Induction of instability of normal length trinucleotide repeats within human disease genes

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Abstract
As with many other tandemly repeated microsatellite sequences, pathogenic TNRs are highly unstable in both the somatic and germ cell lineage, leading to expansions and contractions in the length of the repeats in successive cell or individual generations.6–8 Expansions in the number of TNRs are known to be a molecular basis of genetic anticipation,9 the progressively earlier age of onset of a disease with increasing severity in successive generations. An important consequence of genetic anticipation is that the genetic transmission is interrupted and, therefore, new pathogenic alleles have to be generated from unexpanded alleles. Little is known, however, about the mechanism(s) that cause a stable, non-expanded allele to become unstable and pathogenic, probably because normal length alleles are thought to be stable compared with expanded pathogenic alleles. In addition, much of the evidence for the mechanisms that are thought to produce repeat expansion in pathological TNRs are dismissed as irrelevant for normal alleles. Therefore, understanding the factors influencing the instability of normal unexpanded alleles is of critical importance.

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