic variants, including more than 300 protein-coding changes, are specific to this individual. Our analyses of DU Mongolians and the first Mongolian genome provide valuable insight into genetic adaptation to extreme environments.

Vyšlo v časopise: Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003634
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003634

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Zdroje

1. Keyser-TracquiC, CrubezyE, PamzsavH, VargaT, LudesB (2006) Population origins in Mongolia: genetic structure analysis of ancient and modern DNA. Am J Phys Anthropol 131: 272–281.

2. NasidzeI, QuinqueD, DupanloupI, CordauxR, KokshunovaL, et al. (2005) Genetic evidence for the Mongolian ancestry of Kalmyks. Am J Phys Anthropol 128: 846–854.

3. ZerjalT, XueY, BertorelleG, WellsRS, BaoW, et al. (2003) The genetic legacy of the Mongols. Am J Hum Genet 72: 717–721.

4. DulikMC, OsipovaLP, SchurrTG (2011) Y-chromosome variation in Altaian Kazakhs reveals a common paternal gene pool for Kazakhs and the influence of Mongolian expansions. PLoS One 6: e17548.

5. Hei L, Tie Z (2011) Shine Nairuulsan Mongol Undusten-ne dobch tuuh (Mongolian History): Inner Mongolian People Publishing Agency.

6. Nima B (2011) Mingan on ne dunji huun (Great Man of the Millennium): Inner Mongolian people publishing agency.

7. BotchkarevVA, FessingMY (2005) Edar signaling in the control of hair follicle development. J Investig Dermatol Symp Proc 10: 247–251.

8. YaoYG, KongQP, WangCY, ZhuCL, ZhangYP (2004) Different matrilineal contributions to genetic structure of ethnic groups in the silk road region in china. Mol Biol Evol 21: 2265–2280.

9. Zhang M (1988) khoshuu nutug in temteglel (Mongolian Nomadic History). Beijing: Nationality Press.

10. GeRL, SimonsonTS, CookseyRC, TannaU, QinG, et al. (2012) Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. Mol Genet Metab 106: 244–247.

11. ChevironZA, BachmanGC, ConnatyAD, McClellandGB, StorzJF (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.

12. BrownEA (2012) Genetic explorations of recent human metabolic adaptations: hypotheses and evidence. Biol Rev Camb Philos Soc 87: 838–55.

13. SabetiPC, SchaffnerSF, FryB, LohmuellerJ, VarillyP, et al. (2006) Positive natural selection in the human lineage. Science 312: 1614–1620.

14. HardwickRJ, MachadoLR, ZuccheratoLW, AntolinosS, XueY, et al. (2011) A worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing DEFB103 gene copy in East Asia. Hum Mutat 32: 743–750.

15. SpiegelmanBM (1997) Peroxisome proliferator-activated receptor gamma: A key regulator of adipogenesis and systemic insulin sensitivity. Eur J Med Res 2: 457–464.

16. AuwerxJ (1999) PPARgamma, the ultimate thrifty gene. Diabetologia 42: 1033–1049.

17. KolbleK (1993) Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225. Genomics 18: 702–704.

18. FujimotoA, KimuraR, OhashiJ, OmiK, YuliwulandariR, et al. (2008) A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness. Hum Mol Genet 17: 835–843.

19. SabetiPC, VarillyP, FryB, LohmuellerJ, HostetterE, et al. (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913–918.

20. SimonsonTS, YangY, HuffCD, YunH, QinG, et al. (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329: 72–75.

21. YiX, LiangY, Huerta-SanchezE, JinX, CuoZ, et al. (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329: 75–78.

22. BeallCM, CavalleriGL, DengL, ElstonRC, GaoY, 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.

23. FormentiF, Constantin-TeodosiuD, EmmanuelY, CheesemanJ, DorringtonKL, et al. (2010) Regulation of human metabolism by hypoxia-inducible factor. Proc Natl Acad Sci U S A 107: 12722–12727.

24. XuS, LiS, YangY, TanJ, LouH, et al. (2011) A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol 28: 1003–1011.

25. WangB, ZhangYB, ZhangF, LinH, WangX, et al. (2011) On the origin of Tibetans and their genetic basis in adapting high-altitude environments. PLoS One 6: e17002.

26. BighamA, BauchetM, PintoD, MaoX, AkeyJM, et al. (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6: e1001116.

27. PengY, YangZ, ZhangH, CuiC, QiX, et al. (2011) Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol 28: 1075–1081.

28. SimonsonTS, McClainDA, JordeLB, PrchalJT (2012) Genetic determinants of Tibetan high-altitude adaptation. Hum Genet 131: 527–533.

29. BeallCM (2007) Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A 104 Suppl 1: 8655–8660.

30. AdamsWH, StrangLJ (1975) Hemoglobin levels in persons of tibetan ancestry living at high altitude. Proc Soc Exp Biol Med 149: 1036–1039.

31. BeallCM, ReichsmanAB (1984) Hemoglobin levels in a Himalayan high altitude population. Am J Phys Anthropol 63: 301–306.

32. WuT, WangX, WeiC, ChengH, LiY, et al. (2005) Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J Appl Physiol 98: 598–604.

33. van OvenM, KayserM (2009) Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat 30: E386–394.

34. CobleMD, JustRS, O'CallaghanJE, LetmanyiIH, PetersonCT, et al. (2004) Single nucleotide polymorphisms over the entire mtDNA genome that increase the power of forensic testing in Caucasians. Int J Legal Med 118: 137–146.

35. HerrnstadtC, ElsonJL, FahyE, PrestonG, TurnbullDM, et al. (2002) Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70: 1152–1171.

36. RoostaluU, KutuevI, LoogvaliEL, MetspaluE, TambetsK, et al. (2007) Origin and expansion of haplogroup H, the dominant human mitochondrial DNA lineage in West Eurasia: the Near Eastern and Caucasian perspective. Mol Biol Evol 24: 436–448.

37. International Society of Genetic Genealogy (2012) Y-DNA Haplogroup Tree 2012, Version 7.17. http://www.isogg.org/tree/.

38. HammerMF, KarafetTM, ParkH, OmotoK, HariharaS, et al. (2006) Dual origins of the Japanese: common ground for hunter-gatherer and farmer Y chromosomes. J Hum Genet 51: 47–58.

39. SuB, XiaoC, DekaR, SeielstadMT, KangwanpongD, et al. (2000) Y chromosome haplotypes reveal prehistorical migrations to the Himalayas. Hum Genet 107: 582–590.

40. EilbeckK, LewisSE, MungallCJ, YandellM, SteinL, et al. (2005) The Sequence Ontology: a tool for the unification of genome annotations. Genome Biol 6: R44.

41. OhnishiA, YoshimuraT, KanehisaY, FukushimaY (1995) [A case of hereditary motor and sensory neuropathy type I with a new type of peripheral myelin protein (PMP)-22 mutation]. Rinsho Shinkeigaku 35: 788–792.

42. TennessenJA, BighamAW, O'ConnorTD, FuW, KennyEE, et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69.

43. LevyS, SuttonG, NgPC, FeukL, HalpernAL, et al. (2007) The diploid genome sequence of an individual human. PLoS Biol 5: e254.

44. WheelerDA, SrinivasanM, EgholmM, ShenY, ChenL, et al. (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452: 872–876.

45. MacArthurDG, BalasubramanianS, FrankishA, HuangN, MorrisJ, et al. (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335: 823–828.

46. KumarP, HenikoffS, NgPC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4: 1073–1081.

47. AldenderferM (2011) Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol 12: 141–147.

48. ZhaoM, KongQP, WangHW, PengMS, XieXD, et al. (2009) Mitochondrial genome evidence reveals successful Late Paleolithic settlement on the Tibetan Plateau. Proc Natl Acad Sci U S A 106: 21230–21235.

49. HuffCD, WitherspoonDJ, SimonsonTS, XingJ, WatkinsWS, et al. (2011) Maximum-likelihood estimation of recent shared ancestry (ERSA). Genome Res 21(5): 768–74.

50. XingJ, WatkinsWS, ShlienA, WalkerE, HuffCD, et al. (2010) Toward a more uniform sampling of human genetic diversity: A survey of worldwide populations by high-density genotyping. Genomics 96: 199–210.

51. XingJ, WatkinsWS, WitherspoonDJ, ZhangY, GutherySL, et al. (2009) Fine-scaled human genetic structure revealed by SNP microarrays. Genome Res 19: 815–825.

52. AlexanderDH, NovembreJ, LangeK (2009) Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19: 1655–1664.

53. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

54. VoightBF, KudaravalliS, WenX, PritchardJK (2006) A Map of Recent Positive Selection in the Human Genome. PLoS Biol 4: e72.

55. Alkorta-AranburuG, BeallCM, WitonskyDB, GebremedhinA, PritchardJK, et al. (2012) The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet 8: e1003110.

56. YandellM, HuffC, HuH, SingletonM, MooreB, et al. (2011) A probabilistic disease-gene finder for personal genomes. Genome Res 21: 1529–1542.

57. LiH (2011) Tabix: fast retrieval of sequence features from generic TAB-delimited files. Bioinformatics 27: 718–719.