The DNA of most vertebrates is depleted in CpG dinucleotides, the target for DNA methylation. The remaining CpGs tend to cluster in regions referred to as CpG islands (CGI). CGI have been useful as marking functionally relevant epigenetic loci for genome studies. For example, CGI are enriched in the promoters of vertebrate genes and thought to play an important role in regulation. Currently, CGI are defined algorithmically as an observed-to-expected ratio (O/E) of CpG greater than 0.6, G+C content greater than 0.5, and usually but not necessarily greater than a certain length. Here we find that the current definition leaves out important CpG clusters associated with epigenetic marks, relevant to development and disease, and does not apply at all to nonvertabrate genomes. We propose an alternative Hidden Markov model-based approach that solves these problems. We fit our model to genomes from 30 species, and the results support a new epigenomic view toward the development of DNA methylation in species diversity and evolution. The O/E of CpG in islands and nonislands segregated closely phylogenetically and showed substantial loss in both groups in animals of greater complexity, while maintaining a nearly constant difference in CpG O/E between islands and nonisland compartments. Lists of CGI for some species are available at http://www.rafalab.org.
Hide Markov Model Zebra Finch Fugu Hide Markov Model Model Algorithmic Definition
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NIH grants P50HG003233 and R01GM083084 supported this work. We also thank Harris Jaffee and Brian Caffo for their input and the reviewers for useful comments that reshaped the manusctipt.
Churchill GA (1989) Stochastic models for heterogeneous DNA sequences. Bull Math Biol 51:79–94PubMedGoogle Scholar
Cokus SJ, Feng S, Zhang X, Chen Z, Merriman B et al (2008) Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452:215–219CrossRefPubMedGoogle Scholar
Durbin R, Eddy SR, Krogh A, Mitchison G (1998) Biological sequence analysis: probabilistic models of proteins and nucleic acids. Cambridge, UK: Cambridge University PressGoogle Scholar
Elango N, Hunt BG, Goodisman MA, Yi SV (2009) DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera. Proc Natl Acad Sci U S A 106:11206–11211CrossRefPubMedGoogle Scholar
Glass J, Thompson RF, Khulan B, Figueroa ME, Olivier EN et al (2007) CG dinucleotide clustering is a species-specific property of the genome. Nucleic Acids Res 35:6798–6807CrossRefPubMedGoogle Scholar
Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C et al (2009) Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):246–250CrossRefPubMedGoogle Scholar
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH et al (2002) The human genome browser at UCSC. Genome Res 12:996–1006PubMedGoogle Scholar
Kucharski R, Maleszka J, Foret S, Maleszka R (2008) Nutritional control of reproductive status in honeybees via DNA methylation. Science 319:1827–1830CrossRefPubMedGoogle Scholar
Larsen F, Gundersen G, Lopez R, Prydz H (1992) CpG islands as gene markers in the human genome. Genomics 13:1095–1107CrossRefPubMedGoogle Scholar
Rabiner L (1989) A tutorial on hidden Markov models and selected applications in speech recognition. Proc IEEE 77:257–286CrossRefGoogle Scholar
Takai D, Jones P (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99:3740–3745CrossRefPubMedGoogle Scholar
Wu H, Caffo B, Jaffee HA, Feinberg AP, Irizarry RA (2009) Redefining CpG Islands using a Hideen Markov model. Johns Hopkins University, Dept. of Biostatistics Working Papers. Working Paper 199Google Scholar
Yagi S, Hirabayashi K, Sato S, Li W, Takahashi Y et al (2008) DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression. Genome Res 18:1969–1978CrossRefPubMedGoogle Scholar