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Replication in mammalian cells recapitulates the locus-specific differences in somatic instability of genomic GAA triplet-repeats

By Paul M. Rindler, Rhonda M. Clark, Laura M. Pollard, Irene De Biase and Sanjay I. Bidichandani

Abstract

Friedreich ataxia is caused by an expanded (GAA·TTC)n sequence in intron 1 of the FXN gene. Small pool PCR analysis showed that pure (GAA·TTC)44+ sequences at the FXN locus are unstable in somatic cells in vivo, displaying both expansions and contractions. On searching the entire human and mouse genomes we identified three other genomic loci with pure (GAA·TTC)44+ sequences. Alleles at these loci showed mutation loads of <1% compared with 6.3–30% for FXN alleles of similar length, indicating that somatic instability in vivo is regulated by locus-specific factors. Since distance between the origin of replication and the (CTG·CAG)n sequence modulates repeat instability in mammalian cells, we tested if this could also recapitulate the locus-specific differences for genomic (GAA·TTC)n sequences. Repeat instability was evaluated following replication of a (GAA·TTC)115 sequence in transfected COS1 cells under the control of the SV40 origin of replication located at one of five different distances from the repeat. Indeed, depending on the location of the SV40 origin relative to the (GAA·TTC)n sequence, we noted either no instability, predominant expansion or both expansion and contraction. These data suggest that mammalian DNA replication is a possible mechanism underlying locus-specific differences in instability of GAA triplet-repeat sequences

Topics: Molecular Biology
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:1669776
Provided by: PubMed Central
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