Frequency of abnormal human haemoglobins caused by C----T transitions in CpG dinucleotides.
A large part of human genetic disease apparently arises from deamination of cytosines 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 contain 35 CpG's. The CpG's in the beta-and gamma-globin genes are methylated, while those in the alpha-globin genes are undermethylated. One would therefore have expected the CpG's 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's 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's are abnormally high, which conflicts with published evidence, or that there is a finite chance of some CpG's in the alpha-globin genes of certain individuals being methylated and therefore subject to mutation.
Perutz
M F
MF
MRC Laboratory of Molecular Biology, Cambridge, U.K.
D044503:5-Methylcytosine; D003596:Cytosine / Q000031:analogs & derivatives; D003641:Deamination; D005787:Gene Frequency; D005914:Globins / Q000235:genetics*; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D009154:Mutation
D006455:Hemoglobins, Abnormal; D044503:5-Methylcytosine; D003596:Cytosine; D005914:Globins