Journal
GENOMICS
Volume 80, Issue 4, Pages 423-432Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/geno.2002.6849
Keywords
fragile X syndrome; triplet repeat sequence; yeast artificial chromosome; mouse model; dynamic mutation
Funding
- NICHD NIH HHS [HD24064, HD29256, HD38038] Funding Source: Medline
- NIGMS NIH HHS [GM52982] Funding Source: Medline
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Fragile X syndrome results from the massive expansion of a CGG repeat in the 5' untranslated region of the gene FMR1. Data suggest that the hyperexpansion properties of FMR1 CGG repeats may depend on flanking cis-acting elements. We have therefore used homologous recombination in yeast to introduce an in situ CGG expansion corresponding to a premutation-sized allele into a human YAC carrying the FMR1 locus. Several transgenic lines were generated that carried repeats of varying lengths and amounts of flanking sequence. Length-dependent instability in the form of small expansions and contractions was observed in both male and female transmissions over five generations. No parent-of-origin effect or somatic instability was observed. Alterations in tract length were found to occur exclusively in the 3' uninterrupted CGG tract. Large expansion events indicative of a transition from a premutation to a full mutation were not observed. Overall, our results indicate both similarities and differences between the behavior of a premutation-sized repeat in mouse and that in human.
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