Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth >1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.

激活诱导的脱氨酶（AID）通过对免疫球蛋白基因上的胞嘧啶脱氨基来启动生发中心（GC）B细胞中的抗体多样化。AID还可以靶向基因组中的其他区域，触发突变或染色体易位，这对致癌性转化具有重要意义。但是，了解AID的特异性已被证明极具挑战性。我们已经对来自GC B细胞的> 1,500个基因组区域进行了非常高的测序，并鉴定了275种被AID靶向的基因，包括30种先前已知的35种AID靶标。我们还确定了迄今为止描述的AID活动变异最高的热点。此外，对与机器学习耦合的突变基因的分子特征进行的综合分析已经为AID目标提供了强大的预测工具。我们还发现，基础切除修复和错配修复相互支持，可以忠实地修复AID诱导的病变。最后，我们的数据建立了AID诱变活性与淋巴瘤发生之间的新型联系。