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Nucleic Acids Res. 1982 December 11; 10(23): 7865–7877.
PMCID: PMC327052

Asymmetrical distribution of CpG in an 'average' mammalian gene.


The frequency and distribution of the rare dinucleotide CpG was examined in 15 mammalian genes. CpG is highly methylated at cytosine in mammalian DNA (1,2) and 5-methylcytosine (5mC) is thought to undergo a transition mutation via deamination to produce thymine (3). This would result in the accumulation of TpG and CpA and depletion of CpG during evolution (4). Consistent with this hypothesis, the gene sample of 26,541 dinucleotides contained CpG at 40% the frequency expected by base composition and the CpG transition products, TpG+CpA, were significantly elevated at 124% of expected random frequency. However, because CpG occurs at only 25% of expected random frequency in the genome, the sampled genes were considerably enriched in this dinucleotide. CpGs were asymmetrically distributed in sequences flanking the genes. 5'-flanking sequences were enriched in CpG at 135% of the frequency expected assuming a symmetrical distribution of all the CpGs in the sampled genes (p less than 0.01), while 3'-flanking regions were depleted in CpG at 40% of expected values (p less than 0.0001). This asymmetry may reflect the role of 5-methylcytosine in gene expression. In contrast the frequencies of GpC and GpT+ ApC did not differ significantly from that predicted by base composition and these dinucleotides were not asymmetrically distributed.

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Selected References

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  • Razin A, Riggs AD. DNA methylation and gene function. Science. 1980 Nov 7;210(4470):604–610. [PubMed]
  • Ehrlich M, Wang RY. 5-Methylcytosine in eukaryotic DNA. Science. 1981 Jun 19;212(4501):1350–1357. [PubMed]
  • Salser W. Globin mRNA sequences: analysis of base pairing and evolutionary implications. Cold Spring Harb Symp Quant Biol. 1978;42(Pt 2):985–1002. [PubMed]
  • Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980 Apr 11;8(7):1499–1504. [PMC free article] [PubMed]
  • Lawn RM, Efstratiadis A, O'Connell C, Maniatis T. The nucleotide sequence of the human beta-globin gene. Cell. 1980 Oct;21(3):647–651. [PubMed]
  • Spritz RA, Jagadeeswaran P, Choudary PV, Biro PA, Elder JT, deRiel JK, Manley JL, Gefter ML, Forget BG, Weissman SM. Base substitution in an intervening sequence of a beta+-thalassemic human globin gene. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2455–2459. [PubMed]
  • Proudfoot NJ, Maniatis T. The structure of a human alpha-globin pseudogene and its relationship to alpha-globin gene duplication. Cell. 1980 Sep;21(2):537–544. [PubMed]
  • Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM. Sequence of the human insulin gene. Nature. 1980 Mar 6;284(5751):26–32. [PubMed]
  • Ullrich A, Dull TJ, Gray A, Brosius J, Sures I. Genetic variation in the human insulin gene. Science. 1980 Aug 1;209(4456):612–615. [PubMed]
  • Bell GI, Pictet R, Rutter WJ. Analysis of the regions flanking the human insulin gene and sequence of an Alu family member. Nucleic Acids Res. 1980 Sep 25;8(18):4091–4109. [PMC free article] [PubMed]
  • Nagata S, Mantei N, Weissmann C. The structure of one of the eight or more distinct chromosomal genes for human interferon-alpha. Nature. 1980 Oct 2;287(5781):401–408. [PubMed]
  • Chang AC, Cochet M, Cohen SN. Structural organization of human genomic DNA encoding the pro-opiomelanocortin peptide. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4890–4894. [PubMed]
  • Spritz RA, DeRiel JK, Forget BG, Weissman SM. Complete nucleotide sequence of the human delta-globin gene. Cell. 1980 Oct;21(3):639–646. [PubMed]
  • Shine J, Seeburg PH, Martial JA, Baxter JD, Goodman HM. Construction and analysis of recombinant DNA for human chorionic somatomammotropin. Nature. 1977 Dec 8;270(5637):494–499. [PubMed]
  • Fiddes JC, Goodman HM. Isolation, cloning and sequence analysis of the cDNA for the alpha-subunit of human chorionic gonadotropin. Nature. 1979 Oct 4;281(5730):351–356. [PubMed]
  • Glanville N, Durnam DM, Palmiter RD. Structure of mouse metallothionein-I gene and its mRNA. Nature. 1981 Jul 16;292(5820):267–269. [PubMed]
  • Honjo T, Obata M, Yamawaki-Katoaka Y, Kataoka T, Kawakami T, Takahashi N, Mano Y. Cloning and complete nucleotide sequence of mouse immunoglobulin gamma 1 chain gene. Cell. 1979 Oct;18(2):559–568. [PubMed]
  • Nishioka Y, Leder P. The complete sequence of a chromosomal mouse alpha--globin gene reveals elements conserved throughout vertebrate evolution. Cell. 1979 Nov;18(3):875–882. [PubMed]
  • Seiler-Tuyns A, Birnstiel ML. Structure and expression in L-cells of a cloned H4 histone gene of the mouse. J Mol Biol. 1981 Oct 5;151(4):607–625. [PubMed]
  • Law SW, Dugaiczyk A. Homology between the primary structure of alpha-fetoprotein, deduced from a complete cDNA sequence, and serum albumin. Nature. 1981 May 21;291(5812):201–205. [PubMed]
  • Page GS, Smith S, Goodman HM. DNA sequence of the rat growth hormone gene: location of the 5' terminus of the growth hormone mRNA and identification of an internal transposon-like element. Nucleic Acids Res. 1981 May 11;9(9):2087–2104. [PMC free article] [PubMed]
  • Ohno S, Taniguchi T. Structure of a chromosomal gene for human interferon beta. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5305–5309. [PubMed]
  • Malissen M, Malissen B, Jordan BR. Exon/intron organization and complete nucleotide sequence of an HLA gene. Proc Natl Acad Sci U S A. 1982 Feb;79(3):893–897. [PubMed]
  • Lawn RM, Adelman J, Franke AE, Houck CM, Gross M, Najarian R, Goeddel DV. Human fibroblast interferon gene lacks introns. Nucleic Acids Res. 1981 Mar 11;9(5):1045–1052. [PMC free article] [PubMed]
  • Quinto C, Quiroga M, Swain WF, Nikovits WC, Jr, Standring DN, Pictet RL, Valenzuela P, Rutter WJ. Rat preprocarboxypeptidase A: cDNA sequence and preliminary characterization of the gene. Proc Natl Acad Sci U S A. 1982 Jan;79(1):31–35. [PubMed]
  • Efstratiadis A, Posakony JW, Maniatis T, Lawn RM, O'Connell C, Spritz RA, DeRiel JK, Forget BG, Weissman SM, Slightom JL, et al. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653–668. [PubMed]
  • Niall HD, Hogan ML, Sauer R, Rosenblum IY, Greenwood FC. Sequences of pituitary and placental lactogenic and growth hormones: evolution from a primordial peptide by gene reduplication. Proc Natl Acad Sci U S A. 1971 Apr;68(4):866–870. [PubMed]
  • Bewley TA, Dixon JS, Li CH. Sequence comparison of human pituitary growth hormone, human chorionic somatomammotropin, and ovine pituitary growth and lactogenic hormones. Int J Pept Protein Res. 1972;4(4):281–287. [PubMed]
  • Cooke NE, Coit D, Weiner RI, Baxter JD, Martial JA. Structure of cloned DNA complementary to rat prolactin messenger RNA. J Biol Chem. 1980 Jul 10;255(13):6502–6510. [PubMed]
  • Grantham R, Gautier C, Gouy M, Jacobzone M, Mercier R. Codon catalog usage is a genome strategy modulated for gene expressivity. Nucleic Acids Res. 1981 Jan 10;9(1):r43–r74. [PMC free article] [PubMed]
  • Nussinov R. The universal dinucleotide asymmetry rules in DNA and the amino acid codon choice. J Mol Evol. 1981;17(4):237–244. [PubMed]
  • McGhee JD, Wood WI, Dolan M, Engel JD, Felsenfeld G. A 200 base pair region at the 5' end of the chicken adult beta-globin gene is accessible to nuclease digestion. Cell. 1981 Nov;27(1 Pt 2):45–55. [PubMed]
  • McGhee JD, Ginder GD. Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature. 1979 Aug 2;280(5721):419–420. [PubMed]
  • Ivarie RD, Morris JA, Martial JA. Prolactin-deficient variants of GH3 rat pituitary tumor cells: linked expression of prolactin and another hormonally responsive protein in GH3 cells. Mol Cell Biol. 1982 Feb;2(2):179–189. [PMC free article] [PubMed]
  • Ivarie RD, Morris JA. Induction of prolactin-deficient variants of GH3 rat pituitary tumor cells by ethyl methanesulfonate: reversion by 5-azacytidine, a DNA methylation inhibitor. Proc Natl Acad Sci U S A. 1982 May;79(9):2967–2970. [PubMed]
  • van der Ploeg LH, Flavell RA. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues. Cell. 1980 Apr;19(4):947–958. [PubMed]
  • Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, Gehrke C. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 1982 Apr 24;10(8):2709–2721. [PMC free article] [PubMed]
  • Sano H, Sager R. Tissue specificity and clustering of methylated cystosines in bovine satellite I DNA. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3584–3588. [PubMed]
  • Bird AP, Taggart MH, Smith BA. Methylated and unmethylated DNA compartments in the sea urchin genome. Cell. 1979 Aug;17(4):889–901. [PubMed]
  • Gruenbaum Y, Naveh-Many T, Cedar H, Razin A. Sequence specificity of methylation in higher plant DNA. Nature. 1981 Aug 27;292(5826):860–862. [PubMed]

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