Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
|
| pubmed:dateCreated |
1995-2-28
|
| pubmed:abstractText |
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) > or = 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).
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Sep
|
| pubmed:issn |
0964-6906
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
3
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1543-51
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:7833909-Alleles,
pubmed-meshheading:7833909-Base Sequence,
pubmed-meshheading:7833909-Biological Evolution,
pubmed-meshheading:7833909-Chromosome Fragility,
pubmed-meshheading:7833909-DNA,
pubmed-meshheading:7833909-Female,
pubmed-meshheading:7833909-Fragile X Syndrome,
pubmed-meshheading:7833909-Genetic Markers,
pubmed-meshheading:7833909-Humans,
pubmed-meshheading:7833909-Male,
pubmed-meshheading:7833909-Models, Genetic,
pubmed-meshheading:7833909-Molecular Sequence Data,
pubmed-meshheading:7833909-Mutation,
pubmed-meshheading:7833909-Oligodeoxyribonucleotides,
pubmed-meshheading:7833909-Pedigree,
pubmed-meshheading:7833909-Phylogeny,
pubmed-meshheading:7833909-Repetitive Sequences, Nucleic Acid,
pubmed-meshheading:7833909-X Chromosome
|
| pubmed:year |
1994
|
| pubmed:articleTitle |
Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation.
|
| pubmed:affiliation |
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.
|
| pubmed:publicationType |
Journal Article
|