CGIs that not contain CEs (with its standard error), the number of CE CGIs, the number of non-CE CGIs and the Bootstrap p- values. (DOC) Table S8 Lists, for each cell type, the mean methylation of HIR+CE CGIs (with its standard error), the mean methylation of CE CGIs (with its standard error), the number of HIR+CE CGIs, the number of CE CGIs and the Bootstrap p-values. (DOC) Table S9 Lists, for each cell type, the mean methylation of 5SLR+CE CGIs (with its standard error), the mean methylation of CE CGIs (with its standard error), the number of 5SLR+CE CGIs, the number of CE CGIs and the Bootstrap p-values. (DOC) References 1. Pelizzola M, Ecker JR (2010) The DNA methylome. FEBS Lett. 2. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16: 6–21. 3. Illingworth RS, Bird AP (2009) CpG islands–‘a rough guide’. FEBS Lett 583: 1713–1720. 4. 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: 3418–3422. 5. Duthie SJ (2011) Epigenetic modifications and human pathologies: cancer and CVD. Proc Nutr Soc 70: 47–56. 6. Petronis A (2010) Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465: 721–727. 7. Handel AE, Ebers GC, Ramagopalan SV (2010) Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med 16: 7–16. 8. Jones PA, Liang G (2009) Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10: 805–811. 9. Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, et al. (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450: 908–912. 10. Haaf T (2006) Methylation dynamics in the early mammalian embryo: implications of genome reprogramming defects for development. Curr Top Microbiol Immunol 310: 13–22. 11. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, et al. (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454: 49–55. 12. Bock C, Paulsen M, Tierling S, Mikeska T, Lengauer T, et al. (2006) CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genet 2: e26. 13. Jeong S, Liang G, Sharma S, Lin JC, Choi SH, et al. (2009) Selective anchoring of DNA methyltransferases 3A and 3B to nucleosomes containing methylated DNA. Mol Cell Biol 29: 5366–5376. 14. Lin JC, Jeong S, Liang G, Takai D, Fatemi M, et al. (2007) Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12: 432–444. 15. Johnson LJ, Tricker PJ (2010) Epigenomic plasticity within populations: its evolutionary significance and potential. Heredity 105: 113–121. 16. Britten RJ, Davidson EH (1969) Gene regulation for higher cells: a theory. Science 165: 349–357. 17. Nielsen R (2005) Molecular signatures of natural selection. Annu Rev Genet 39: 197–218. 18. Fouse SD, Nagarajan RP, Costello JF (2010) Genome-scale DNA methylation analysis. Epigenomics 2: 105–117. 19. Celniker SE, Dillon LA, Gerstein MB, Gunsalus KC, Henikoff S, et al. (2009) Unlocking the secrets of the genome. Nature 459: 927–930. 20. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, et al. (2008) Genome- scale DNA methylation maps of pluripotent and differentiated cells. Nature 454: 766–770. 21. Yi SV, Goodisman MA (2009) Computational approaches for understanding the evolution of DNA methylation in animals. Epigenetics 4: 551–556. 22. Bock C, Lengauer T (2008) Computational epigenetics. Bioinformatics 24: 1–10. 23. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4: e72. CpG Islands Methylation and Selective Pressure Table S10 Lists, for each cell type, the number, the mean methylation and the standard error of 59 CGIs, intragenic CGIs, 39 CGIs and intergenic CGIs. (DOC) Table S11 Lists, for each cell type and for each CGIs class (59 CGIs, intragenic CGIs, 39 CGIs and intergenic CGIs) the number and the mean methylation of CGIs containing CEs (with its standard error), the number and the mean methylation of CGIs that do not contain CEs (with its standard error), and the Bootstrap p-values. (DOC) Author Contributions Conceived and designed the experiments: SC AM GM. Analyzed the data: MMA AM SC. Wrote the paper: GM AM SC. 24. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, et al. (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419: 832–837. 25. Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, et al. (2010) A draft sequence of the Neandertal genome. Science 328: 710–722. 26. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010) Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20: 110–121. 27. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15: 1034–1050. 28. Medvedeva YA, Fridman MV, Oparina NJ, Malko DB, Ermakova EO, et al. (2010) Intergenic, gene terminal, and intragenic CpG islands in the human genome. BMC Genomics 11: 48. 29. Law JA, Jacobsen SE (2010) Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11: 204–220. 30. Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4: 143–153. 31. Holliday R, Grigg GW (1993) DNA methylation and mutation. Mutat Res 285: 61–67. 32. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321: 209–213. 33. Tomso DJ, Bell DA (2003) Sequence context at human single nucleotide polymorphisms: overrepresentation of CpG dinucleotide at polymorphic sites and suppression of variation in CpG islands. J Mol Biol 327: 303–308. 34. Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, et al. (2008) Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. Am J Hum Genet 82: 188–193. 35. Smilinich NJ, Day CD, Fitzpatrick GV, Caldwell GM, Lossie AC, et al. (1999) A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc Natl Acad Sci U S A 96: 8064–8069. 36. Han L, Witmer PD, Casey E, Valle D, Sukumar S (2007) DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6: 1284–1288. 37. Wang G, Wang Y, Shen C, Huang YW, Huang K, et al. (2010) RNA polymerase II binding patterns reveal genomic regions involved in microRNA gene regulation. PLoS One 5: e13798. 38. Bonasio R, Tu S, Reinberg D (2010) Molecular signals of epigenetic states. Science 330: 612–616. 39. Saferali A, Grundberg E, Berlivet S, Beauchemin H, Morcos L, et al. (2010) Cell culture-induced aberrant methylation of the imprinted IG DMR in human lymphoblastoid cell lines. Epigenetics 5: 50–60. 40. Bork S, Pfister S, Witt H, Horn P, Korn B, et al. (2010) DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 9: 54–63. 41. Sanborn JZ, Benz SC, Craft B, Szeto C, Kober KM, et al. (2011) The UCSC Cancer Genomics Browser: update 2011. Nucleic Acids Res 39: D951–959. 42. R_Development_Core_Team, (2009) R: A Language and Environment for Statistical Computing. Vienna Austria. PLoS ONE | www.plosone.org 9 August 2011 | Volume 6 | Issue 8 | e23156