Nath Neetika, Esche Jennifer, Müller Jessica, Jensen Lars R, Port Matthias, Stanke Mario, Kaderali Lars, Scherthan Harry, Kuss Andreas W
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.
Health Phys. 2018 Jul;115(1):151-160. doi: 10.1097/HP.0000000000000880.
Ionizing radiation can induce genomic lesions such as DNA double-strand breaks whose incomplete or faulty repair can result in mutations, which in turn can influence cellular functions and alter the fate of affected cells and organ systems. Ionizing-radiation-induced sequence alterations/mutations occur in a stochastic manner, which contributes to an increased cancer risk in irradiated individuals. Ionizing radiation exposure, and particularly acute doses at high dose rates (as often observed in radiation accidents), induce alterations in the genome that in part will reflect specific characteristics of the DNA damage response and the repair mechanisms involved. Here, the exome of primary human gingival fibroblasts not exposed or exposed to 0.2, 2, 5, or 10 Gy of x rays was investigated after 16 h of DNA repair for ionizing-radiation-induced mutations. The irradiation effect with varying dose was investigated using three different bioinformatic filters for the analysis of accumulated variants per Mb of genomic DNA and per cytogenetic bands. A highly stringent cutoff of 20-fold coverage was used for all analyses. Comparing exome DNA from irradiated and nonirradiated cells disclosed a characteristic variation of the frequency of ionizing-radiation-induced single-nucleotide variants as well as small insertions and deletions among chromosomes and their subregions. Increases in ionizing-radiation-induced variants with increasing dose were highly significant (p = 2.2 × 10, Kruskal-Wallis test). These results indicate that certain chromosomal regions may be more prone to accumulating particular ionizing-radiation-induced alterations than others, which points to a characteristic metasignature in the irradiated exome.
电离辐射可诱发基因组损伤，如DNA双链断裂，其修复不完全或有误可导致突变，进而影响细胞功能并改变受影响细胞及器官系统的命运。电离辐射诱发的序列改变/突变以随机方式发生，这会增加受辐射个体患癌风险。电离辐射暴露，尤其是高剂量率下的急性剂量（如在辐射事故中常见），会诱发基因组改变，部分改变将反映DNA损伤反应及相关修复机制的特定特征。在此，对未暴露或暴露于0.2、2、5或10 Gy X射线的原代人牙龈成纤维细胞的外显子组进行了研究，在DNA修复16小时后检测电离辐射诱发的突变。使用三种不同的生物信息学筛选方法，研究不同剂量的辐射效应，以分析每兆碱基基因组DNA和每条细胞遗传学带累积变异的情况。所有分析均采用20倍覆盖度的高严格截断值。比较受辐射细胞和未受辐射细胞的外显子组DNA发现，电离辐射诱发的单核苷酸变异以及染色体及其亚区域间小插入和缺失的频率存在特征性差异。随着剂量增加，电离辐射诱发变异的增加具有高度显著性（p = 2.2 × 10，Kruskal-Wallis检验）。这些结果表明，某些染色体区域可能比其他区域更容易累积特定的电离辐射诱发改变，这表明受辐射外显子组存在特征性元特征。
