Precursor arrays for triplet repeat expansion at the fragile X locus.
To determine factors governing triplet repeat expansion at FMR1, we need to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are interrupted with a regularly spaced AGG trinucleotide giving an ordered structure to the array. Five types of arrays were identified consisting of varying numbers of a core unit with consensus [AGG(CGG)9]. Additional variation in the length of the (CGG)n portion within each unit generates 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 interrupted arrays. Haplotype analysis of arrays carrying long, uninterrupted (CGG)n tracts suggests that they occur more frequently on genetic backgrounds which are more highly represented on fragile X chromosomes. These arrays may well be precursors from which the larger fragile X associated arrays have arisen by further expansion.
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
M C
MC
Hirst
P K
PK
Grewal
K E
KE
Davies
D001483:Base Sequence; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics*; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D014960:X Chromosome
D017931:DNA Primers; D005819:Genetic Markers; D009838:Oligodeoxyribonucleotides; D004247:DNA