Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
Mol Immunol. 2013 Jul;54(3-4):397-402. doi: 10.1016/j.molimm.2013.01.005. Epub 2013 Feb 9.
Ig gene somatic hypermutation in the germinal center (GC) B cells occurs at C and G at roughly the same frequency. In contrast, there is a 2-fold increase of mutations at A relative to T on the non-transcribed strand of the V genes but it is unclear what triggers such strand bias. Using an efficient mutagenesis system that recapitulates characteristic features of Ig gene hypermutation in the GC B cells, we found that low levels of AID induced similar frequency of mutations at A and T. However, high levels of AID specifically increased mutations at A, but not T, leading to strand bias. These results explain why strand bias of A:T mutations is observed only in the highly mutated V genes but not in the less mutated switch region or the BCL-6 gene. High levels of AID also increased the proportion of transversions at G relative to transversions at C. Our results identify a clue to the strand bias of A:T mutations and provide an in vitro model to elucidate this unsolved mystery in the hypermutation field.
在生发中心（GC）B 细胞中，Ig 基因体细胞高频突变在 C 和 G 处的发生频率大致相同。相比之下，在 V 基因的非转录链上，A 相对于 T 的突变频率增加了 2 倍，但尚不清楚是什么引发了这种链偏向。利用一种高效的诱变系统，该系统再现了 GC B 细胞中 Ig 基因高频突变的特征，我们发现，低水平的 AID 诱导 A 和 T 处的突变频率相似。然而，高水平的 AID 特异性增加了 A 的突变，但不是 T，导致链偏向。这些结果解释了为什么 A:T 突变的链偏向仅在高度突变的 V 基因中观察到，而不在突变较少的开关区或 BCL-6 基因中观察到。高水平的 AID 还增加了 G 相对于 C 的颠换比例。我们的结果为 A:T 突变的链偏向提供了线索，并提供了一个体外模型来阐明高频突变领域中这一未解决的谜团。
