title: Frequency of abnormal human haemoglobins caused by C----T transitions in CpG dinucleotides.
abstract: A large part of human genetic disease apparently arises from deamination of cytosine residues in methylated CpG dinucleotides. Their mutation rate is known to be high when C is present as 5-methyl-cytosine, but is believed to be normal when it is unmethylated. The beta-globin gene contains five, the gamma-globin gene two, and each of the alpha-globin genes contains 35 CpG dinucleotides. The CpG dinucleotides in the beta and gamma-globin genes are methylated, while those in the alpha-globin genes are under-methylated. One would therefore have expected the CpG dinucleotides to be a frequent source of mutations in the beta and gamma-globin genes, but not in the alpha-globin genes. In fact, the evidence points to CpG dinucleotides being a frequent source of mutations in both the alpha and beta-globin genes. This suggests either that the mutation rates of both methylated and unmethylated CpG dinucleotides are abnormally high, which conflicts with published evidence, or that there is a finite chance of some of these in the alpha-globin genes of certain individuals being methylated and therefore subject to mutation.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, U.K.
authors.forename: M F
authors.initials: MF
authors.lastname: Perutz
mesh_terms: D001483:Base Sequence; D015226:Dinucleoside Phosphates / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006454:Hemoglobins / Q000235:genetics*; D006801:Humans; D008745:Methylation; D009154:Mutation
chemical_list: D015226:Dinucleoside Phosphates; D005914:Globins; D006454:Hemoglobins; C015772:CpG dinucleotide