Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells.
Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells.
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正常和自身反应性 B 细胞中体细胞诱变的二核苷酸和三核苷酸靶点偏好。
DOI：
10.4049/jimmunol.156.7.2642
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发表时间：
1996
影响因子：
4.4
通讯作者：
L. Wysocki
中科院分区：
文献类型：
--
作者：
Diana S. Smith;G. Creadon;Prasanna K. Jena;Joseph P. Portanova;Brian L. Kotzin;L. Wysocki
在抗原驱动的记忆B细胞发育过程中，抗体V基因被体细胞突变所修饰。虽然V基因体细胞突变在生理和自身免疫抗体应答中都有重要的生物学后果，但人们对突变的机制以及它是否在自身反应性B细胞中正常工作知之甚少。为了探讨这些问题，我们分析了抗体基因的体细胞突变，以寻找序列特异性靶标偏好的证据。我们的分析局限于V基因的非编码片段，因此体细胞突变过程的内在特征可以可靠地从细胞选择的间接但实质性的影响中分离出来。我们一直观察到，一些二核苷酸，特别是GC和TA，根据它们的出现频率，以高于预期的频率突变。大多数二核苷酸突变偏好不能直接从单核苷酸突变偏好中推断出来。特定的三核苷酸，包括AGC、TAC和它们的反向重复序列(GCT、GTA)，也比预期的突变更频繁。这些突变特征和其他突变特征在正常和自身反应性B细胞的V基因中几乎无法区分。对已发表的侧翼序列的突变分析证实了靶标偏好，对编码V序列中报告的“热点”的检查也证实了这一点。V基因编码区和非编码区的共同偏好表明，体细胞突变是从头产生的。总而言之，我们的发现表明，体细胞突变过程表现出序列特异性的偏好，与非模板化机制一致，似乎在正常和自身反应的B细胞中操作相似。
During Ag-driven development of memory B cells, Ab V genes are modified by somatic mutagenesis. Although V gene somatic mutations have important biologic consequences in both physiologic and autoimmune Ab responses, little is known about the mechanism of mutation, or whether it operates normally in autoreactive B cells. To approach these issues, we analyzed somatic mutations in Ab genes for evidence of sequence-specific target preferences. Our analysis was confined to noncoding segments of V genes so that the intrinsic characteristics of the somatic mutation process could be reliably dissociated from the indirect but substantial influences of cellular selection. We consistently observed that some dinucleotides, GC and TA in particular, mutated at frequencies that were higher than expected based on their frequency of occurrence. Most of the dinucleotide mutation preferences could not be extrapolated directly from mononucleotide mutation preferences. Specific trinucleotides, including AGC, TAC, and their inverse repeats (GCT, GTA), also mutated more frequently than expected. These and other mutation characteristics were virtually indistinguishable in V genes of normal and autoreactive B cells. An analysis of mutations in published flanking sequences confirmed the target preferences, as did an examination of reported "hot spots" within coding V sequences. The shared preferences in coding and noncoding regions of V genes suggests that somatic mutations are generated de novo. Collectively, our findings indicate that the somatic mutation process exhibits sequence-specific preferences, consistent with an untemplated mechanism, and appears to operate similarly in normal and autoreactive B cells.