Recovering probabilities for nucleotide trimming processes for T cell receptor TRA and TRG V-J junctions analyzed with IMGT tools
Recovering probabilities for nucleotide trimming processes for T cell receptor TRA and TRG V-J junctions analyzed with IMGT tools
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DOI：
10.1186/1471-2105-9-408
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发表时间：
2008-10-02
影响因子：
3
通讯作者：
Biau, Gerard
中科院分区：
文献类型：
--
作者：
Bleakley, Kevin;Lefranc, Marie-Paule;Biau, Gerard
背景：在免疫系统的B细胞和T细胞的免疫球蛋白（IG）和T细胞受体（TR）重排过程中，核苷酸从可变(V)、多样性(D)和连接(J)基因的末端被修剪。这种修剪之后是随机添加核苷酸，形成V-J和V-D-J连接的N个区域（核苷酸为N）。这些过程对于产生免疫反应的多样性至关重要，因为每个B细胞或T细胞中修剪的核苷酸数量和添加的核苷酸数量各不相同。IMGT (R)序列分析工具，IMGT/V-QUEST和IMGT/JunctionAnalysis，能够提供详细和准确的分析最终观察到的连接核苷酸序列（工具“输出”）。然而，由于在此过程中修剪的核苷酸可能会被相同的N区核苷酸所取代，因此观察到的“输出”代表了对“真正修剪过程”的有偏见的估计。结果：提出了一种基于标准化工具“输出”分析的概率方法来推断“真实修剪过程”的概率分布，并提供合理的生物学假设来解释这一过程。我们整理了TR α (TRA)和TR γ （TRG) V-J重排序列和连接的基准数据集，使用IMGT/V-QUEST和IMGT/JunctionAnalysis（来自国际免疫遗传学信息系统(R), http://imgt.cines.fr）的核苷酸序列分析工具）进行分析。工具输出的标准化描述基于IMGT-ONTOLOGY公理和概念。我们提出了一个简单的一阶模型，试图将观察到的“输出”概率分布转换为更接近“真实修剪过程”概率分布的估计。我们用这个估计来检验泊松过程参与修剪的假设。这一假设在四个修剪过程中的三个：TRAV， TRAJ和TRGV的标准置信水平上没有被拒绝。结论：通过使用重排TR基因的修剪作为基准，我们表明，应用于IMGT (R)标准化工具“输出”的概率方法为“真正的修剪过程”所涉及的事件的合理假设开辟了道路，并最终精确量化修剪本身。随着标准化免疫遗传学数据的高通量增加，类似的概率方法将提高对迄今为止仅以标准化工具的“输出”为特征的过程的理解。
Background: Nucleotides are trimmed from the ends of variable (V), diversity (D) and joining (J) genes during immunoglobulin (IG) and T cell receptor (TR) rearrangements in B cells and T cells of the immune system. This trimming is followed by addition of nucleotides at random, forming the N regions (N for nucleotides) of the V-J and V-D-J junctions. These processes are crucial for creating diversity in the immune response since the number of trimmed nucleotides and the number of added nucleotides vary in each B or T cell. IMGT (R) sequence analysis tools, IMGT/V-QUEST and IMGT/JunctionAnalysis, are able to provide detailed and accurate analysis of the final observed junction nucleotide sequences (tool "output"). However, as trimmed nucleotides can potentially be replaced by identical N region nucleotides during the process, the observed "output" represents a biased estimate of the "true trimming process."Results: A probabilistic approach based on an analysis of the standardized tool "output" is proposed to infer the probability distribution of the "true trimmming process" and to provide plausible biological hypotheses explaining this process. We collated a benchmark dataset of TR alpha (TRA) and TR gamma (TRG) V-J rearranged sequences and junctions analysed with IMGT/V-QUEST and IMGT/JunctionAnalysis, the nucleotide sequence analysis tools from IMGT (R), the international ImMunoGeneTics information system (R), http://imgt.cines.fr. The standardized description of the tool output is based on the IMGT-ONTOLOGY axioms and concepts. We propose a simple first-order model that attempts to transform the observed "output" probability distribution into an estimate closer to the "true trimming process" probability distribution. We use this estimate to test the hypothesis that Poisson processes are involved in trimming. This hypothesis was not rejected at standard confidence levels for three of the four trimming processes: TRAV, TRAJ and TRGV.Conclusion: By using trimming of rearranged TR genes as a benchmark, we show that a probabilistic approach, applied to IMGT (R) standardized tool "outputs" opens the way to plausible hypotheses on the events involved in the "true trimming process" and eventually to an exact quantification of trimming itself. With increasing high-throughput of standardized immunogenetics data, similar probabilistic approaches will improve understanding of processes so far only characterized by the "output" of standardized tools.