FMR1 IN GLOBAL POPULATIONS

Fragile X syndrome, a frequent form of inherited mental retardation, r esults from the unstable expansion of a cryptic CGG repeat within the 5' UTR region of the FMR1 gene. The CGG repeat is normally polymorphic in length, and the content is frequently interrupted by AGG triplets. These interruptions are believed to stabilize the repeat, and their a bsence, leading to long tracts of perfect CGG repeats, may give rise t o predisposed alleles. In order to examine the stability of normal FMR 1 alleles, the repeat length of 345 chromosomes from nine global popul ations was examined with the content also determined from 114 chromoso mes as assessed by automated DNA sequencing. The FMR1 alleles, defined by the CGG repeat, as well as by the haplotypes of nearby polymorphic loci, were very heterogeneous, although the level of variation correl ated with the age and/or genetic history of a particular population. N ative American alleles, interrupted by three AGG repeats, exhibited ma rked stability over 7,000 years. However, in older African populations , parsimony analysis predicts the occasional loss of an AGG, leading t o more perfect CGG repeats. These data therefore support the suggestio n that AGG interruptions enhance the stability of the FMR1 repeat and indicate that the rare loss of these interruptions leads to alleles wi th longer perfect CGG-repeat tracts.