LARGE MAJORITY OF SINGLE-NUCLEOTIDE MUTATIONS ALONG THE DYSTROPHIN GENE CAN BE EXPLAINED BY MORE THAN ONE MECHANISM OF MUTAGENESIS

The present study reports for the first time on the analysis of the po ssible origin of single base mutations along the highly mutable human dystrophin gene. Seventy-two mutations were considered and analyzed fo r consistency with the ''slipped-mispairing'' and ''hypermutable CpG'' models of mutagenesis. Moreover, repeated and symmetric elements, whi ch could participate in the formation of secondary structures, were se arched in each stretch of sequence including a given mutant base. Unex pectedly the frequency of CpG mutations was found less than reported f or other genes, whereas the frequency of transitions was found to be m uch higher than expected. Base substitutions in CpG dinucleotides that could be explained by methylation-mediated deamination were all C-->T transitions. No G-->A transitions in CpG dinucleotides were found. A sequence motif, which has been shown to act as an arrest site for poly merase cc, occurred associated with > 50% of single-base mutations. Al l the mutations but one can be explained by at least two mechanisms of mutagenesis. This would mean that mutation could occur with higher pr obability at a given position, when it might be produced independently by different mechanisms. According to the present data, direct or inv erted repeats seem to play a major role in this context. Therefore, th e search for repeats along the dystrophin gene might help in identifyi ng potential sites of mutation. (C) 1997 Wiley-Liss, Inc.