CLUSTERS OF POINT MUTATIONS ARE FOUND EXCLUSIVELY AROUND REARRANGED ANTIBODY VARIABLE GENES
CLUSTERS OF POINT MUTATIONS ARE FOUND EXCLUSIVELY AROUND REARRANGED ANTIBODY VARIABLE GENES
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DOI：
10.1073/pnas.80.11.3439
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发表时间：
1983-01-01
期刊：
影响因子：
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通讯作者：
BOGENHAGEN, DF
中科院分区：
文献类型：
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作者：
GEARHART, PJ;BOGENHAGEN, DF
对一系列源自κ轻链基因的鼠抗体基因的核苷酸序列进行了检测，以深入了解特异性突变可变基因的机制。从噬菌体λ文库中克隆了来自杂交瘤和骨髓瘤细胞的6个重排的VK167基因。将这些序列与VK167基因、JK基因和CK基因的种系序列进行比较，以确定突变位点。6个重排基因中有4个发生了广泛的突变，这些突变仅发生在以V - J基因为中心的1千碱基对的DNA区域。在间隔序列或恒定基因中较远处的位点未发现突变。突变频率约为0.5%（32个突变/6749个碱基对）。突变主要是由于核苷酸替换，对转换或颠换没有偏好。每个基因周围突变的位置表明它们在随机位点成簇出现。在JK5基因下游的间隔序列中观察到突变，这排除了仅依赖基因转换或重组的诱变机制模型。突变的分布和高频率最容易用在细胞分裂的几个周期中发生的易错修复机制来解释。
The nucleotide sequences of a series of murine antibody genes derived from .kappa. L chain gene were examined in order to gain insight into the mechanism that specifically mutates variable genes. Six rearranged VK167 genes from hybridoma and myeloma cells were cloned from bacteriophage .lambda. libraries. The sequences were compared to the germ-line sequence of the VK167 gene, the JK genes, and the CK gene to identify sites of mutation. Four of 6 rearranged genes had extensive mutation which occurred exclusively in a 1-kilobase region of DNA centered around the V-J gene. No mutations were found at more distant sites in the intervening sequence or in the constant gene. The frequency of mutation was approximately 0.5% (32 mutations/6749 base pairs). Mutations were mostly due to nucleotide substitutions with no preference for transitions or transversions. The location of mutations around each gene indicates that they occur in clusters at random sites. The observation of mutations in the intervening sequence downstream from the JK5 gene rules out models for the mechanism of mutagenesis that rely solely on gene conversion or recombination. The distribution and high frequency of mutations are most easily explained by a mechanism of error-prone repair that occurs during several cycles of cell division.