Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologous recombination. These DSBs are usually repaired faithfully, but here, we uncover a distinct type of mutational event in which deletions form via joining of ends from two closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspots on the same or different chromatids. Deletions occur in normal meiosis but are much more frequent when DSB formation is dysregulated in the absence of the ATM kinase. Events between chromosome homologs point to multi-chromatid damage and aborted gap repair. Some deletions contain DNA from other hotspots, indicating that double cutting at distant sites creates substrates for insertional mutagenesis. End joining at double cuts can also yield tandem duplications or extrachromosomal circles. Our findings highlight the importance of DSB regulation and reveal a previously hidden potential for meiotic mutagenesis that is likely to affect human health and genome evolution.

在减数分裂过程中出现许多 DNA 双链断裂 (DSB) 以启动同源重组。这些 DSB 通常会得到忠实修复，但在这里，我们发现了一种不同类型的突变事件，在这种事件中，删除是通过在单个热点或相同或不同染色单体上的相邻热点处连接两个紧密间隔的 DSB（双切）的末端而形成的。缺失发生在正常的减数分裂中，但当 DSB 形成在没有 ATM 激酶的情况下失调时，缺失会更加频繁。染色体同系物之间的事件指向多染色单体损伤和中止的间隙修复。一些缺失包含来自其他热点的 DNA，表明在远距离位点的双重切割为插入诱变创造了底物。双切末端连接也可能产生串联重复或染色体外环。