The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene

Abstract

Mutations at CpG dinucleotides were delineated in the factor IX gene of 38 hemophilia B patients. When transitions at CpG were considered with those previously reported by us and those compiled in the factor IX mutation database, the following patterns emerged. Many CpG sites were mutated with high frequency, while two CpG sites were infrequently mutated (R29-->Q and R116-->TGA). Of the 6 possible nonsense mutations and the 14 missense mutations that would produce a nonconservative change at conserved amino acids, all have been observed to cause hemophilia B except A-10-->T and R338-->Q. By contrast, none of the 6 missense changes at nonconserved amino acids have been observed to cause hemophilia B. At those CpG sites that are frequently mutated, the rate of transitions is estimated to be 20-fold higher than transitions at non-CpG sites. Point mutations in close proximity to CpG dinucleotides did not seem elevated.

DNA Methylation: An Alternative Pathway to Cancer

“…70 This event would be consistent with a methylation-induced genetic effect, and similar patterns have been noted in other genes such as the factor IX gene. 76 Some other theories for mutational induction secondary to DNA methylation are:…”

Analysis of recurrent germline mutations in theMEN1 gene encountered in apparently unrelated families

“…These observations suggest that slippage and substitution errors during replication are the predominant mechanisms of mutagenesis contributing to MEN1 mutations. Similar mechanisms for mutagenesis have been proposed for other tumor suppressor genes like NF1 , P53 (Jego et al, 1993), BRCA1 (Rodenhiser et al, 1996) and RB (Canning and Dryja, 1989;Mancini et al, 1997), and also for other genes with inactivating mutations like the gene for dystrophin (Todovora and Danieli, 1997), antithrombin I (Emmerich et al, 1994), antithrombin III (Perry and Carrell, 1989) and factor IX (Bottema et al, 1993).…”

Utilities for high throughput use of the single strand conformational polymorphism method: screening of 791 patients with familial hypercholesterolaemia for mutations in exon 3 of the low density lipoprotein receptor gene.

“…It is likely that there is mutational drive owing to methylation at these CpG sites, and therefore it can be expected that there will be both founder effects (minor or major) because mutations will have occurred early in human evolution (apparently with low negative selection bias"4) and recurrent mutations at the same sites because they are estimated to be 20-fold more susceptible to mutation than other dinucleotides,32 mutating at an estimated rate of 10-7 per site per gamete. 35 Construction of simple diagnostic assays for mutations at these sites should therefore prove worthwhile.…”