DNA damage is a threat to genome integrity and can be a cause of many human diseases, owing to either changes in the chemical structure of DNA or conversion of the damage into a mutation, that is, a permanent change in DNA sequence. Determining the exact positions of DNA damage and ensuing mutations in the genome are important for identifying mechanisms of disease aetiology when characteristic mutations are prevalent and probably causative in a particular disease. However, this approach is challenging particularly when levels of DNA damage are low, for example, as a result of chronic exposure to environmental agents or certain endogenous processes, such as the generation of reactive oxygen species. Over the past few years, a comprehensive toolbox of genome-wide methods has been developed for the detection of DNA damage and rare mutations at single-nucleotide resolution in mammalian cells. Here, we review and compare these methods, describe their current applications and discuss future research questions that can now be addressed.

DNA 损伤对基因组完整性构成威胁，并且可能是许多人类疾病的原因，这是由于 DNA 化学结构的变化或损伤转化为突变，即 DNA 序列的永久性变化。当特征性突变普遍存在并且可能在特定疾病中致病时，确定 DNA 损伤的确切位置和随之而来的突变对于确定疾病病因机制非常重要。然而，这种方法具有挑战性，特别是当 DNA 损伤水平较低时，例如，由于长期暴露于环境因素或某些内源性过程，例如活性氧的产生。在过去的几年里，已经开发了一个全面的全基因组方法工具箱，用于以单核苷酸分辨率检测哺乳动物细胞中的 DNA 损伤和罕见突变。在这里，我们回顾和比较这些方法，描述它们当前的应用，并讨论现在可以解决的未来研究问题。