Random breakage and reunion chromosome aberration formation model; an interaction-distance version based on chromatin geometry

Purpose: Using published FISH data for chromosome aberration production in human fibroblasts by hard X-rays to test a breakage-and-reunion model. Methods: The model assumed pairwise misrejoining, random apart from proximi ty effects, of DNA double-strand break (DSB) free ends. CAS (chromosome abe rration simulator) Monte Carlo computer software implementing the model was modified to use a distance algorithm for misrejoining instead of using DSB interaction sites. The modification (called CAS2) allowed a somewhat more realistic approach to large-scale chromatin geometry, chromosome territorie s and proximity effects. It required adding a third adjustable parameter, t he chromosome territory intersection factor, quantifying the amount of inte rtwining among different chromosomes. Results: CAS2 gave somewhat better results than GAS. A reasonable fit with a few discrepancies was obtained for the frequencies at three different rad iation doses of many different aberration types and of aberrations involvin g Various specific chromosomes in a large data set using one-paint FISH sco ring. The optimal average chromosome territory intersection factor was simi lar to1.1, indicating that, for an arbitrarily chosen location in the nucle us, on average slightly more than two chromosomes have very nearby loci. Wi thout changing the three parameter values, a fit was also obtained for a co rresponding, smaller, two-paint data set. Conclusions: A random breakage-and-reunion model incorporating proximity ef fects by using a distance algorithm gave acceptable approximations for many details of hard X-ray aberration patterns. However, enough discrepancies w ere found that the possibility of an additional or alternate formation mech anism remains.