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

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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 alleles 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 fragile 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 alleles to small premutations (S alleles); 3) conversion from S alleles 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
Volume3
Issue number9
StatePublished - Sep 1994

Fingerprint

Trinucleotide Repeats
Sequence Analysis
Ferromagnetic resonance
Mutation
Alleles
Chromosomes
Replication
Chromosome
Haplotype
Transcription
Accumulate
Stretch
Unstable
Predict
Configuration
Sequence analysis
Slippage
Haplotypes
Population
General population

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Molecular Biology
  • Genetics(clinical)

Cite this

Sequence analysis of the fragile X trinucleotide repeat : Implications for the origin of the fragile X mutation. / Snow, Karen; Tester, David J.; Kruckeberg, Kent E.; Schaid, Daniel J; Thibodeau, Stephen N.

In: Human Molecular Genetics, Vol. 3, No. 9, 09.1994, p. 1543-1551.

Research output: Contribution to journalArticle

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