Clustering of radiation-produced breaks along chromosomes: modelling the effects on chromosome aberrations

Purpose: For high-LET radiations, and perhaps even for hard X-rays, DNA dou ble-strand breaks (dsb) are clustered non-randomly along chromosomes; dispr oportionately, many inter-dsb segments are less than a few Mbp (10(6) base pairs). The implications of such dsb clustering for chromosome aberrations are analysed. Methods: Chromosome segments between different dsb within one dsb cluster a re assumed too small to detect in the aberration assay. Enumeration or Mont e-Carlo computer simulations are used to compute the relative frequencies o f many observable aberration patterns: apparently simple or visibly complex . The theoretical predictions are compared with X-ray data for human fibrob lasts, involving painted chromosomes 1, 2, 4, 5, 7 or 13. Results and conclusions: Surprisingly, cryptic dsb multiplicity does not af fect the frequency ratios predicted for aberration patterns by a random bre akage-and-rejoining model. The model is generally consistent with current d ata on many different types of aberrations, whether or not dsb usually occu r in cryptic clusters. For a Revell-type exchange model, however, the predi ctions do depend on clustering configurations; they gradually approach the predictions of the breakage-and-rejoining model as average cluster multipli city increases. The model is consistent with the data, for example with the ratio of visibly complex to apparently simple aberrations, only if there i s considerable dsb clustering even at low-LET, with similar to 1.5 or more reactive dsb per cluster on average.