Center for Information Theory and Applications, University of California, San Diego, San Diego, CA, United States.
Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA, United States.
Front Immunol. 2019 May 3;10:987. doi: 10.3389/fimmu.2019.00987. eCollection 2019.
The V(D)J recombination forms the immunoglobulin genes by joining the variable (V), diversity (D), and joining (J) germline genes. Since variations in germline genes have been linked to various diseases, personalized immunogenomics aims at finding alleles of germline genes across various patients. Although recent studies described algorithms for inference of V and J genes from immunosequencing data, they stopped short of solving a more difficult problem of reconstructing D genes that form the highly divergent CDR3 regions and provide the most important contribution to the antigen binding. We present the IgScout algorithm for D gene reconstruction and apply it to reveal new alleles of human D genes and previously unknown D genes in camel, an important model organism in immunology. We further analyze non-canonical V(DD)J recombination that results in unusually long CDR3s with tandem fused IGHD genes and thus expands the diversity of the antibody repertoires. We demonstrate that tandem CDR3s represent a consistent and functional feature of all analyzed immunosequencing datasets, reveal ultra-long CDR3s, and shed light on the mechanism responsible for their formation.
V(D)J 重组通过连接胚系基因的可变 (V)、多样性 (D) 和连接 (J) 来形成免疫球蛋白基因。由于胚系基因的变异与各种疾病有关，个性化免疫基因组学旨在寻找各种患者的胚系基因等位基因。尽管最近的研究描述了从免疫测序数据推断 V 和 J 基因的算法，但它们没有解决更困难的问题，即重建形成高度变异的 CDR3 区域的 D 基因，这些区域对抗原结合贡献最大。我们提出了 IgScout 算法来进行 D 基因重建，并将其应用于揭示人类 D 基因的新等位基因和骆驼（免疫学中的重要模型生物）中以前未知的 D 基因。我们进一步分析了非典型的 V(DD)J 重组，该重组导致具有串联融合 IGHD 基因的异常长的 CDR3，从而扩大了抗体库的多样性。我们证明串联 CDR3 是所有分析的免疫测序数据集的一致和功能特征，揭示了超长的 CDR3，并阐明了其形成的机制。
