Large-mutation spectra induced at hemizygous loci by low-LET radiation: Evidence for intrachromosomal proximity effects

A mathematical model is used to analyze mutant spectra for large mutations induced by low-LET radiation. The model equations are based mainly on two-b reak misrejoining that leads to deletions or translocations. It is assumed, as a working hypothesis, that the initial damage induced by low-LET radiat ion is located randomly in the genome. Specifically, we analyzed data for t wo hemizygous loci: CD59(-) mutants, mainly very large-scale deletions (>3 Mbp), in human-hamster hybrid cells, and data from the literature on those HPRT-mutants which involve at least deletion of the whole gene, and often o f additional flanking markers (similar to 50-kbp to similar to4.4-Mbp delet ions). For five data sets, we estimated f, the probability that two given b reaks on the same chromosome will misrejoin to make a deletion, as a functi on of the separation between the breaks. We found that f is larger for near by breaks than for breaks that are more widely separated; i.e., there is a "proximity effect". For acute irradiation, the values off determined from t he data are consistent with the corresponding break misrejoining parameters found previously in quantitative modeling of chromosome aberrations. The v alue off was somewhat smaller for protracted irradiation than for acute irr adiation at a given total dose; i.e., the mutation data show a decrease tha t was smaller than expected for dose protraction by fractionation or low do se rate. (C) 2001 by Radiation Research Society.