Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations.
Vyšlo v časopise: Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003404 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003404
1. GrossmanSR, ShylakhterI, KarlssonEK, ByrneEH, MoralesS, et al. (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327 : 883–886.
2. TennessenJA, MadeoyJ, AkeyJM (2010) Signatures of positive selection apparent in a small sample of human exomes. Genome Res 20 : 1327–1334.
3. VoightBF, KudaravalliS, WenX, PritchardJK (2006) A map of recent positive selection in the human genome. PLoS Biol 4: e72 doi:10.1371/journal.pbio.0040072.
4. AkeyJM (2009) Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res 19 : 711–722.
5. PickrellJK, CoopG, NovembreJ, KudaravalliS, LiJZ, et al. (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19 : 826–837.
6. NielsenR, HellmannI, HubiszM, BustamanteC, ClarkAG (2007) Recent and ongoing selection in the human genome. Nat Rev Genet 8 : 857–868.
7. AndresAM, HubiszMJ, IndapA, TorgersonDG, DegenhardtJD, et al. (2009) Targets of balancing selection in the human genome. Mol Biol Evol 26 : 2755–2764.
8. FumagalliM, CaglianiR, PozzoliU, RivaS, ComiGP, et al. (2009) Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res 19 : 199–212.
9. BubbKL, BoveeD, BuckleyD, HaugenE, KibukawaM, et al. (2006) Scan of human genome reveals no new Loci under ancient balancing selection. Genetics 173 : 2165–2177.
10. HedrickPW, ThomsonG (1983) Evidence for balancing selection at HLA. Genetics 104 : 449–456.
11. AllisonAC (1954) The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Trans R Soc Trop Med Hyg 48 : 312–318.
12. AndresAM, DennisMY, KretzschmarWW, CannonsJL, Lee-LinSQ, et al. (2010) Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet 6: e1001157 doi:10.1371/journal.pgen.1001157.
13. WoodingS, KimUK, BamshadMJ, LarsenJ, JordeLB, et al. (2004) Natural selection and molecular evolution in PTC, a bitter-taste receptor gene. Am J Hum Genet 74 : 637–646.
14. VerrelliBC, McDonaldJH, ArgyropoulosG, Destro-BisolG, FromentA, et al. (2002) Evidence for balancing selection from nucleotide sequence analyses of human G6PD. Am J Hum Genet 71 : 1112–1128.
15. BamshadMJ, MummidiS, GonzalezE, AhujaSS, DunnDM, et al. (2002) A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci U S A 99 : 10539–10544.
16. SunC, HuoD, SouthardC, NemesureB, HennisA, et al. (2011) A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk. Hum Genet 130 : 767–775.
17. WilsonJN, RockettK, KeatingB, JallowM, PinderM, et al. (2006) A hallmark of balancing selection is present at the promoter region of interleukin 10. Genes Immun 7 : 680–683.
18. CharlesworthD (2006) Balancing selection and its effects on sequences in nearby genome regions. PLoS Genet 2: e64 doi:10.1371/journal.pgen.0020064.
19. CharlesworthB, NordborgM, CharlesworthD (1997) The effects of local selection, balanced polymorphism and background selection on equilibrium patterns of genetic diversity in subdivided populations. Genet Res 70 : 155–174.
20. GreenRE, KrauseJ, BriggsAW, MaricicT, StenzelU, et al. (2010) A draft sequence of the Neandertal genome. Science 328 : 710–722.
21. ReichD, GreenRE, KircherM, KrauseJ, PattersonN, et al. (2010) Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468 : 1053–1060.
22. MendezFL, WatkinsJC, HammerMF (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.
23. Abi-RachedL, JobinMJ, KulkarniS, McWhinnieA, DalvaK, et al. (2011) The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334 : 89–94.
24. LiH, DurbinR (2011) Inference of human population history from individual whole-genome sequences. Nature 475 : 493–496.
25. IafrateAJ, FeukL, RiveraMN, ListewnikML, DonahoePK, et al. (2004) Detection of large-scale variation in the human genome. Nat Genet 36 : 949–951.
26. SebatJ, LakshmiB, TrogeJ, AlexanderJ, YoungJ, et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305 : 525–528.
27. IskowRC, GokcumenO, LeeC (2012) Exploring the role of copy number variants in human adaptation. Trends Genet 28 : 245–257.
28. StrangerBE, ForrestMS, DunningM, IngleCE, BeazleyC, et al. (2007) Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes. Science 315 : 848–853.
29. McCarrollSA, HuettA, KuballaP, ChilewskiSD, LandryA, et al. (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40 : 1107–1112.
30. The 1000 Genomes Project Consortium (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491 : 56–65.
31. HinchAG, TandonA, PattersonN, SongY, RohlandN, et al. (2011) The landscape of recombination in African Americans. Nature 476 : 170–175.
32. WegmannD, KessnerDE, VeeramahKR, MathiasRA, NicolaeDL, et al. (2011) Recombination rates in admixed individuals identified by ancestry-based inference. Nat Genet 43 : 847–853.
33. ConradDF, PintoD, RedonR, FeukL, GokcumenO, et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464 : 704–712.
34. AltshulerDM, GibbsRA, PeltonenL, DermitzakisE, SchaffnerSF, et al. (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467 : 52–58.
35. NeiM, LiWH (1979) Mathematical model for studying genetic variation in terms of restriction endonucleases. Proc Natl Acad Sci U S A 76 : 5269–5273.
36. JakobssonM, ScholzSW, ScheetP, GibbsJR, VanLiereJM, et al. (2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451 : 998–1003.
37. Akazawa T, Aoki K, Bar-Yosef O (1998) Neandertals and modern humans in Western Asia. New York: Plenum Press. xi, 539 p. p.
38. HennBM, BotigueLR, GravelS, WangW, BrisbinA, et al. (2012) Genomic ancestry of North Africans supports back-to-Africa migrations. PLoS Genet 8: e1002397 doi:10.1371/journal.pgen.1002397.
39. TajimaF (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123 : 585–595.
40. 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.
41. KeinanA, ClarkAG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336 : 740–743.
42. NelsonMR, WegmannD, EhmMG, KessnerD, St JeanP, et al. (2012) An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science 337 : 100–104.
43. HudsonRR, KreitmanM, AguadeM (1987) A test of neutral molecular evolution based on nucleotide data. Genetics 116 : 153–159.
44. MendezFL, WatkinsJC, HammerMF (2012) Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations. Mol Biol Evol 29 : 1513–1520.
45. CelnikerSE, DillonLA, GersteinMB, GunsalusKC, HenikoffS, et al. (2009) Unlocking the secrets of the genome. Nature 459 : 927–930.
46. PekowskaA, BenoukrafT, FerrierP, SpicugliaS (2010) A unique H3K4me2 profile marks tissue-specific gene regulation. Genome Res 20 : 1493–1502.
47. StrangerBE, MontgomerySB, DimasAS, PartsL, StegleO, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639 doi:10.1371/journal.pgen.1002639.
48. WardLD, KellisM (2012) Evidence of abundant purifying selection in humans for recently acquired regulatory functions. Science 337 : 1675–1678.
49. SripathySP, StevensJ, SchultzDC (2006) The KAP1 corepressor functions to coordinate the assembly of de novo HP1-demarcated microenvironments of heterochromatin required for KRAB zinc finger protein-mediated transcriptional repression. Mol Cell Biol 26 : 8623–8638.
50. RoweHM, JakobssonJ, MesnardD, RougemontJ, ReynardS, et al. (2010) KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463 : 237–240.
51. ErikssonA, ManicaA (2012) Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. Proc Natl Acad Sci U S A 109 : 13956–13960.
52. YotovaV, LefebvreJF, MoreauC, GbehaE, HovhannesyanK, et al. (2011) An X-linked haplotype of neandertal origin is present among all non-african populations. Mol Biol Evol 28 : 1957–1962.
53. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529 doi:10.1371/journal.pgen.1000529.
54. BrowningBL, BrowningSR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84 : 210–223.
55. BarrettJC, FryB, MallerJ, DalyMJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 : 263–265.
56. BandeltHJ, ForsterP, RohlA (1999) Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16 : 37–48.
57. ForsterP (2004) Ice Ages and the mitochondrial DNA chronology of human dispersals: a review. Philos Trans R Soc Lond B Biol Sci 359 : 255–264 discussion 264.
58. LibradoP, RozasJ (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25 : 1451–1452.
59. HudsonRR, SlatkinM, MaddisonWP (1992) Estimation of levels of gene flow from DNA sequence data. Genetics 132 : 583–589.
60. NielsenR (2005) Molecular signatures of natural selection. Annu Rev Genet 39 : 197–218.
61. WrightSI, CharlesworthB (2004) The HKA test revisited: a maximum-likelihood-ratio test of the standard neutral model. Genetics 168 : 1071–1076.
62. BeresfordGW, BossJM (2001) CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter. Nat Immunol 2 : 652–657.
63. JurkaJ (2000) Repbase update: a database and an electronic journal of repetitive elements. Trends Genet 16 : 418–420.
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