CpG Islands: A Historical Perspective

  • Francisco Antequera
  • Adrian Bird
Part of the Methods in Molecular Biology book series (MIMB, volume 1766)


The discovery of CpG islands (CGIs) and the study of their structure and properties run parallel to the development of molecular biology in the last two decades of the twentieth century and to the development of high-throughput genomic technologies at the turn of the millennium. First identified as discrete G + C-rich regions of unmethylated DNA in several vertebrates, CGIs were soon found to display additional distinctive chromatin features from the rest of the genome in terms of accessibility and of the epigenetic modifications of their histones. These features, together with their colocalization with promoters and with origins of DNA replication in mammals, highlighted their relevance in the regulation of genomic processes. Recent approaches have shown with unprecedented detail the dynamics and diversity of the epigenetic landscape of CGIs during normal development and under pathological conditions. Also, comparative analyses across species have started revealing how CGIs evolve and contribute to the evolution of the vertebrate genome.

Key words

CpG islands DNA mehylation Chromatin Transcription Evolution 


  1. 1.
    Hotchkiss RD (1948) The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem 175:315–332PubMedGoogle Scholar
  2. 2.
    Wyatt GR (1951) Recognition and estimation of 5-methylcytosine in nucleic acids. Biochem J 48:581–584CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Doskocil J, Sorm F (1962) Distribution of 5-methylcytosine in pyrimidine sequences of deoxyribonucleic acids. Biochim Biophys Acta 55:953–959CrossRefPubMedGoogle Scholar
  4. 4.
    Grippo P, Iaccarino M, Parisi E, Scarano E (1968) Methylation of DNA in developing sea urchin embryos. J Mol Biol 36:195–208CrossRefPubMedGoogle Scholar
  5. 5.
    Sinsheimer RL (1955) The action of pancreatic deoxyribonuclease. II Isomeric dinucleotides. J Biol Chem 215:579–583PubMedGoogle Scholar
  6. 6.
    Gruenbaum Y, Stein R, Cedar H, Razin A (1981) Methylation of CpG sequences in eukaryotic DNA. FEBS Lett 124:67–71CrossRefPubMedGoogle Scholar
  7. 7.
    Naveh-Many T, Cedar H (1981) Active gene sequences are undermethylated. Proc Natl Acad Sci U S A 78:4246–4250CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Razin A, Cedar H (1977) Distribution of 5-methylcytosine in chromatin. Proc Natl Acad Sci U S A 74:2725–2728CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Solage A, Cedar H (1978) Organization of 5-methylcytosine in chromosomal DNA. Biochemistry 17:2934–2938CrossRefPubMedGoogle Scholar
  10. 10.
    Bird AP (1978) Use of restriction enzymes to study eukaryotic DNA methylation: II The symmetry of methylated sites supports semi-conservative copying of the methylation pattern. J Mol Biol 118:49–60CrossRefPubMedGoogle Scholar
  11. 11.
    Bird AP, Southern EM (1978) Use of restriction enzymes to study eukaryotic DNA methylation: I The methylation pattern in ribosomal DNA from Xenopus laevis. J Mol Biol 118:27–47CrossRefPubMedGoogle Scholar
  12. 12.
    Gautier F, Bunemann H, Grotjahn L (1977) Analysis of calf-thymus satellite DNA: evidence for specific methylation of cytosine in C-G sequences. Eur J Biochem 80:175–183CrossRefPubMedGoogle Scholar
  13. 13.
    Mandel JL, Chambon P (1979) DNA methylation: organ specific variations in the methylation pattern within and around ovalbumin and other chicken genes. Nucleic Acids Res 7:2081–2103CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Waalwijk C, Flavell RA (1978) DNA methylation at a CCGG sequence in the large intron of the rabbit beta-globin gene: tissue-specific variations. Nucleic Acids Res 5:4631–4634CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517CrossRefPubMedGoogle Scholar
  16. 16.
    Busslinger M, Hurst J, Flavell RA (1983) DNA methylation and the regulation of globin gene expression. Cell 34:197–206CrossRefPubMedGoogle Scholar
  17. 17.
    Kruczek I, Doerfler W (1982) The unmethylated state of the promoter/leader and 5′-regions of integrated adenovirus genes correlates with gene expression. EMBO J 1:409–414PubMedPubMedCentralGoogle Scholar
  18. 18.
    Ott MO, Sperling L, Cassio D, Levilliers J, Sala-Trepat J, Weiss MC (1982) Undermethylation at the 5′ end of the albumin gene is necessary but not sufficient for albumin production by rat hepatoma cells in culture. Cell 30:825–833CrossRefPubMedGoogle Scholar
  19. 19.
    Shen CK, Maniatis T (1980) Tissue-specific DNA methylation in a cluster of rabbit beta-like globin genes. Proc Natl Acad Sci U S A 77:6634–6638CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Stein R, Razin A, Cedar H (1982) In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc Natl Acad Sci U S A 79:3418–3422CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Stein R, Sciaky-Gallili N, Razin A, Cedar H (1983) Pattern of methylation of two genes coding for housekeeping functions. Proc Natl Acad Sci U S A 80:2422–2426CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mohandas T, Sparkes RS, Shapiro LJ (1981) Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science 211:393–396CrossRefPubMedGoogle Scholar
  23. 23.
    Venolia L, Gartler SM, Wassman ER, Yen P, Mohandas T, Shapiro LJ (1982) Transformation with DNA from 5-azacytidine-reactivated X chromosomes. Proc Natl Acad Sci U S A 79:2352–2354CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bird AP, Taggart MH, Smith BA (1979) Methylated and unmethylated DNA compartments in the sea urchin genome. Cell 17:889–901CrossRefPubMedGoogle Scholar
  25. 25.
    Antequera F, Tamame M, Villanueva JR, Santos T (1984) DNA methylation in the fungi. J Biol Chem 259:8033–8036PubMedGoogle Scholar
  26. 26.
    Bird AP, Taggart MH (1980) Variable patterns of total DNA and rDNA methylation in animals. Nucleic Acids Res 8:1485–1497CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Whittaker PA, Hardman N (1980) Methylation of nuclear DNA in Physarum polycephalum. Biochem J 191:859–862CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cooper DN, Taggart MH, Bird AP (1983) Unmethylated domains in vertebrate DNA. Nucleic Acids Res 11:647–658CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bird A, Taggart M, Frommer M, Miller OJ, Macleod D (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40:91–99CrossRefPubMedGoogle Scholar
  30. 30.
    Bird A (1987) CpG islands as gene markers in the vertebrate nucleus. Trends Genet 3:342–347Google Scholar
  31. 31.
    McClelland M, Ivarie R (1982) Asymmetrical distribution of CpG in an “average” mammalian gene. Nucleic Acids Res 10:7865–7877CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tykocinski ML, Max EE (1984) CG dinucleotide clusters in MHC genes and in 5′ demethylated genes. Nucleic Acids Res 12:4385–4396CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    McKeon C, Ohkubo H, Pastan I, de Crombrugghe B (1982) Unusual methylation pattern of the alpha 2 (l) collagen gene. Cell 29:203–210CrossRefPubMedGoogle Scholar
  34. 34.
    Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP (2010) Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet 6:e1001134CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Coulondre C, Miller JH, Farabough PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780CrossRefPubMedGoogle Scholar
  36. 36.
    Bird A (1980) DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8:1499–1504Google Scholar
  37. 37.
    Nick H, Bowen B, Ferl RJ, Gilbert W (1986) Detection of cytosine methylation in the maize alcohol dehydrogenase gene by genomic sequencing. Nature 319:243–246CrossRefGoogle Scholar
  38. 38.
    Pfeifer GP, Steigerwald SD, Mueller PR, Wold B, Riggs AD (1989) Genomic sequencing and methylation analysis by ligation mediated PCR. Science 246:810–813CrossRefPubMedGoogle Scholar
  39. 39.
    Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89:1827–1831CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Yong WS, Hsu FM, Chen PY (2016) Profiling genome-wide DNA methylation. Epigenetics Chromatin 9:26CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Brown WR, Bird AP (1986) Long-range restriction site mapping of mammalian genomic DNA. Nature 322:477–481CrossRefPubMedGoogle Scholar
  42. 42.
    Lindsay S, Bird AP (1987) Use of restriction enzymes to detect potential gene sequences in mammalian DNA. Nature 327:336–338CrossRefPubMedGoogle Scholar
  43. 43.
    Lavia P, Macleod D, Bird A (1987) Coincident start sites for divergent transcripts at a randomly selected CpG islands as gene markers in the vertebrate nucleus. Trends Genet 3: 342–347Google Scholar
  44. 44.
    Adachi N, Lieber MR (2002) Bidirectional gene organization: a common architectural feature of the human genome. Cell 109:807–809CrossRefPubMedGoogle Scholar
  45. 45.
    Core LJ, Waterfall JJ, Lis JT (2008) Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–1848CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Seila AC, Calabrese JM, Levine SS, Yeo GW, Rahl PB, Flynn RA, Young RA, Sharp PA (2008) Divergent transcription from active promoters. Science 322:1849–1851CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Keshet I, Yisraeli J, Cedar H (1985) Effect of regional DNA methylation on gene expression. Proc Natl Acad Sci U S A 82:2560–2564CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pfeifer GP, Tanguay RL, Steigerwald SD, Riggs AD (1990) In vivo footprint and methylation analysis by PCR-aided genomic sequencing: comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1. Genes Dev 4:1277–1287CrossRefPubMedGoogle Scholar
  49. 49.
    Toniolo D, Martini G, Migeon BR, Dono R (1988) Expression of the G6PD locus on the human X chromosome is associated with demethylation of three CpG islands within 100 kb of DNA. EMBO J 7:401–406PubMedPubMedCentralGoogle Scholar
  50. 50.
    Wolf SF, Jolly DJ, Lunnen KD, Friedmann T, Migeon BR (1984) Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc Natl Acad Sci U S A 81:2806–2810CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Yen PH, Patel P, Chinault AC, Mohandas T, Shapiro LJ (1984) Differential methylation of hypoxanthine phosphoribosyltransferase genes on active and inactive human X chromosomes. Proc Natl Acad Sci U S A 81:1759–1763CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Boyes J, Bird A (1992) Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein. EMBO J 11:327–333PubMedPubMedCentralGoogle Scholar
  53. 53.
    Hsieh CL (1994) Dependence of transcriptional repression on CpG methylation density. Mol Cell Biol 14:5487–5494CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    de Bustros A, Nelkin BD, Silverman A, Ehrlich G, Poiesz B, Baylin SB (1988) The short arm of chromosome 11 is a “hot spot” for hypermethylation in human neoplasia. Proc Natl Acad Sci U S A 85:5693–5697CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Antequera F, Boyes J, Bird A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62:503–514CrossRefPubMedGoogle Scholar
  56. 56.
    Jones PA, Wolkowicz MJ, Rideout WM III, Gonzales FA, Marziasz CM, Coetzee GA, Tapscott SJ (1990) De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc Natl Acad Sci U S A 87:6117–6121CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Stirzaker C, Taberlay PC, Statham AL, Clark SJ (2014) Mining cancer methylomes: prospects and challenges. Trends Genet 30:75–84CrossRefPubMedGoogle Scholar
  58. 58.
    Bartolomei MS, Ferguson-Smith AC (2011) Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 3:a002592CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117CrossRefPubMedGoogle Scholar
  60. 60.
    Borgel J, Guibert S, Li Y, Chiba H, Schübeler D, Sasaki H, Forné T, Weber M (2010) Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42:1093–1100CrossRefPubMedGoogle Scholar
  61. 61.
    Bestor TH, Edwards JR, Boulard M (2015) Notes on the role of dynamic DNA methylation in mammalian development. Proc Natl Acad Sci U S A 112:6796–6799CrossRefPubMedGoogle Scholar
  62. 62.
    Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213CrossRefPubMedGoogle Scholar
  63. 63.
    Walsh CP, Bestor TH (1999) Cytosine methylation and mammalian development. Genes Dev 13:26–34CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Vassilev L, Johnson EM (1990) An initiation zone of chromosomal DNA replication located upstream of the c-myc gene in proliferating HeLa cells. Mol Cell Biol 10:4899–4904CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Biamonti G, Giacca M, Perini G, Contreas G, Zentilin L, Weighardt F, Guerra M, Della Valle G, Saccone S, Riva S et al (1992) The gene for a novel human lamin maps at a highly transcribed locus of chromosome 19 which replicates at the onset of S-phase. Mol Cell Biol 12:3499–3506CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Giacca M, Zentilin L, Norio P, Diviacco S, Dimitrova D, Contreas G, Biamonti G, Perini G, Weighardt F, Riva S et al (1994) Fine mapping of a replication origin of human DNA. Proc Natl Acad Sci U S A 91:7119–7123CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Taira T, Iguchi-Ariga SM, Ariga H (1994) A novel DNA replication origin identified in the human heat shock protein 70 gene promoter. Mol Cell Biol 14:6386–6397CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Besnard E, Babled A, Lapasset L, Milhavet O, Parrinello H, Dantec C, Marin JM, Lemaitre JM (2012) Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat Struct Mol Biol 19:837–844CrossRefPubMedGoogle Scholar
  69. 69.
    Cayrou C, Coulombe P, Vigneron A, Stanojcic S, Ganier O, Peiffer I, Rivals E, Puy A, Laurent-Chabalier S, Desprat R, Mechali M (2011) Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features. Genome Res 21:1438–1449CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Delgado S, Gomez M, Bird A, Antequera F (1998) Initiation of DNA replication at CpG islands in mammalian chromosomes. EMBO J 17:2426–2435CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Sequeira-Mendes J, Diaz-Uriarte R, Apedaile A, Huntley D, Brockdorff N, Gomez M (2009) Transcription initiation activity sets replication origin efficiency in mammalian cells. PLoS Genet 5:e1000446CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Tazi J, Bird A (1990) Alternative chromatin structure at CpG islands. Cell 60:909–920CrossRefPubMedGoogle Scholar
  73. 73.
    Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ, Klose RJ (2010) CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell 38:179–190CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr AR, Deaton A, Andrews R, James KD, Turner DJ, Illingworth R, Bird A (2010) CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464:1082–1086CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ooi SKT, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30:733–750CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914CrossRefPubMedGoogle Scholar
  78. 78.
    Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58:499–507CrossRefPubMedGoogle Scholar
  79. 79.
    Nan X, Meehan RR, Bird AP (1993) Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res 21:4886–4892CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Baubec T, Schubeler D (2014) Genomic patterns and context specific interpretation of DNA methylation. Curr Opin Genet Dev 25:85–92CrossRefPubMedGoogle Scholar
  81. 81.
    Hendrich B, Bird A (1998) Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 18:6538–6547CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Du Q, Luu PL, Stirzaker C, Clark SJ (2015) Methyl-CpG-binding domain proteins: readers of the epigenome. Epigenomics 7:1051–1073CrossRefPubMedGoogle Scholar
  83. 83.
    Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NYGoogle Scholar
  84. 84.
    Long HK, Sims D, Heger A, Blackledge NP, Kutter C, Wright ML, Grutzner F, Odom DT, Patient R, Ponting CP, Klose RJ (2013) Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates. elife 2:e00348CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP (2007) Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet 3:2023–2036CrossRefPubMedGoogle Scholar
  87. 87.
    Smallwood SA, Tomizawa S, Krueger F, Ruf N, Carli N, Segonds-Pichon A, Sato S, Hata K, Andrews SR, Kelsey G (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43:811–814CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Han L, Lin IG, Hsieh CL (2001) Protein binding protects sites on stable episomes and in the chromosome from de novo methylation. Mol Cell Biol 21:3416–3424CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Lienert F, Mohn F, Tiwari VK, Baubec T, Roloff TC, Gaidatzis D, Stadler MB, Schubeler D (2011) Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells. PLoS Genet 7:e1002090CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Scholer A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D, Tiwari VK, Schubeler D (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490–495PubMedGoogle Scholar
  91. 91.
    Takai D, Jones PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99:3740–3745CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Antequera F, Bird A (1993) Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A 90:11995–11999CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Cross S, Kovarik P, Schmidtke J, Bird A (1991) Non-methylated islands in fish genomes are GC-poor. Nucleic Acids Res 19:1469–1474CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Cuadrado M, Sacristan M, Antequera F (2001) Species-specific organization of CpG island promoters at mammalian homologous genes. EMBO Rep 2:586–592CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Carninci P, Sandelin A, Lenhard B, Katayama S, Shimokawa K, Ponjavic J, Semple CA, Taylor MS, Engstrom PG, Frith MC, Forrest AR, Alkema WB, Tan SL, Plessy C, Kodzius R, Ravasi T, Kasukawa T, Fukuda S, Kanamori-Katayama M, Kitazume Y, Kawaji H, Kai C, Nakamura M, Konno H, Nakano K, Mottagui-Tabar S, Arner P, Chesi A, Gustincich S, Persichetti F, Suzuki H, Grimmond SM, Wells CA, Orlando V, Wahlestedt C, Liu ET, Harbers M, Kawai J, Bajic VB, Hume DA, Hayashizaki Y (2006) Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 38:626–635CrossRefPubMedGoogle Scholar
  96. 96.
    Cohen NM, Kenigsberg E, Tanay A (2011) Primate CpG islands are maintained by heterogeneous evolutionary regimes involving minimal selection. Cell 145:773–786CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Instituto de Biología Funcional y GenómicaConsejo Superior de Investigaciones Científicas (CSIC)/Universidad de SalamancaSalamancaSpain
  2. 2.Wellcome Trust Centre for Cell BiologyUniversity of EdinburghEdinburghUK

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