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. 1987 Apr;6(4):999–1004. doi: 10.1002/j.1460-2075.1987.tb04851.x

Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene.

A P Bird, M H Taggart, R D Nicholls, D R Higgs
PMCID: PMC553495  PMID: 3595568

Abstract

We have analysed CpG frequency and CpG methylation across part of the human alpha-globin locus. Clusters of CpG at the alpha 1 and alpha 2 genes resemble the 'HpaII tiny fragment (HTF) islands' that are characteristic of mammalian 'housekeeping' genes: CpG frequency is not suppressed; testable CpGs are not methylated in DNA from erythroid or nonerythroid tissues, although flanking CpGs are methylated; CpG clusters are approximately 1.5 kb long and extend both upstream and downstream of the alpha-globin transcription start site. These features are not found at genes of the beta-globin locus. The alpha-globin pseudogene (psi alpha 1) is highly homologous to the alpha 2 and alpha 1 genes, but it lacks an HTF island. Sequence comparison shows that a high proportion of CpGs in the alpha 2 gene are substituted by TpG or CpA in the pseudogene. This strongly suggests that an ancestral HTF island at the pseudogene became methylated in the germline, and was lost due to the mutability of 5-methylcytosine.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams R. L., Eason R. Increased G + C content of DNA stabilizes methyl CpG dinucleotides. Nucleic Acids Res. 1984 Jul 25;12(14):5869–5877. doi: 10.1093/nar/12.14.5869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bernardi G., Olofsson B., Filipski J., Zerial M., Salinas J., Cuny G., Meunier-Rotival M., Rodier F. The mosaic genome of warm-blooded vertebrates. Science. 1985 May 24;228(4702):953–958. doi: 10.1126/science.4001930. [DOI] [PubMed] [Google Scholar]
  3. Bird A. P. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. doi: 10.1038/321209a0. [DOI] [PubMed] [Google Scholar]
  4. Bird A. P. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980 Apr 11;8(7):1499–1504. doi: 10.1093/nar/8.7.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bird A., Taggart M., Frommer M., Miller O. J., Macleod D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell. 1985 Jan;40(1):91–99. doi: 10.1016/0092-8674(85)90312-5. [DOI] [PubMed] [Google Scholar]
  6. Brown W. R., Bird A. P. Long-range restriction site mapping of mammalian genomic DNA. 1986 Jul 31-Aug 6Nature. 322(6078):477–481. doi: 10.1038/322477a0. [DOI] [PubMed] [Google Scholar]
  7. Cooper D. N., Taggart M. H., Bird A. P. Unmethylated domains in vertebrate DNA. Nucleic Acids Res. 1983 Feb 11;11(3):647–658. doi: 10.1093/nar/11.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coulondre C., Miller J. H., Farabaugh P. J., Gilbert W. Molecular basis of base substitution hotspots in Escherichia coli. Nature. 1978 Aug 24;274(5673):775–780. doi: 10.1038/274775a0. [DOI] [PubMed] [Google Scholar]
  9. D'Onofrio C., Colantuoni V., Cortese R. Structure and cell-specific expression of a cloned human retinol binding protein gene: the 5'-flanking region contains hepatoma specific transcriptional signals. EMBO J. 1985 Aug;4(8):1981–1989. doi: 10.1002/j.1460-2075.1985.tb03881.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Deisseroth A., Nienhuis A., Turner P., Velez R., Anderson W. F., Ruddle F., Lawrence J., Creagan R., Kucherlapati R. Localization of the human alpha-globin structural gene to chromosome 16 in somatic cell hybrids by molecular hybridization assay. Cell. 1977 Sep;12(1):205–218. doi: 10.1016/0092-8674(77)90198-2. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  12. Higgs D. R., Wainscoat J. S., Flint J., Hill A. V., Thein S. L., Nicholls R. D., Teal H., Ayyub H., Peto T. E., Falusi A. G. Analysis of the human alpha-globin gene cluster reveals a highly informative genetic locus. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5165–5169. doi: 10.1073/pnas.83.14.5165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kolsto A. B., Kollias G., Giguere V., Isobe K. I., Prydz H., Grosveld F. The maintenance of methylation-free islands in transgenic mice. Nucleic Acids Res. 1986 Dec 22;14(24):9667–9678. [PMC free article] [PubMed] [Google Scholar]
  14. Lauer J., Shen C. K., Maniatis T. The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell. 1980 May;20(1):119–130. doi: 10.1016/0092-8674(80)90240-8. [DOI] [PubMed] [Google Scholar]
  15. McGhee J. D., Wood W. I., Dolan M., Engel J. D., 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. doi: 10.1016/0092-8674(81)90359-7. [DOI] [PubMed] [Google Scholar]
  16. McKeon C., Ohkubo H., Pastan I., de Crombrugghe B. Unusual methylation pattern of the alpha 2 (l) collagen gene. Cell. 1982 May;29(1):203–210. doi: 10.1016/0092-8674(82)90104-0. [DOI] [PubMed] [Google Scholar]
  17. Mellon P., Parker V., Gluzman Y., Maniatis T. Identification of DNA sequences required for transcription of the human alpha 1-globin gene in a new SV40 host-vector system. Cell. 1981 Dec;27(2 Pt 1):279–288. doi: 10.1016/0092-8674(81)90411-6. [DOI] [PubMed] [Google Scholar]
  18. Peschle C., Mavilio F., Carè A., Migliaccio G., Migliaccio A. R., Salvo G., Samoggia P., Petti S., Guerriero R., Marinucci M. Haemoglobin switching in human embryos: asynchrony of zeta----alpha and epsilon----gamma-globin switches in primitive and definite erythropoietic lineage. Nature. 1985 Jan 17;313(5999):235–238. doi: 10.1038/313235a0. [DOI] [PubMed] [Google Scholar]
  19. Proudfoot N. J., 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. doi: 10.1016/0092-8674(80)90491-2. [DOI] [PubMed] [Google Scholar]
  20. Russell G. J., Walker P. M., Elton R. A., Subak-Sharpe J. H. Doublet frequency analysis of fractionated vertebrate nuclear DNA. J Mol Biol. 1976 Nov;108(1):1–23. doi: 10.1016/s0022-2836(76)80090-3. [DOI] [PubMed] [Google Scholar]
  21. SINSHEIMER R. L. The action of pancreatic deoxyribonuclease. II. Isomeric dinucleotides. J Biol Chem. 1955 Aug;215(2):579–583. [PubMed] [Google Scholar]
  22. SWARTZ M. N., TRAUTNER T. A., KORNBERG A. Enzymatic synthesis of deoxyribonucleic acid. XI. Further studies on nearest neighbor base sequences in deoxyribonucleic acids. J Biol Chem. 1962 Jun;237:1961–1967. [PubMed] [Google Scholar]
  23. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  24. Tykocinski M. L., Max E. E. CG dinucleotide clusters in MHC genes and in 5' demethylated genes. Nucleic Acids Res. 1984 May 25;12(10):4385–4396. doi: 10.1093/nar/12.10.4385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Weintraub H., Larsen A., Groudine M. Alpha-Globin-gene switching during the development of chicken embryos: expression and chromosome structure. Cell. 1981 May;24(2):333–344. doi: 10.1016/0092-8674(81)90323-8. [DOI] [PubMed] [Google Scholar]

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