Both DNA strands of antibody genes are hypermutation targets
Both DNA strands of antibody genes are hypermutation targets
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DOI：
10.1073/pnas.95.15.8791
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发表时间：
1998-07-21
影响因子：
11.1
通讯作者：
Staden, R
中科院分区：
文献类型：
--
作者：
Milstein, C;Neuberger, MS;Staden, R
在免疫应答成熟期间，抗体基因经历局部超突变。突变并不沿V基因沿着均匀分布;存在与一级序列基序相关的内在热点。尽管超突变的机制仍然未知，但已经提出表现出DNA链极性，因为编码链上的嘌呤残基比嘧啶更频繁地被靶向突变。然而，这种极性可能不是超突变机制的内在属性，而是V基因序列进化选择特性的结果。此外，两条链都是超突变靶点的可能性很少受到关注。为了区分这些可能性，我们已经通过使用从V和非V突变靶标获取的大型数据库分析了所有核苷酸三联体的三个碱基中的每一个的突变的平均频率。我们还重新评估了与热点相关的序列基序。我们发现，即使在非Ig序列中，A突变多于T，这与靶向的链依赖性组分一致。然而，三联体及其反向互补序列的突变偏好是相关的，表明突变靶向存在序列特异性但不依赖于链的组分。因此，存在对局部DNA序列敏感的超突变过程的两个方面，一个是DNA链依赖性的，另一个不是。
During the maturation of the immune response, antibody genes are subjected to localized hypermutation. Mutations are not evenly distributed along the V gene; intrinsic hot spots exist that are correlated with primary sequence motifs. Although the mechanism of hypermutation remains unknown, it has been proposed to exhibit DNA strand polarity because purine residues on the coding strand are more frequently targeted for mutation than pyrimidines. However, this polarity may not be an intrinsic property of the hypermutation mechanism but a consequence of evolutionary-selected peculiarities of V gene sequences. Furthermore, the possibility that both strands are hypermutation targets has received little attention. To discriminate between these possibilities, we have analyzed the average frequency of mutations of each of the three bases of all nucleotide triplets by using large databases taken from both V and non-V mutation targets, We also have reassessed the sequence motifs associated with hot spots, We find that even in non-Ig sequences, A mutates more than T, consistent with a strand-dependent component to targeting. However, the mutation biases of triplets and of their inverted complements are correlated, demonstrating that there is a sequence-specific but strand-independent component to mutational targeting, Thus, there are two aspects of the hypermutation process that are sensitive to local DNA sequences, one that is DNA strand-dependent and the other that is not.