Sequence analysis of the fragile X trinucleotide repeat: Implications for the origin of the fragile X mutation

Karen Snow, David J. Tester, Kent E. Kruckeberg, Daniel J. Schaid, Stephen N. Thibodeau

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143 Scopus citations


This study addresses mechanism of instability of the FMR-1 (CGG)n-repeat, and investigates features which may distinguish between normal stable and fragile X unstable repeats. To achieve this, we have sequenced 178 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n-repeat at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines Instability. We predict that certain sequence configurations [no AGG, and (CGG)9-11AGG(CGG)≥20] present in the general population, are predisposed towards replication slippage. Association between these proposed predisposing repeats and DXS548 alleies may explain the previously reported frequencies of fragile X mutations and large-size normal repeats on specific haplotype backgrounds. We propose that predisposing alleles arise in the general population by as yet undefined mechanism(s) which introduce a relatively long stretch of pure CGG repeat at the 3'-end (relative to the direction of transcription) of the FMR-1 repeat region. The 3' pure repeat may then be susceptible to further expansion by replication slippage. Slippage on these predisposing chromosomes could accumulate over many generations until a threshold size is reached, at which point the repeat is susceptible to greater instability (i.e. premutation stage). Thus, results suggest that evolution of fraglle X full mutations could involve 4 definable stages: 1) ancestral events leading to the formation of predisposing alleles which have large total repeat length (e.g. between 35 to 50) but no AGG or 1 AGG; 2) gradual slippage of these predisposing alleies to small premutations (S alleles); 3) conversion from S alleies to larger premutations (Z); 4) massive expansion from a Z allele to a full mutation (L).

Original languageEnglish (US)
Pages (from-to)1543-1551
Number of pages9
JournalHuman molecular genetics
Issue number9
StatePublished - Sep 1 1994

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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