Complex interchanges as a complex function of chromosome organisation

Abstract

A Monte Carlo technique was developed for biophysical modelling of structural organisation of 46 chromosomes within human lymphocyte interphase nucleus. The technique takes into account: different levels of chromatin organisation, non-random localisation of particular chromosomes and chromosome loci dynamics. All chromosomes in a nucleus were modelled as polymer globules. A dynamic pattern of intra/interchromosomal contacts was simulated to predict radiation-induced chromosomal exchange aberrations (CA). Distance dependence of interaction probability was calculated directly with taking DNA break repair into account. Dose-response for simple and complex CA was calculated to analyse mFISH data for human lymphocytes. Calculated simple CA frequencies fitted the experimental data well. Unexpectedly, complex aberrations were underestimated, despite the dense packaging of chromosome territories within a nucleus. To study sensitivity of dose-response to uncertainty of chromosome organisation, CA were recalculated for the alternative concept of nucleus organisation, the SCD model. The simulation showed the underestimation of complex CA yield as well. The movement of damaged loci from different chromosomes to common repair factories was proposed as an additional mechanism of complex CA formation.