FRAGILE-X FOUNDER CHROMOSOMES IN ITALY - A FEW INITIAL EVENTS AND POSSIBLE EXPLANATION FOR THEIR HETEROGENEITY

A total of 137 fragile X and 235 control chromosomes from various regi ons of Italy were haplotyped by analyzing two neighbouring marker micr osatellites, FRAXAC1 and DXS548, The number of CGG repeats at the 5' e nd of the FMR1 gene was also assessed in 141 control chromosomes and c orrelated with their haplotypes. Significant linkage disequilibrium be tween some ''major'' haplotypes and fragile X was observed, while othe r ''minor'' haplotypes may have originated by subsequent mutation at t he marker microsatellite loci and/or recombination between them, Recen t evidence suggests that the initial mechanism leading to CGG instabil ity might consist of rare (10(-6/-7)) CGG repeat slippage events and/o r loss of a stabilizing AGG via A-to-C transversion, Also, the apparen tly high variety of fragile X chromosomes may be partly due to the rel atively high mutation rate (10(-4/-5)) of the microsatellite markers u sed in haplotyping, Our fragile X sample also showed a higher than exp ected heterozygosity when compared to the control sample and we sugges t that this might be explained by the chance occurrence of the few fou nding events on different chromosomes, irrespective of their actual fr equency in the population, Alternatively, a local mechanism could enha nce the microsatellite mutation rate only on fragile X chromosomes, or fragile X mutations might occur more frequently on certain background haplotypes. (C) 1996 Wiley-Liss, Inc.