A COMPLEX MUTABLE POLYMORPHISM LOCATED WITHIN THE FRAGILE X-GENE

While studying founder chromosomes in the fragile X syndrome, we have unexpectedly found linkage equilibrium to FRAXZC2, an Alu-associated m icrosatellite within the defective gene, FMR-1. DNA sequencing of 265 chromosomes revealed 39 alleles and a complex microsatellite of form ( GT)x-C-(TA)y-(T)z. A mutation rate of 3.3% was observed but only among fragile X maternally derived meioses. Finding a second mutable locus within FMR-1 suggests that the target for tandem repeat instability ma y not be confined to the (CGG)n repeat alone and raises the possibilit y of an FMR-1 mutation mechanism involving microsatellites.