Mechanisms Of Trinucleotide Repeat Instability During Human Development

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Mechanisms of trinucleotide repeat instability during human development
Cynthia T. McMurray*‡§

Abstract | Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have beendescribed, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understandthe mechanism of expansion as it occurs in human disease.
Threshold length
In the context of trinucleotide repeat alleles, the number of trinucleotide repeats at which the tract becomes unstable.

*Lawrence Berkeley National Laboratory, Life Sciences Division, 1 Cyclotron Rd, 83R0101, Berkeley, California 94720, USA. ‡ Department of Molecular Pharmacology and Experimental Therapeutics, MayoClinic and Foundation, 200 First St. SW, Guggenheim 7, Rochester, Minnesota 55905, USA. § Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 First St. SW, Guggenheim 7, Rochester, Minnesota 55905, USA. e-mail: ctmcmurray@lbl.gov doi:10.1038/nrg2828

Expansions in simple DNA repeats underlie ~20 severe neuromuscular and neurodegenerative disorders 1,2. Our understandingof the pathogenic mechanisms for trinucleotide repeat (TNR) expansion diseases has advanced substantially in recent years (recently reviewed in refs 3–6 ), but many aspects of the mutational mechanism remain enigmatic. Repetitive sequences constitute 30% of the human genome and, in most species, alterations in the lengths of repetitive DNA during evolution create diversity 7. However, the rapidalteration in TNR length observed in human expansion diseases is surprising. Mammals have developed systems for resisting rapid changes that could be deleterious. However, when longer than a crucial threshold length, these simple TNRs override genomic safeguards and expand during most parent–child transmissions and during development of the progeny. The changes in TNR length can be substantial. ForTNR repeats in coding sequences, the repeats become unstable at ~29–35 units in length, and the changes in tract size are modest, typically ≤10 repeats per generation1,2 (TABLe 1). By contrast, unstable parent–child transmissions of TNRs in non-coding regions initiate from pre-mutation alleles of ~55–200 units and increase by 100–10,000 units per generation1,2 (TABLe 1). For both coding andnon-coding alleles, as the repeat length grows beyond a threshold length, the size of the successive expansions and the likelihood of another unstable event increase. Also, the disease becomes more severe and has an earlier age of onset with each successive generation, a phenomenon known as anticipation1,2.

Why some repeats expand more than others remains an important unresolved question. Mostmodels for repeat expansion agree that expansion occurs through the formation of looped intermediates1,2, which are incorporated into DNA. However, thermodynamically, the differences in the physical properties of looped intermediates formed from different TNRs are subtle. For example, although the complementary sequences CAG and CTG are associated with short and long expansions, respectively, the freeenergy difference between CAG and CTG is only 1–2 kcal/mole for hairpins comprising a 30-repeat tract 8,9. Neither the sequences nor the hairpin structure accounts for the differences in the expansion size. We now know that DNA repair and/or replication promote expansion in some manner. What we do not know is whether there are mechanistic differences between expansions of long and short repeats...