Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage.

转录是遗传不稳定的来源，这可能主要是由于新生的mRNA及其模板之间形成遗传毒性的DNA：RNA杂种或R环而引起的。在这里，我们报告了一个内含子在抵消真核基因组中R环积累的意外功能。内源内含子的缺失增加了R-环的形成，而将内含子插入无内含子的基因抑制了R-环的积累及其对酵母转录和重组的有害影响。剪接体在mRNA上的募集（而不是剪接本身）被证明对于减弱R环的形成和与转录相关的遗传不稳定性至关重要。对许多内含子含量不同的远距离物种进行全基因组分析，包括人类，进一步揭示了含内含子的基因和最富内含子的基因组能最好地防止R环积累和随后的遗传不稳定。因此，我们的结果为整个真核细胞系内含子的保守提供了可能的理由。