Trends in Genetics
ReviewInstability and chromatin structure of expanded trinucleotide repeats
Section snippets
Long triplet repeats are unstable and cause several neurological disorders
In 1991, a novel type of mutation – the expansion of trinucleotide repeats – was shown to cause two human neurological diseases: fragile X syndrome (FRAXA) and spinal and bulbar muscular atrophy (SBMA) 1, 2. To date, 17 such diseases have been identified [3]. Normal individuals typically harbor <30 repeats, whereas patients can carry from 35 to several thousand repeats. The disease incidence can be as common as 1 in 4000 males for FRAXA and as rare as 1 in 50 000 for Friedreich ataxia (FRDA) [3]
The chromatin environment of expanded triplet repeats
Several studies have identified alterations in DNA methylation, histone modification and chromatin structure around expanded repeat tracts that are not present at the corresponding wild-type alleles (Table 2). Expanded CGG repeats at the fragile X mental retardation 1 (FMR1) locus in FRAXA patients provided the first indication that such repeats are associated with heterochromatin marks. The absence of FMR1 expression, which is responsible for the mental retardation phenotype in FRAXA, is
Repeat instability during early embryogenesis
Several studies in FRAXA individuals indicate that instability can occur during early embryogenesis. Some individuals harbor two major FMR1 CGG repeat lengths – derivatives of the same allele – at high frequency in every examined tissue, suggesting that repeat instability arose during the first zygotic cell division 27, 28. This possibility is supported by the existence of monozygotic twins who carry different allele lengths 27, 29.
In support of these conclusions from patient studies, Savouret
Repeat instability during germline development
Instability in the germline and during gametogenesis is well documented in humans and mice. FRAXA patients, for example, show a striking parent-of-origin effect. Expanded alleles are often observed in children whose asymptomatic mothers harbor pre-mutation alleles. Male fetuses from these mothers carry the full mutation in all tested tissues except fetal testes, in which contractions were observed [43]. Similar analyses of female fetuses support the conclusion that CGG expansions occur in the
Repeat instability in somatic tissues
Somatic instability of CGG repeats, which, unlike CAGs and GAAs, can be methylated, is low in patients harboring the full mutation (>200 CGGs) 50, 51. By contrast, FRAXA males expressing FMR1 have unmethylated repeats with a high degree of instability in somatic tissues, although they harbor a large expansion 52, 53. One such individual displayed instability in some tissues and not in others, a pattern that correlated perfectly with methylation status of the repeat [52]. Cultured cells from
Concluding remarks
The instability of trinucleotide repeats presents a surprisingly complex puzzle. One key point of agreement is that instability follows from the capacity of unstable repeats to form secondary structures, which in turn engage a variety of DNA repair activities in an attempt to regenerate a normal Watson–Crick duplex. In the past decade, most of the effort geared towards elucidating the mechanisms of triplet repeat instability has focused on knocking out or knocking down individual candidate
Acknowledgements
We thank the members of the Wilson laboratory for helpful discussion, Susan Gasser for support and F. Hamaratoğlu, H. Ferreira, S. Kueng, B. Pike, B. Towbin, M. Bühler, R. Waterland and T. Punga for critical reading of the manuscript. V.D. is currently supported by a post-doctoral fellowship from the Terry Fox Foundation through The Canadian Cancer Society Research Institute. Work on triplet repeats in the Wilson laboratory is supported by NIH grant GM38219.
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