DNA secondary structure: A common and causative factor for expansion in human disease

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Abstract
The discovery of unstable transmission has changed the face of genetics because it provides an alternative to the single-gene/single-trait pattern of Mendelian inheritance. More than 10 hereditary diseases are caused by instability at simple trinucleotides. Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product (1–2). As the length of the repeat grows, so also do the size of the successive expansions and the likelihood of another unstable event. This accounts for clinical anticipation in which the severity increases and the age of onset decreases in successive generations. In Huntington’s disease, for example, instability and pathogenesis are not observed at 28 repeats, occur frequently at 38 repeats, and are almost certain above 60 repeats. Although different genes are affected and different features of pathogenesis are evident, there is a common pattern of unstable transmission among the trinucleotide repeat diseases, suggesting common elements to the mechanism. Data from human genetic studies, from structural analysis, and from model organisms are consistent with the notion that instability initiates from improper DNA secondary structure during replication and/or repair (3–5). However, unambiguous proof of secondary structure in vivo has been extraordinarily difficult because it requires a solution to the controversial problem of whether duplex DNA can adopt single-stranded structures at any time during the cell cycle in the presence of a complementary partner strand. In issue 4 of the Proceedings, however, Moore et al. (6) may well provide one of the first demonstrations that secondary structure not only forms at repeats in vivo but also that structure formation can elude the cellular machinery designed to detect and to repair single-stranded loops. Thus, the notion that secondary structure mediates repeat expansion in double-stranded DNA may finally be …