CpG Dinucleotides and Human Disorders

Stylianos E Antonarakis, University of Geneva Medical School, Geneva, Switzerland

Published online: January 2006

DOI: 10.1038/npg.els.0005497

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 1 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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 Web Links
    ePath Codon Usage Database (data for Homo sapiens) http://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=Homo+sapiens+[gbpri]
    ePath 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/
    ePath 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/
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    book Locus Specific Mutation Database http://ariel.ucs.unimelb.edu.au:80/~cotton/glsdb.htm
    ePath Bruton agammaglobulinemia tyrosine kinase (BTK); Locus ID: 695. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=695
    ePath Coagulation factor VIII, procoagulant component (hemophilia A) (F8); Locus ID: 2157. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2157
    ePath 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
    ePath 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
    ePath Ornithine carbamoyltransferase (OTC); Locus ID: 5009. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5009
    ePath Bruton agammaglobulinemia tyrosine kinase (BTK); MIM number: 300300. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300300
    ePath Coagulation factor VIII, procoagulant component (hemophilia A) (F8); MIM number: 306700. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306700
    ePath 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
    ePath 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
    ePath Ornithine carbamoyltransferase (OTC); MIM number: 311250. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?311250

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Inter-Individual Variation and Polymorphism | Genetic Code | DNA Damage and Repair | Nucleic Acids: Structure, Function, Metabolism
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Article Title: CpG Dinucleotides and Human Disorders
 
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]