Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1

In at least 98% of fragile X syndrome cases, the disease results fromexpansion of the CGG repeat in the 5' end of FMR1. The use ofmicrosatellite markers in the FMR1 region has revealed a disparity of riskbetween haplotypes for CGG repeat expansion. Although instability appearsto depend on both the haplotype and the AGG interspersion pattern of therepeat, these factors alone do not completely describe the molecular basisfor the linkage disequilibrium between normal and fragile X chromosomes, inpart due to instability of the marker loci themselves. In an effort tobetter understand the mechanism of dynamic mutagenesis, we have searchedfor and discovered a single nucleotide polymorphism in intron 1 of FMR1 andcharacterized this marker, called ATL1, in 564 normal and 152 fragile Xchromosomes. The G allele of this marker is found in 40% of normalchromosomes, in contrast to 83% of fragile X chromosomes. Not only is the Gallele exclusively linked to haplotypes over-represented in fragile Xsyndrome, but G allele chromosomes also appear to transition to instabilityat a higher rate on haplotypes negatively associated with risk ofexpansion. The two alleles of ATL1 also reveal a highly significant linkagedisequilibrium between unstable chromosomes and the 5' end of the CGGrepeat itself, specifically the position of the first AGG interruption. Thedata expand the number of haplotypes associated with FMR1 and specificallyallow discrimination, by ATL1 alleles, of single haplotypes with differingpredispositions to expansion. Such haplotypes should prove useful infurther defining the mechanism of dynamic mutagenesis.