Skip to main content
SpringerLink
Log in

The CpG dinucleotide and human genetic disease

  • Original Investigations
  • Published:
Human Genetics Aims and scope Submit manuscript

Summary

Reports of single base-pair mutations within gene coding regions causing human genetic disease were collated. Thirty-five per cent of mutations were found to have occurred within CpG dinucleotides. Over 90% of these mutations were C → T or G → A transitions, which thus occur within coding regions at a frequency 42-fold higher than that predicted from random mutation. These findings are consistent with methylation-induced deamination of 5-methyl cytosine and suggest that methylation of DNA within coding regions may contribute significantly to the incidence of human genetic disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Antonarakis SE, Kazazian H, Orkin SH (1985a) DNA polymorphism and molecular pathology of the human globin gene clusters. Hum Genet 69:1–14

    Google Scholar 

  • Antonarakis SE, Waber PG, Kittur SD, Patel AS, Kazazian HH, Mellis MA, Counts RB, Stamatoyannopoulos G, Bowie W, Fass DN, Pittman DD, Wozney JM, Toole JJ (1985b) Hemophila A; detection of molecular defects and of carriers by DNA analysis. N Engl J Med 313:842–848

    Google Scholar 

  • Antonarakis SE, Youssoufian H, Kazazian HH (1987) Molecular genetics of hemophilia A in man (factor VIII deficiency). Mol Biol Med 4:81–84

    Google Scholar 

  • Barker D, Schäfer M, White R (1984) Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 36:131–138

    Google Scholar 

  • Bentley AK, Rees DJG, Rizza C, Brownlee GG (1986) Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position-4. Cell 45:343–348

    Google Scholar 

  • Bird AP (1980) DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8:1499–1504

    Google Scholar 

  • Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213

    Google Scholar 

  • 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 40:91–99

    Google Scholar 

  • Bird AP, Taggart MH, Nichols RD, Higgs DR (1987) Non-methylated CpG-rich islands at the human α-globin locus: implications for evolution of the α-globin pseudogene. EMBO J 6:999–1004

    Google Scholar 

  • Bonthron DT, Markham AF, Ginsburg D, Orkin SH (1985) Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J Clin Invest 76:894–897

    Google Scholar 

  • Brown WRA, Bird AP (1986) Long-range restriction site mapping of mammalian genomic DNA. Nature 322:477–481

    Google Scholar 

  • Bullock E, Elton RA (1972) Dipeptide frequencies in proteins and the CpG deficiency in vertebrate DNA. J Mol Evol 1:315–325

    Google Scholar 

  • Chan SJ, Seino S, Gruppuso PA, Schwartz R, Steiner DF (1987) A mutation in the β chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinaemia. Proc Natl Acad Sci USA 84:2194–2197

    Google Scholar 

  • Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G, Zannis VI (1987) The molecular basis of a familial Apo E deficiency. J Biol Chem 262:2310–2315

    Google Scholar 

  • Cohn DH, Byers PH, Steinman B, Gelinas RE (1986) Lethal osteogenesis imperfecta resulting from a single nucleotide change in one human pro α1 (I) collagen allele. Proc Natl Acad Sci USA 83:6045–6047

    Google Scholar 

  • Cooper DN (1983) Eukaryotic DNA methylation. Hum Genet 64:315–333

    Google Scholar 

  • Cooper DN, Gerber-Huber S (1985) DNA methylation and CpG suppression. Cell Differ 17:199–205

    Google Scholar 

  • Cooper DN, Schmidtke J (1984) DNA restriction fragment length polymorphisms and heterozygosity in the human genome. Hum Genet 66:1–16

    Google Scholar 

  • Cooper DN, Schmidtke J (1986) Diagnosis of genetic disease using recombinant DNA. Hum Genet 73:1–11

    Google Scholar 

  • Cooper DN, Schmidtke J (1987) Diagnosis of genetic disease using recombinant DNA. Supplement. Hum Genet 77:66–75

    Google Scholar 

  • Cooper DN, Taggart MH, Bird AP (1983) Unmethylated domains in vertebrate DNA. Nucleic Acids Res 11:647–658

    Google Scholar 

  • Cooper DN, Smith BA, Cooke HJ, Niemann S, Schmidtke J (1985) An estimate of unique DNA sequence heterozygosity in the human genome. Hum Genet 69:201–205

    Google Scholar 

  • Cooper DN, Gerber-Huber S, Nardelli D, Schubiger J-L, Wahli W (1987) The distribution of the dinucleotide CpG and cytosine methylation in the vitellogenin gene family. J Mol Evol 25:107–115

    Google Scholar 

  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780

    Google Scholar 

  • Daar IO, Artymiuk PJ, Phillips DC, Maquat LE (1986) Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. Proc Natl Acad Sci USA 83:7903–7907

    Google Scholar 

  • Davis LM, McGraw RA, Ware JL, Roberts HR, Stafford DW (1987) Factor IX alabama: a point mutation in a clotting protein results in hemophilia B. Blood 69:140–143

    Google Scholar 

  • De Verneuil H, Grandchamp B, Beaumont C, Picat C, Nordmann Y (1986) Uroporphyrinogen decarboxylase structural mutant (Gly281 → Glu) in a case of porphyria. Science 234:732–734

    Google Scholar 

  • DiLella AG, Marvit J, Lidsky AS, Guttler F, Woo SLC (1986) Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria. Nature 322:799–803

    Google Scholar 

  • DiLella AG, Marvit J, Brayton K, Woo SLC (1987) An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. Nature 327:333–336

    Google Scholar 

  • Duchange N, Chassé J-F, Cohen GN, Zakin NM (1986) Antithrombin III Tours gene: identification of a point mutation leading to an arginine → cysteine replacement in a silent deficiency. Nucleic Acids Res 14:2408

    Google Scholar 

  • Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282

    Google Scholar 

  • Gitschier J, Wood WL, Tuddenham EGD, Shuman MA, Goralka TM, Chen EY, Lawn RM (1985) Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature 315:427–430

    Google Scholar 

  • Gitschier J, Wood WI, Shuman MA, Lawn RM (1986) Identification of a missense mutation in the factor VIII gene of a mild hemophiliac. Science 232:1415–1416

    Google Scholar 

  • Grippo P, Iaccarino M, Parisi E, Scarano E (1968) Methylation of DNA in developing sea urchin embryos. J Mol Biol 36:195–208

    Google Scholar 

  • Haneda M, Chan SJ, Kwok SCM, Rubenstein AH, Steiner DF (1983) Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding [Ser B24] insulin. Proc Natl Acad Sci USA 80:6366–6370

    Google Scholar 

  • Josse J, Kaiser AD, Kornberg A (1961) Enzymatic synthesis of deoxyribonucleic acid. VIII. Frequencies of nearest neightbor base sequences in deoxyribonucleic acid. J Biol Chem 236:864–875

    Google Scholar 

  • Keshet I, Lieman-Hurwitz J, Cedar H (1986) DNA methylation affects the formation of active chromatin. Cell 44:535–543

    Google Scholar 

  • Kidd VJ, Wallace RB, Itakura K, Woo SLC (1983) 155-1 deficiency detection by direct analysis of the mutation in the gene. Nature 304:230–234

    Google Scholar 

  • Law SW, Brewer HB (1985) Tangier disease: the complete mRNA sequence encoding for preproapo-A1. J Biol Chem 260:12810–12814

    Google Scholar 

  • Lehrman MA, Goldstein JL, Brown MS, Russell DW, Schneider WJ (1985) Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain. Cell 41:735–743

    Google Scholar 

  • Li Q, Powers PA, Smithies O (1985) Nucleotide sequence of 16 kilobase pairs of DNA 5′ to the human É›-globin gene. J Biol Chem 260:14901–14910

    Google Scholar 

  • Lindsay S, Bird AP (1987) Use of restriction enzymes to detect potential gene sequences in mammalian DNA. Nature 327:336–338

    Google Scholar 

  • Long I (1987) Structure and evolution of the human genes encoding protein C and coagulation factor IX. J Cell Biochem 33:185–190

    Google Scholar 

  • Maeda S, Mita S, Araki S, Shimada K (1986) Structure and expression of the mutant prealbumin gene associated with familial amyloidotic polyneuropathy. Mol Biol Med 3:329–338

    Google Scholar 

  • Nukiwa T, Satoh K, Brantly ML, Ogushi F, Fells GA, Courtney M, Crystal RG (1986) Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-anti-trypsin gene. J Biol Chem 261:15989–15994

    Google Scholar 

  • Nussinov R (1981) Eukaryotic dinucleotide preference rules and their implications for degenerate codon usage. J Mol Biol 149:125–131

    Google Scholar 

  • Razin A, Szyf M (1984) DNA methylation patterns: formation and function. Biochim Biophys Acta 782:331–342

    Google Scholar 

  • Rees DJG, Rizza CR, Brownlee GG (1985) Haemophilia B caused by a point mutation in a donor splice junction of the human factor IX gene. Nature 316:643–645

    Google Scholar 

  • Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vincente V, Mannucci PM, Bertina R, Peschle C, Cortese R (1987) Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci USA 84:2829–2832

    Google Scholar 

  • Savatier P, Trabuchet G, Fauré C, Chebloure Y, Gouy M, Verdier G, Nigon VM (1985) Evolution of the primate beta-globin gene region. High rate of variation in CpG dinucleotides and in short repeated sequences between man and chimpanzee. J Mol Biol 182:21–29

    Google Scholar 

  • Selker EV, Stevens JN (1985) DNA methylation at asymetric sites is associated with numerous transition mutations. Proc Natl Acad Sci USA 82:8114–8118

    Google Scholar 

  • Shibasaki Y, Kawakami T, Kanazawa Y, Akanuma Y, Takaku F (1985) Post-translational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia. J Clin Invest 76:378–380

    Google Scholar 

  • Shoelson S, Haneda M, Blix P, Nanjo A, Sanke T, Inouye K, Steiner D, Rubenstein A, Tager H (1983) Three mutant insulins in man. Nature 302:540–543

    Google Scholar 

  • Stavnezer-Nordgren J, Kekish O, Zegers BJM (1985) Molecular defects in a human immunoglobulin K chain deficiency. Science 230:458–461

    Google Scholar 

  • Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI (1987) A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med 316:570–575

    Google Scholar 

  • Valerio D, Dekker BMM, Duyvesteyn MGC, Voorn L van der, Berkvens TM, Ormondt H van, Eb AJ van der (1986) One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. EMBO J 5:113–119

    Google Scholar 

  • Vogel F, Kopun M (1977) Higher frequencies of transitions among point mutations. J Mol Evol 9:159–180

    Google Scholar 

  • Wallace MR, Dwulet FE, Conneally PM, Benson MD (1986) Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest 78:6–12

    Google Scholar 

  • Wang RY-H, Kuo KC, Gehrke CW, Huang L-H, Ehrich M (1982) Heat and alkali-induced deamination of 5-methylcytosine and cytosine residues in DNA. Biochim Biophys Acta 697:371–377

    Google Scholar 

  • Williams SR, Gekeler V, Mclvor RS, Martin DW (1987) A human purine nucleoside phosphorylase deficiency caused by a single base change. J Biol Chem 262:2332–2338

    Google Scholar 

  • Youssoufian H, Kazazian HH, Phillips DG, Aronis S, Tsiftis G, Brown VA, Antonarakis SE (1986) Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324:380–382

    Google Scholar 

Download references

Author information

Author notes

  1. Hagop Youssoufian

    Present address: Hematology-Oncology Unit, Massachusetts General Hospital, Cox 6, 02114, Boston, MA, USA

Authors and Affiliations

  1. Haematology Department, King's College School of Medicine and Dentistry, Denmark Hill, SE5 8RX, London, UK

    David N. Cooper

  2. Genetics Unit, Department of Pediatrics, The Johns Hopkins University School of Medicine, 21 205, Baltimore, MD, USA

    Hagop Youssoufian

Authors
  1. David N. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hagop Youssoufian
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cooper, D.N., Youssoufian, H. The CpG dinucleotide and human genetic disease. Hum Genet 78, 151–155 (1988). https://doi.org/10.1007/BF00278187

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00278187

Keywords

Search

Navigation