Simulation and modeling of chromothripsis reveals new insights into ecDNA origination

Chromothripsis is a catastrophic chromosomal rearrangement that drives genomic instability and cancer evolution. Although extensive research has focused on biological mechanisms, the development of computational tools for modeling this process remains lacking. Here, we developed two novel programs: a simulation program that models the process of break and repair and outputs the rearrangement results and a computational program that quantitatively calculates the relative abundance of linear and circular DNA products. We employ these programs to analyze how the compaction ratio, break frequency, and repair rate influence the properties of both circular and linear DNA. Furthermore, we demonstrate that individual chromothripsis events produce exceptionally few circular DNA molecules (typically ≤ 4) under most conditions. Our modeling offers new insights into extrachromosomal DNA (ecDNA) biogenesis and a theoretical model for experimental validation.