FREQUENCY OF ABNORMAL HUMAN HEMOGLOBINS 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-methylcytosine, but is believed to be normal when it is unmethylated. The β-globin gene contains five, the γ-globin gene two, and each of the α-globin genes contain 35 CpGs. The CpGs in the β- and γ-globin genes are methylated, while those in the α-globin genes are undermethylated. One would therefore have expected the CpGs to be a frequent source of mutations in the β- and γ-globin genes, but not in the α-globin genes. In fact, the evidence points to CpGs being a frequent source of mutations in both the α- and β-globin genes. This suggests either that the mutation rates of both methylated and unmethylated CpGs are abnormally high, which conflicts with published evidence, or that there is a finite chance of some CpGs in the α-globin genes of certain individuals being methylated and therefore subject to mutation. © 1990.