Implementation of Post-Irradiation DNA Repair Mutation Modelling In a Novel Whole-Genome Sequencing Simulator
Abstract
Purpose
To integrate post-radiation DNA repair, post‑repair mutation creation, and whole‑genome sequencing into a Monte Carlo–based simulation pipeline in order to observe and quantify chromosome translocations resulting from radiation‑induced DNA damage.
Methods
Currently, in our lab, radiation-induced DNA damage is produced using a Monte Carlo simulation pipeline consisting of TOPAS (Tool for Particle Simulation) and its track-structure DNA-scale extension, TOPAS-nBio. The damaged genome is then directly sequenced using RadiSeq, a novel whole-genome DNA sequencing simulator. However, our pipeline does not yet account for DNA repair mechanisms. This project is integrating Medras-MC (Mechanistic DNA Repair and Survival), a DNA repair and post-repair mutation algorithm, into the pipeline, before the genome is subjected to sequencing.
Results
To date, we have established a simulation setup that mimics an in vitro setup to score particles entering a cell population model. We have also modified Medras-MC to output all pairs of double-strand break ends that are rejoined together.
Conclusion
Remaining work to complete the project includes using the scored particles to irradiate each cell in the population model to generate DNA double-strand breaks. After Medras-MC repairs these damages, the damaged genome will undergo DNA sequencing. By comparing the DNA sequences obtained after irradiation with a reference genome, this work seeks to contribute to our lab’s overarching goal of identifying a genomic biomarker of exposure to ionizing radiation.