Abstract
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 de novo 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 de novo 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.
Highlights
Antibodies provide specific binding to an enormous range of antigens and represent a key component of the adaptive immune system
We illustrate the work of IgScout using one of the HEALTHY datasets (Set 1) containing heavy chain repertoires extracted from peripheral blood mononuclear cells (PBMC)
To minimize impact of sequencing and amplification errors, we clustered similar complementarity determining region 3 (CDR3) and constructed consensus for each cluster resulting in 98,576 consensus CDR3 of average length 46 nucleotides
Summary
Antibodies provide specific binding to an enormous range of antigens and represent a key component of the adaptive immune system. Most immunogenomics studies rely on the population-level germline genes rather than germline genes in a specific individual that the immunosequencing data originated from This approach is deficient since the set of known germline genes is incomplete ( for non-Europeans) and contains alleles that resulted from sequencing and annotation errors [2, 3]. As Ralph and Matsen [3] commented, the more challenging task of de novo reconstruction of D genes remains elusive This is unfortunate since D genes contribute to the complementarity determining region 3 (CDR3) that covers the junctions between V, D, and J genes and represents the highly divergent part of antibodies. We revealed ultra-long tandem CDR3s and shed light on the mechanism responsible for their formation
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