Predicting statistics of gene translocation events: Role of chromatin compaction and double-strand DNA break.

Abstract

Chromosomal translocations, arising from unresolved double-stranded DNA breaks (DSBs), play a central role in genome instability and evolution. A prevailing hypothesis suggests that the probability of translocation between two chromatin segments depends on both their spatial proximity and the likelihood of DSB formation and rejoining. To test this, we perform Monte Carlo simulations of chromatin model polymers with varying levels of compaction and three-dimensional organization. Our results reveal that translocation probability cannot be fully explained by simple two-segment contact probabilities. Instead, it is strongly modulated by the global polymer compaction, which increases the incidence of multisegment contacts and introduces higher-order contributions. We further demonstrate that translocation probability exhibits a nontrivial functional dependence on both contact probability and DSB probability. We propose an empirical formula to compute translocation probability and provide analytical arguments for simple cases. Together, our findings highlight the critical role of chromatin organization in shaping the landscape of genome rearrangements and provide a framework to quantitatively predict translocation events from underlying polymer features and breakage statistics.