CpG Dinucleotides and Human Disorders

Abstract

Analysis of the mutation spectra of single nucleotide substitutions associated with monogenic disorders strongly suggests that CG to TG mutations are among the most frequent causes of human genetic disease phenotypes. This is probably due to the mechanism of methylation–deamination of cytosine. In addition, this substitution mechanism results in a substantial fraction of the polymorphic variability of the human genome.

Keywords: mutation; genetic disease; X‐linked; methylation; deamination; single nucleotide polymorphism; missense; nonsense; hypermutability

Figure 1.

Frequency of the CG to TG or CA mutations among (a) 921 missense and nonsense mutations in the F8 gene in unrelated hemophilia A families, (b) 3840 such mutations in the 11 X‐linked disorders in Table and (c) 1248 single nucleotide polymorphisms.

Figure 2.

Schematic representation of the molecules for cytosine, 5‐methylcytosine and thymine and the chemical events for the transformation of cytosine to thymine.

Figure 3.

Histogram of the codon usage in human genes and mutations found in codons for the various amino acids. The codon usage data are from the Codon Usage Database (see Web Links) and the mutation data from the Human Gene Mutation database (see Web Links). The values on the y‐axis were normalized for 10000.

Figure 4.

Histogram of the independent recurrent mutations found in codons of five X‐linked genes (F8, F9, LICAM, OTC and BTK) and the occurrence of these codons in these five genes. The information for the independent mutations was extracted from the locus specific databases.

Figure 5.

Histogram of the codon usage for the various amino acids in human genes and nonsense mutations originating from these codons. The codon usage data are from the Codon Usage Database (see Web Links) and the mutation data from the Human Gene Mutation database (see Web Links). The values on the y‐axis were normalized for 1000.

Figure 6.

Histogram of the independent recurrent mutations found in codons of eight X‐linked genes (F8, F9, L1CAM, CYBB, ALD, OTC, BTK and MECP2) and the occurrence of these codons in these five genes. The information for the independent mutations was extracted from the locus specific databases.

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References

Antonarakis SE, Kazazian HH and Tuddenham EG (1995) Molecular etiology of factor VIII deficiency in hemophilia A. Human Mutation 5: 1–22.

Antonarakis S, Krawczak M and Cooper DN (2001) The nature and mechanisms of human gene mutation. In: Scriver CR, Beaudet AL, Sly WS, et al. (eds.) The Metabolic and Molecular Bases of Inherited Disease, 8th edn, pp. 343–377. New York, NY: McGraw‐Hill.

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

Cargill M, Altshuler D, Ireland J, et al. (1999) Characterization of single‐nucleotide polymorphisms in coding regions of human genes. Nature Genetics 22: 231–238.

Cooper DN (1983) Eukaryotic DNA methylation. Human Genetics 64: 315–333.

Cooper DN, Ball EV and Krawczak M (1998) The human gene mutation database. Nucleic Acids Research 26: 285–287.

Gerard B, El Benna J, Alcain F, et al. (2001) Characterization of 11 novel mutations in the X‐linked chronic granulomatous disease (CYBB gene). Human Mutation 18: 163.

Giannelli F, Anagnostopoulos T and Green PM (1999) Mutation rates in humans. II. Sporadic mutation‐specific rates and rate of detrimental human mutations inferred from hemophilia B. American Journal of Human Genetics 65: 1580–1587.

Giannelli F, Green PM, Sommer SS, et al. (1998) Haemophilia B: database of point mutations and short additions and deletions – eighth edition. Nucleic Acids Research 26: 265–268.

Gottlieb B, Beitel LK and Trifiro MA (2001) Variable expressivity and mutation databases: the androgen receptor gene mutations database. Human Mutation 17: 382–388.

Kemp S, Pujol A, Waterham HR, et al. (2001) ABCD1 mutations and the X‐linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Human Mutation 18: 499–515.

Ketterling RP, Vielhaber E, Bottema CD, et al. (1993) Germ‐line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation. American Journal of Human Genetics 52: 152–166.

Krawczak M, Ball EV and Cooper DN (1998) Neighbouring‐nucleotide effects on the rates of germ‐line single‐base‐pair substitution in human genes. American Journal of Human Genetics 63(2): 474–488.

Krawczak M, Smith‐Sorensen B, Schmidtke J, et al. (1995) Somatic spectrum of cancer‐associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutation and by selection. Human Mutation 5: 48–57.

Laporte J, Biancalana V, Tanner SM, et al. (2000) MTM1 mutations in X‐linked myotubular myopathy. Human Mutation 15: 393–409.

Lissens W, De Meirleir L, Seneca S, et al. (2000) Mutations in the X‐linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Human Mutation 15: 209–219.

Millar DS, Krawczak M and Cooper DN (1998) Variation of site‐specific methylation patterns in the factor VIII (F8C) gene in human sperm DNA. Human Genetics 103: 228–233.

Monnier N, Satre V, Lerouge E, Berthoin F and Lunardi J (2000) OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Human Mutation 16: 157–165.

Sabbagh Y, Jones AO and Tenenhouse HS (2000) PHEXdb, a locus‐specific database for mutations causing X‐linked hypophosphatemia. Human Mutation 16: 1–6.

Sachidanandam R, Weissman D, Schmidt SC, et al. (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409: 928–933.

Shahbazian MD and Zoghbi HY (2001) Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Current Opinion in Neurology 14: 171–176.

Tuchman M, Jaleel N, Morizono H, Sheehy L and Lynch MG (2002) Mutations and polymorphisms in the human ornithine transcarbamylase gene. Human Mutation 19: 93–107.

Venter JC, Adams MD, Myers EW, et al. (2001) The sequence of the human genome. Science 291: 1304–1351.

Vihinen M, Kwan SP, Lester T, et al. (1999) Mutations of the human BTK gene coding for bruton tyrosine kinase in X‐linked agammaglobulinemia. Human Mutation 13: 280–285.

Wacey AI, Kemball‐Cook G, Kazazian HH, et al. (1996) The haemophilia A mutation search test and resource site, home page of the factor VIII mutation database: HAMSTeRS. Nucleic Acids Research 24: 100–102.

Weller S and Gartner J (2001) Genetic and clinical aspects of X‐linked hydrocephalus (L1 disease): mutations in the L1CAM gene. Human Mutation 18: 1–12.

Youssoufian H, Antonarakis SE, Bell W, Griffin AM and Kazazian HHJ (1988) Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. American Journal of Human Genetics 42: 718–725.

Youssoufian H, Kazazian HHJ, Phillips DG, et al. (1986) Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324: 380–382.

Web Links

Codon Usage Database (data for Homo sapiens) http://www.kazusa.or.jp/codon/cgi‐bin/showcodon.cgi?species=Homo+sapiens+[gbpri]

Human Gene Mutation Database. The Human Gene Mutation Database comprises various types of mutation within the coding regions of human nuclear genes causing inherited disease. Somatic mutations and mutations in the mitochondrial genome are thus not included. Each mutation is entered only once in order to avoid confusion between recurrent and identical‐by‐descent lesions. Silent mutations within the coding region which do not alter the encoded amino acid are also not recorded http://www.hgmd.org/

Online Mendelian Inheritance in Man (OMIM). This database is a catalog of human genes and genetic disorders authored and edited by Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. The database contains textual and reference information. http://www.ncbi.nlm.nih.gov/Omim/

HAMSTeRS: The Haemophilia A Mutation, Structure, Test and Resource Site http://europium.csc.mrc.ac.uk

Locus Specific Mutation Database http://ariel.ucs.unimelb.edu.au:80/∼cotton/glsdb.htm

Bruton agammaglobulinemia tyrosine kinase (BTK); Locus ID: 695. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=695

Coagulation factor VIII, procoagulant component (hemophilia A) (F8); Locus ID: 2157. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2157

Coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B) (F9); Locus ID: 2158. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2158

L1 cell adhesion molecule (hydrocephalus, stenosis of aqueduct of Sylvius 1, MASA (mental retardation, aphasia, shuffling gait and adducted thumbs) syndrome, spastic paraplegia 1) (L1CAM); Locus ID: 3897. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3897

Ornithine carbamoyltransferase (OTC); Locus ID: 5009. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5009

Bruton agammaglobulinemia tyrosine kinase (BTK); MIM number: 300300. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?300300

Coagulation factor VIII, procoagulant component (hemophilia A) (F8); MIM number: 306700. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?306700

Coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B) (F9); MIM number: OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?306900

L1 cell adhesion molecule (hydrocephalus, stenosis of aqueduct of Sylvius 1, MASA (mental retardation, aphasia, shuffling gait and adducted thumbs) syndrome, spastic paraplegia 1) (L1CAM); MIM number: 308840. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?308840

Ornithine carbamoyltransferase (OTC); MIM number: 311250. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?311250

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How to Cite close
Antonarakis, Stylianos E(Jan 2006) CpG Dinucleotides and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005497]