Mechanisms of radiation tolerance in Caenorhabditis from Chernobyl

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Many of the technological advances that increase our quality of living also increase our exposure to ionizing radiation, i.e. during medical diagnosis and treatment, nuclear weapons testing, power plant accidents, and air and space travel. Anthropogenic activity has nearly doubled the average background radiation (not including use in cancer therapy), while levels in some regions reach many orders of magnitude higher. Meanwhile, the effects of chronic exposure are poorly understood, including the levels at which nuclear contamination creates selective pressure on the ecosystem, and the unique pathological challenges of constant exposure. Microfauna from highly radioactive areas can help us understand these challenges, and suggest biomolecular remedies. The exploratory project we propose addresses the following three questions: (1) At what threshold does background radiation alter animal mutation rate? (2) Does a population's radiation tolerance depend on (a) avoidance of DNA damage, (b) optimization of DNA repair, or (c) increased fecundity and dispersal? And (3) which elements of DNA repair pathways are naturally variable, and what are the genetic and cellular signatures of the variants? To investigate these questions, we will travel to the Chernobyl Exclusion Zone in Ukraine and collect nematodes from areas with varying levels of contamination. Diverse genetic backgrounds and multiple decades of continuous exposure have likely enriched this region for organisms with high radiation tolerance. To identify how background radiation corresponds to mutational load, we will sequence the genomes of nematodes and microbes collected from each site, and evaluate local genetic divergence. To uncover the strategies used by animals that are successful in the presence of radiation, we will identify nematode strains that are genetically similar but diverge greatly in their sensitivity to multi-generational radiation exposure in the lab. By challenging these strains with radiation and comparing quantities of DNA breaks at various timepoints, we will determine whether the strains differ by protecting against, repairing, or coping with DNA breaks. Risk of human disease due to toxin exposure is often influenced by genetic predisposition. To investigate how heritable variations affect DNA damage repair and mutation rate, we will cross genetically similar sensitive and tolerant strains, and create a panel of recombinant inbred advanced intercross lines (RIAILS). By assaying these RIAILs' responses to DNA damage, we will elucidate which steps of the DNA repair pathways are variable, identify the genetic and cellular signatures of the variants, and measure how these variants optimize mutation rate in a radioactive environment. The work proposed here will utilize a historic environmental disaster and a genetically tractable organism to establish a model system for studying many facets of animal response to chronic radiation exposure. This model system will fuel research well beyond the timeframe of this grant, with direct implications for human pathologies caused by medical, environmental, and cosmic radiation exposure.