Genomic Hypomethylation in the Human Germline Associates with Selective Structural Mutability in the Human Genome

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The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ∼1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR–mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease.

Vyšlo v časopise: Genomic Hypomethylation in the Human Germline Associates with Selective Structural Mutability in the Human Genome. PLoS Genet 8(5): e32767. doi:10.1371/journal.pgen.1002692
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002692

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

2. KorbelJOUrbanAEAffourtitJPGodwinBGrubertF 2007 Paired-end mapping reveals extensive structural variation in the human genome. Science 318 420 426

3. LupskiJR 1998 Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14 417 422

4. LupskiJR 2009 Genomic disorders ten years on. Genome Med 1 42

5. StankiewiczPLupskiJR 2002 Genome architecture, rearrangements and genomic disorders. Trends Genet 18 74 82

6. SharpAJHansenSSelzerRRChengZReganR 2006 Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38 1038 1042

7. CarvalhoCMRamockiMBPehlivanDFrancoLMGonzaga-JaureguiC 2011 Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43 1074 1081

8. StephensPJGreenmanCDFuBYangFBignellGR 2011 Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144 27 40

9. LiuPErezANagamaniSCDharSUKolodziejskaKE 2011 Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146 889 903

10. BaileyJABaertschRKentWJHausslerDEichlerEE 2004 Hotspots of mammalian chromosomal evolution. Genome Biol 5 R23

11. StankiewiczPShawCJWithersMInoueKLupskiJR 2004 Serial segmental duplications during primate evolution result in complex human genome architecture. Genome Res 14 2209 2220

12. HamptonOADen HollanderPMillerCADelgadoDALiJ 2009 A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Res 19 167 177

13. QuinlanARClarkRASokolovaSLeibowitzMLZhangY 2010 Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome. Genome Res 20 623 635

14. LeeJACarvalhoCMLupskiJR 2007 A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131 1235 1247

15. CarvalhoCMZhangFLiuPPatelASahooT 2009 Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 18 2188 2203

16. ZhangFCarvalhoCMLupskiJR 2009 Complex human chromosomal and genomic rearrangements. Trends Genet 25 298 307

17. KiddJMGravesTNewmanTLFultonRHaydenHS 2010 A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143 837 847

18. HastingsPJIraGLupskiJR 2009 A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5 e1000327 doi:10.1371/journal.pgen.1000327

19. KouzaridesT 2007 Chromatin modifications and their function. Cell 128 693 705

20. HassaPOHottigerMO 2005 An epigenetic code for DNA damage repair pathways? Biochem Cell Biol 83 270 285

21. SchottaGSenguptaRKubicekSMalinSKauerM 2008 A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22 2048 2061

22. BaudatFBuardJGreyCFledel-AlonAOberC 2010 PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327 836 840

23. MyersSBowdenRTumianABontropREFreemanC 2010 Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327 876 879

24. CooperDNYoussoufianH 1988 The CpG dinucleotide and human genetic disease. Hum Genet 78 151 155

25. Bourc'hisDBestorTH 2004 Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431 96 99

26. StewartCLStuhlmannHJahnerDJaenischR 1982 De novo methylation, expression, and infectivity of retroviral genomes introduced into embryonal carcinoma cells. Proc Natl Acad Sci U S A 79 4098 4102

27. WalshCPChailletJRBestorTH 1998 Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20 116 117

28. Evgen'evMB 2007 [Mobile elements and evolution]. Mol Biol (Mosk) 41 234 245

29. EdenAGaudetFWaghmareAJaenischR 2003 Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300 455

30. EstellerM 2008 Epigenetics in cancer. N Engl J Med 358 1148 1159

31. XuGLBestorTHBourc'hisDHsiehCLTommerupN 1999 Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402 187 191

32. GaudetFHodgsonJGEdenAJackson-GrusbyLDausmanJ 2003 Induction of tumors in mice by genomic hypomethylation. Science 300 489 492

33. CarboneLHarrisRAVessereGMMootnickARHumphrayS 2009 Evolutionary breakpoints in the gibbon suggest association between cytosine methylation and karyotype evolution. PLoS Genet 5 e1000538 doi:10.1371/journal.pgen.1000538

34. HajkovaPJeffriesSJLeeCMillerNJacksonSP 2010 Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 329 78 82

35. MolaroAHodgesEFangFSongQMcCombieWR 2011 Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell 146 1029 1041

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

37. ConradDFPintoDRedonRFeukLGokcumenO 2010 Origins and functional impact of copy number variation in the human genome. Nature 464 704 712

38. The Wellcome Trust Case Control Consortium 2010 Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464 713 720

39. The International Schizophrenia Consortium 2008 Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455 237 241

40. ZhangDChengLQianYAlliey-RodriguezNKelsoeJR 2009 Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry 14 376 380

41. CooperGMCoeBPGirirajanSRosenfeldJAVuTH 2011 A copy number variation morbidity map of developmental delay. Nat Genet 43 838 846

42. PintoDPagnamentaATKleiLAnneyRMericoD 2010 Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 368 372

43. BaileyJAGuZClarkRAReinertKSamonteRV 2002 Recent segmental duplications in the human genome. Science 297 1003 1007

44. BaileyJAYavorAMMassaHFTraskBJEichlerEE 2001 Segmental duplications: organization and impact within the current human genome project assembly. Genome Res 11 1005 1017

45. KimuraM 1983 The neutral theory of molecular evolution Cambridge Cambridge University Press xv,367 p.

46. HarrisRARogersJMilosavljevicA 2007 Human-specific changes of genome structure detected by genomic triangulation. Science 316 235 237

47. SchaeferCBOoiSKBestorTHBourc'hisD 2007 Epigenetic decisions in mammalian germ cells. Science 316 398 399

48. SigurdssonMISmithAVBjornssonHTJonssonJJ 2009 HapMap methylation-associated SNPs, markers of germline DNA methylation, positively correlate with regional levels of human meiotic recombination. Genome Res 19 581 589

49. LaurentLWongELiGHuynhTTsirigosA 2010 Dynamic changes in the human methylome during differentiation. Genome Res 20 320 331

50. ListerRPelizzolaMDowenRHHawkinsRDHonG 2009 Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462 315 322

51. KimuraMCrowJF 1964 The Number of Alleles That Can Be Maintained in a Finite Population. Genetics 49 725 738

52. PachecoSEHousemanEAChristensenBCMarsitCJKelseyKT 2011 Integrative DNA methylation and gene expression analyses identify DNA packaging and epigenetic regulatory genes associated with low motility sperm. PLoS ONE 6 e20280 doi:10.1371/journal.pone.0020280

53. WeberMHellmannIStadlerMBRamosLPaaboS 2007 Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39 457 466

54. MohnFWeberMRebhanMRoloffTCRichterJ 2008 Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 30 755 766

55. KuMKocheRPRheinbayEMendenhallEMEndohM 2008 Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4 e1000242 doi:10.1371/journal.pgen.1000242

56. TanayAO'DonnellAHDamelinMBestorTH 2007 Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A 104 5521 5526

57. ChristensenBCHousemanEAMarsitCJZhengSWrenschMR 2009 Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5 e1000602 doi:10.1371/journal.pgen.1000602

58. AkalinAFredmanDArnerEDongXBryneJC 2009 Transcriptional features of genomic regulatory blocks. Genome Biol 10 R38

59. VaquerizasJMKummerfeldSKTeichmannSALuscombeNM 2009 A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10 252 263

60. WilliamsonLMLees-MillerSP 2011 Estrogen receptor alpha-mediated transcription induces cell cycle-dependent DNA double-strand breaks. Carcinogenesis 32 279 285

61. ManiRSTomlinsSACallahanKGhoshANyatiMK 2009 Induced chromosomal proximity and gene fusions in prostate cancer. Science 326 1230

62. HaffnerMCAryeeMJToubajiAEsopiDMAlbadineR 2010 Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 42 668 675

63. WagnerGPDraghiJ 2010 Evolution of Evolvability. PigliucciMMüllerG Evolution, the extended synthesis Cambridge, Mass. MIT Press viii 379–400

64. NesseRM 2009 Evolution at 150: time for truly biological psychiatry. Br J Psychiatry 195 471 472

65. CoarfaCYuFMillerCAChenZHarrisRA 2010 Pash 3.0: A versatile software package for read mapping and integrative analysis of genomic and epigenomic variation using massively parallel DNA sequencing. BMC Bioinformatics 11 572

66. CoarfaCMilosavljevicA 2008 Pash 2.0: scaleable sequence anchoring for next-generation sequencing technologies. Pac Symp Biocomput 102 113

67. KalafusKJJacksonARMilosavljevicA 2004 Pash: efficient genome-scale sequence anchoring by Positional Hashing. Genome Res 14 672 678

68. KentWJ 2002 BLAT–the BLAST-like alignment tool. Genome Res 12 656 664

69. KurtzSPhillippyADelcherALSmootMShumwayM 2004 Versatile and open software for comparing large genomes. Genome Biol 5 R12

70. IafrateAJFeukLRiveraMNListewnikMLDonahoePK 2004 Detection of large-scale variation in the human genome. Nat Genet 36 949 951

71. OlshenABVenkatramanESLucitoRWiglerM 2004 Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5 557 572

72. HartlDLClarkAG 2007 Principles of population genetics Sunderland, Mass. Sinauer Associates xv, 652 p.

73. Huang daWShermanBTLempickiRA 2009 Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4 44 57

74. MasseroliMGalatiOPinciroliF 2005 GFINDer: genetic disease and phenotype location statistical analysis and mining of dynamically annotated gene lists. Nucleic Acids Res 33 W717 723