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两个表达的Vκ基因中体细胞突变的低频:5'和3'侧翼区域突变的分布不均

Low frequencies of somatic mutation in two expressed V kappa genes: unequal distribution of mutation in 5' and 3' flanking regions.

作者信息

Rickert R, Clarke S

机构信息

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599.

出版信息

Int Immunol. 1993 Mar;5(3):255-63. doi: 10.1093/intimm/5.3.255.

Abstract

Somatic mutation of antibody variable region genes is a hallmark of secondary responses. Most often the coexpressed VH and V kappa genes of a B cell mutate at nearly equal rates. We have previously identified hybridomas from two B cell clones that exhibited > 10-fold lower frequency of mutation in their expressed V kappa 12 or V kappa 1A genes relative to their coexpressed VH genes. To gain insight into the mechanism(s) responsible for this low frequency V kappa mutation, we determined the frequency of mutation in non-coding flanking DNA from multiple members of each clone. We find a low frequency of mutation in the 5' (4/700) and 3' (1/670) non-coding regions of the expressed V kappa 1A genes consistent with the low frequency of coding region mutation. In contrast, the distribution and frequency of mutation surrounding the expressed V kappa 12.37 gene are unusual. Among the six members of this clone there are 31 mutations 3' (31/2100 bp) and no mutations 5' (0/2010 bp) of the V kappa exon. This V kappa exon has acquired mutations that are intermediate in number to its flanking regions and are significantly skewed in distribution to the 3' end. None of the 31 3' mutations are shared by two or more members of this clone, indicating that they all occurred late in clonal expansion. These results raise the possibility that some V kappa genes may lack functional cis-regulatory elements which direct V kappa coding region mutation.

摘要

抗体可变区基因的体细胞突变是二次免疫反应的一个标志。大多数情况下,B细胞共表达的VH和Vκ基因以几乎相同的速率发生突变。我们之前从两个B细胞克隆中鉴定出杂交瘤,其表达的Vκ12或Vκ1A基因的突变频率相对于共表达的VH基因低10倍以上。为了深入了解导致这种低频率Vκ突变的机制,我们测定了每个克隆多个成员非编码侧翼DNA的突变频率。我们发现,表达的Vκ1A基因的5'(4/700)和3'(1/670)非编码区的突变频率较低,这与编码区的低突变频率一致。相比之下,围绕表达的Vκ12.37基因的突变分布和频率则不同寻常。在该克隆的六个成员中,Vκ外显子的3'端有31个突变(31/2100 bp),而5'端没有突变(0/2010 bp)。这个Vκ外显子获得的突变数量介于其侧翼区域之间,并且在分布上明显偏向3'端。该克隆的两个或更多成员没有共享这31个3'端突变中的任何一个,这表明它们都是在克隆扩增后期发生的。这些结果增加了一种可能性,即某些Vκ基因可能缺乏指导Vκ编码区突变的功能性顺式调控元件。

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