PRECURSOR ARRAYS FOR TRIPLET REPEAT EXPANSION AT THE FRAGILE-X LOCUS

To determine factors governing triplet repeat expansion at FMR1, we ne ed to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are inter rupted with a regularly spaced AGG trinucleotide giving an ordered str ucture to the array. Five types of arrays were identified consisting o f varying numbers of a core unit with consensus [AGG(CGG)(9)]. Additio nal variation in the length of the (CGG)(n) portion within each unit g enerates the continuum of lengths seen on normal chromosomes. Ten per cent contain long, uninterrupted tracts of (CGG)(n), and their lengths suggest they have arisen by the loss of AGG triplets from longer inte rrupted arrays. Haplotype analysis of arrays carrying long, uninterrup ted (CGG)(n) tracts suggests that they occur more frequently on geneti c backgrounds which are more highly represented on fragile X chromosom es. These arrays may well be precursors from which the larger fragile X associated arrays have arisen by further expansion.