Somatic hypermutation targeting is influenced by location within the immunoglobulin V region

被引:18
作者
Cohen, Reuma Magori [1 ,2 ]
Kleinstein, Steven H. [3 ,4 ]
Louzoun, Yoram [1 ,2 ]
机构
[1] Bar Ilan Univ, Dept Math, IL-52900 Ramat Gan, Israel
[2] Bar Ilan Univ, Gonda Brain Res Ctr, IL-52900 Ramat Gan, Israel
[3] Yale Univ, Interdept Program Computat Biol & Bioinformat, New Haven, CT USA
[4] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
关键词
B cells; Immunoglobulin; AID; Hypermutation; Germinal centers; Selection; DNA-POLYMERASE-ETA; CYTIDINE DEAMINASE AID; ANTIBODY GENES; AFFINITY MATURATION; IMMUNE-RESPONSE; B-CELLS; MUTAGENESIS; MUTATION; SEQUENCES; REVEAL;
D O I
10.1016/j.molimm.2011.04.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
The observed mutation pattern in immunoglobulin (Ig) V genes from peripheral B cells is influenced by several mechanisms, including the targeting of AID to specific DNA motifs, negative selection of B cells unable to express Ig receptor, and positive selection of B cells that carry affinity-increasing mutations. These influences, combined with biased codon usage, produce the well-known pattern of increased replacement mutation frequency in the CDR regions, and decreased replacement frequency in the framework regions. Through the analysis of over 12,000 mutated sequences, we show that the specific location in the V gene also significantly influences mutation accumulation. While this position-specific effect is partially explained by selection, it appears independently of the CDR/FWR structure. To further explore the specific targeting of SHM, we propose a statistical formalism describing the mutation probability of a sequence through the multiplication of independent probabilities. Using this model, we show that C -> G (or G -> C) mutations are almost as frequent as C -> T and G -> A mutations, in contrast with C -> A (or G -> T) mutations, which are as any other mutation. The proposed statistical framework allows us to precisely quantify the effect of V gene position, mutation substitution type, and micro-sequence specificity on the observed mutation pattern. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1477 / 1483
页数:7
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