Might gene conversion be the mechanism of somatic hypermutation of mammalian immunoglobulin genes?
Might gene conversion be the mechanism of somatic hypermutation of mammalian immunoglobulin genes?
复制标题
基因转换可能是哺乳动物免疫球蛋白基因体细胞超突变的机制吗？
DOI：
10.1016/0168-9525(89)90004-8
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Maizels,N
中科院分区：
文献类型：
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作者：
Maizels,N
术语“基因转化”是指供体序列向基因组中其他地方密切相关的序列贡献信息的遗传事件。与同源重组相反，同源重组涉及两个参与的 1) NA 分子的断裂和重新连接，基因转换单向传输信息，并且供体序列不经历 1I 迭代。因此，非孟德尔遗传分离表征了基因转换的产物。基因转化的分子机制尚未明确，但通常被认为涉及用部分同源的供体核酸替换受体基因中的序列区域；然后修复或复制将解决所产生的异源双链体。基因转换的生化标志是同一基因组中两个不同基因共有的序列区域。随着 DNA 序列信息的积累，令人惊讶的事情之一是基因转换在产生和调节真核基因组可塑性方面发挥的主要作用。此外，在酵母、锥虫和鸡等不同的生物体中，迄今为止已定义的所有发育调节和靶向基因多样化的实例都与基因转换有关。这使我重新思考基因转换的激活过程是否可能导致哺乳动物免疫球蛋白基因的体细胞“超突变”的问题。在体细胞超突变过程中，单碱基变化在编码抗体分子重链和轻链的重排基因的可变区中积累。这种靶向突变过程仅在抗原激活后发生，并产生产生对抗原具有更高亲和力的抗体分子的克隆，从而提高免疫反应的效率和特异性。其突变率接近每代细胞每个碱基 10-3 个，比哺乳动物体细胞的典型突变率高 105-106 倍。免疫球蛋白基因体细胞超突变的机制尚不清楚。虽然基因转换已被认为在此过程中发挥作用，但缺乏种系供体的突变的存在先前已被解释为反对基因转换在免疫球蛋白基因1,-'的体细胞超突变中发挥重要作用的证据。在这里，我首先考虑目标基因转换事件的参数，这些参数主要通过对鸡~轻链基因座~-*'的研究来定义。 The primary~.鸡的链库通过基因转换经历多样化，序列分析揭示的一个特别有趣的特征是非模板突变与基因转换诱导的模板突变以协调方式出现。这表明非模板突变的引入可能是基因转换的分子机制所固有的。
Ate term gene conversion refers to a genetic event in w.'hich a donor sequence contributes information to a closely related sequence elsewhere in the genome. In contrast to homok) gous recombination, which involves breakage and rejoining of both participating 1) NA molecules, gene conversion transtL~ rs information unidirectionally and the donor sequence undergoes no: 1I-teration. Nonmendelian genetic segregation therefore characterizes the products of gene conversion. The molecular mechanism of gene conversion has not been defined, but it is commonly pictured as involving replacement of a region of sequence in the recipient gene by a partially homologous donor nucleic acid; repair or replication would then resolve the resulting heteroduplex. The biochemical hallmark of gene conversion is a region of sequence common to two different genes in the same genome. As DNA sequence information has accumulated, one of the surprises has been the major role that gene conversion plays in generating and regulating the plasticity of the eukaryotic genome. Moreover, gene conversion is responsible fbr all instances of developmentally regulated and targeted gene diversification that have thus far been defined, in organisms as different as yeasts, trypanosomes and chickens.This leads me to reopen the question of whether an activated process of gene conversion may be responsible for somatic'hypermutation'of mammalian immunoglobulin genes. In the process of somatic hypermutation, single base changes accumulate in the variable regions of the rearranged genes encoding both the heavy and light chains of antibody molecules. This targeted mutational process occurs only after antigen activation, and gives rise to clones that produce antibody molecules with increased affinity for antigen, thus increasing the efficiency and specificity of the immune response. Its rate approaches 10-3 per base per cell generation, 105-106 times higher than the typical rate of mutation in mammalian somatic cells. The mechanism of somatic hypermutation of immunoglobulin genes is not understood. While gene conversion has been suggested to play a role in this process, the existence of mutations that lack germ-line donors has previously been interpreted as evidence against a significant role for gene conversion in somatic hypermutation of the intmunoglobulin genes 1,-'. Here I begin by considering the parameters of targeted gene conversion events, as defined primarily by studies of the chicken~, light chain locus,~-*'. The primary~. chain repertoire in the chicken undergoes diversification by gene conversion, and an especially interesting feature revealed by sequence analysis is that untemplated mutations appear in a coordinate fashion with templated mutations induced by gene conversion3. This suggests that introduction of untemplated mutations may be inherent to the molecular mechanism of gene conversion.