Natural Variation in Radiotolerance Is Associated With Differences in Innate Immune Activity and S-Phase Transcription in Drosophila Melanogaster

ABSTRACT Organismal tolerance of ionizing radiation is a complex trait whose genetic basis has been studied extensively, in large part due to its significance to human health and technological advancement. Conventional mutant screens in model organisms have revealed the paramount role of DNA damage response (DDR) and repair pathways in determining tolerance to ionizing radiation. However, uncovering natural genetic variation in radiotolerance is also of critical importance, as individual differences are associated with the differential susceptibility to cancer as well as differential response to radiation treatment. Genetic variation that underlies phenotype differences in natural populations often occurs in distinct genes and pathways as compared to the genes of major effect revealed by mutant screens, owing to the impact of natural selection on the former. We therefore sought to isolate natural variation in radiotolerance of Drosophila melanogaster by performing extreme QTL mapping. We generated a large genetically diverse multiparental population and exposed 3rd instar larvae to a semi-lethal dose or ionizing radiation. By sequencing surviving adults and comparing their haplotypes to unexposed controls from the same population, we identified a single major effect QTL spanning the 3rd chromosome centromere. The QTL contains 34 genes, none of which are previously implicated in radiotolerance. We interrogated the impact of these genes on radiotolerance through forward genetic analysis and RNA-seq. Our findings implicate diverse processes in radiotolerance including cell-cycle regulation and innate immune function.