Mechanisms of radiation tolerance in Caenorhabditis from Chernobyl

许多提高我们生活质量的技术进步也增加了我们接触电离的机会 辐射，即在医疗诊断和治疗、核武器试验、发电厂事故和空气中 以及太空旅行。人类活动几乎是平均本底辐射的两倍(不包括 用于癌症治疗)，而一些地区的水平高出许多个数量级。同时， 人们对慢性暴露的影响知之甚少，包括核污染造成的水平 对生态系统的选择性压力，以及持续暴露的独特病理挑战。微型动物群 可以帮助我们理解这些挑战，并提出生物分子补救措施。 我们提出的探索性项目解决了以下三个问题：(1)在什么门槛 背景辐射改变动物突变率？(2)种群的辐射耐受性取决于(A) 避免DNA损伤，(B)优化DNA修复，或(C)增加繁殖力和繁殖力？和(3) DNA修复途径的哪些元素是自然变化的，遗传和细胞特征是什么？ 变种的？为了调查这些问题，我们将前往乌克兰的切尔诺贝利隔离区， 从污染程度不同的地区收集线虫。不同的遗传背景和多重 数十年的持续暴露可能丰富了这一地区具有高辐射耐受性的生物。 为了确定背景辐射如何与突变负荷相对应，我们将对 从每个地点收集线虫和微生物，并评估当地的遗传差异。为了揭开 动物使用的策略是在辐射存在的情况下成功的，我们将鉴定线虫菌株 它们在基因上相似，但在对多代人的辐射暴露的敏感度上存在很大差异 实验室。通过用辐射挑战这些菌株，并比较不同时间点的DNA断裂量， 我们将确定菌株是否在保护、修复或应对DNA断裂方面有所不同。 人类因接触毒素而患病的风险往往受到遗传易感性的影响。调查是如何 可遗传变异会影响DNA损伤修复和突变率，我们会将遗传相似的敏感和 耐受性菌株，并创造一组重组自交系先进异交系(RIAILS)。通过分析 这些RIAIL对DNA损伤的反应，我们将阐明DNA修复途径的哪些步骤 变量，识别变种的遗传和细胞特征，并测量这些变种如何优化 在放射性环境中的突变率。 这里提出的这项工作将利用一场历史性的环境灾难和一种遗传易驯服的生物来 建立一个研究动物对慢性辐射反应的多方面的模型系统。这 模型系统将大大超出这笔拨款的时间框架来推动研究，对人类有直接的影响 由医疗、环境和宇宙辐射暴露引起的病理。

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.