COMPUTER-SIMULATION OF EXPANSIONS OF DNA TRIPLET REPEATS IN THE FRAGILE-X-SYNDROME AND HUNTINGTONS-DISEASE

The expansion of DNA triplet repeats has been shown to be responsible for about a dozen hereditary diseases. In this paper we are concerned with a computer model of such expansion, applied to the fragile X synd rome and Huntington's disease, for which enough quantitative data have been collected. The nucleotide sequence associated with the fragile X consists of CGG repeats and is located inside the FMR1 gene. In norma l individuals there is a variable number of triplet repeats less than 60; in asymptomatic carriers the number of repeats is 60-200 (premutat ion). From the premutation range, the number of triplet repeats can in crease within one generation to more than 200 producing affected indiv iduals. In Huntington's disease the CAG repeats are located inside the HD gene. In normal individuals the number of repeats varies from arou nd 11, up to 34. In the intermediate range (34-37 repeats), the mutabi lity is increased, frequently leading to alleles of more than 37 repea ts, and the disease phenotype. The rapid increase of the number of tri plet repeats in affected individuals has been proposed to be due to th e formation of folded DNA structures (hairpins) and their repair or mi srepair. In order to determine if this proposed mechanism is adequate to account for the rapid increase of repeats and the large number of r epeats in affected individuals we developed a mathematical model that includes the known mechanisms of hairpin formation, and strand synthes is and repair. Simulations based on the model using realistic probabil ities of hairpin formation produced results that corresponded with the observed range of repeats and transition probabilities from normal to affected individuals. Similar modeling has been published for the Hun tington's disease data. However, in this paper we demonstrate that a u niform approach works for fragile X and Huntington's disease, although the detailed assumptions of the model have to be different. These dif ferences provide insight into the mechanism of expansion in both cases . Among these insights is that an apparent threshold in the number of repeats for rapid expansion, and the preference for expansion over con traction, may be accounted for by relative probabilities of hairpin fo rmation, replication, slippage and repair. (C) 1997 Academic Press Lim ited.