The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence (original) (raw)

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Review Articles| October 15 2003

J.D. Cleary;

Program of Genetics and Genomic Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario (Canada)

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C.E. Pearson

Program of Genetics and Genomic Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario (Canada)

Search for other works by this author on:

Cytogenet Genome Res (2003) 100 (1-4): 25–55.

Article history

Received:

December 24 2002

Accepted:

February 11 2003

Published Online:

October 15 2003

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Abstract

Alterations in the length (instability) of gene-specific microsatellites and minisatellites are associated with at least 35 human diseases. This review will discuss the various _cis_-elements that contribute to repeat instability, primarily through examination of the most abundant disease-associated repetitive element, trinucleotide repeats. For the purpose of this review, we define _cis_-elements to include the sequence of the repeat units, the length and purity of the repeat tracts, the sequences flanking the repeat, as well as the surrounding epigenetic environment, including DNA methylation and chromatin structure. Gender-, tissue-, developmental- and locus-specific _cis_-elements in conjunction with _trans_-factors may facilitate instability through the processes of DNA replication, repair and/or recombination. Here we review the available human data that supports the involvement of _cis_-elements in repeat instability with limited reference to model systems. In diverse tissues at different developmental times and at specific loci, repetitive elements display variable levels of instability, suggesting vastly different mechanisms may be responsible for repeat instability amongst the disease loci and between various tissues.

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