title: Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles.
abstract: Fragile X syndrome results from the expansion of a CGG repeat that is normally interrupted by occasional AGG triplets. Linkage disequilibrium suggests that certain normal haplotypes may contribute unequally to the pool of fragile X chromosomes. Sequence analysis of normal alleles demonstrates haplotype-specific variation of the cryptic nature of the repeat. Variation occurs principally at the 3' end of the repeat, suggesting stability differences between the leading and lagging strands of DNA replication. Normal alleles with greater than 24 perfect 3' CGG repeats appear more frequently on haplotypes overrepresented among fragile X chromosomes. Such alleles are found in 2% of normal chromosomes and could comprise the ancestral allelic pool from which fragile X chromosomes are derived. These data also may imply that equilibrium between certain predisposed alleles and fragile X expansions has not yet been attained, indicating ongoing evolutionary change at this locus.
authors.affiliation: Howard Hughes Medical Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: C B
authors.initials: CB
authors.lastname: Kunst
authors.forename: S T
authors.initials: ST
authors.lastname: Warren
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004247:DNA; D004261:DNA Replication; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D016601:RNA-Binding Proteins; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D004247:DNA; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human