A formalism for analysing large-scale clustering of radiation-induced breaks along chromosomes.

PURPOSE To model intrachromosomal clustering of DSB (DNA double strand breaks) induced by ionizing radiation. That DSB are located non-randomly along chromosomes after high LET irradiation, with clustering even at extremely large scales, has been confirmed by recent pulsed field gel electrophoresis data for size distributions of DNA fragments. We therefore extend the standard random-breakage model for DNA fragment-size distributions to a more general 'clustered-breakage' formalism, which can take correlations of DSB locations along a chromosome into account. METHODS The new formalism is based mainly on a one-track probability distribution, describing the DNA fragment-size pattern due to a single primary high-energy particle, a pattern determined by track structure and chromatin geometry. Multi-track fragment-size distributions are derived mathematically from the one-track distribution, so that dose response relations are obtained. RESULTS The clustered-breakage formalism is applicable to any chromosomal geometry and any radiation track structure. It facilitates extrapolations of high-dose data to the much lower doses of interest for most applications. When applied to recently published data for irradiation of mammalian cells with ions of LET approximately 100 keV microm(-1) it indicates a pattern of Mbp-scale DSB clusters, each containing a number of DSB and corresponding to a very large-scale, multiply-damaged chromatin site. Although DSB are bunched, DSB clusters are scattered almost at random throughout the genome. Estimates of DSB yield are markedly increased by resolving such clusters into individual DSB. The dose response relation for fragments of a given size becomes non-linear when clusters from different tracks interlace or adjoin, as can occur for high doses and large sizes. CONCLUSIONS DSB clustering along chromosomes, which influences important radiobiological endpoints, is described quantitatively by the clustered-breakage formalism.