Coalescence of DNA double strand breaks induced by galactic cosmic radiation is modulated by genetics in 15 inbred strains of mice

This study analyzes the variability of responses to simulated deep space radiation among 15 commonly used mouse strains. Ex vivo primary skin fibroblast responses to high mass-high charge particles and X-rays were analyzed by quantifying DNA damage-sensing protein 53BP1 positive radiation-induced foci (RIF) as a surrogate biomarker of DNA double strand breaks (DSBs). Primary skin fibroblasts were isolated from 10 collaborative cross strains and five reference inbred mice (C57Bl/6, BALB/CByJ, B6C3, C3H and CBA/CaJ) and exposed to 350 MeV/n Ar and 600 MeV/n Fe particles as well as X-rays. Our results indicate that nearby DSBs coalesced into repair units characterized by large RIFs. Such model has the advantage of being much more efficient molecularly, but is poorly suited to deal with cosmic radiation, where energy is concentrated along the particle trajectory. Thus, we observed a large density of DSBs along each particle track and the percentage of unrepaired DSBs that increased with linear energy transfer of the particle over 48 hours post irradiation. Furthermore, persistent RIF levels ex vivo were well correlated with T and B lymphocyte survival in vivo in 10 collaborative cross strains 24 hours after 0.1 Gy whole-body dose of X-rays, suggesting that persistent RIFs might serve as an ex vivo biomarker for in vivo radiation toxicity. Finally, we performed genome-wide association study to identify the genomic associations with dose responses to ionizing radiation, marked as Foci per Gray (FPG), as well as with background DNA repair levels (BGD). This dataset includes GWAS data as well as FPG and BGD values for each sample and condition.