Abstract
BackgroundImmunoglobulin (IG) complementarity determining region (CDR) includes VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3. Of these, VH CDR3 plays a dominant role in recognizing and binding antigens. Three major mechanisms are involved in the formation of the VH repertoire: germline gene rearrangement, junctional diversity and somatic hypermutation. Features of the generation mechanisms of VH repertoire in humans and mice share similarities while VH CDR3 amino acid (AA) composition differs. Previous studies have mainly focused on germline gene rearrangement and the composition and structure of the CDR3 AA in humans and mice. However the number of AA changes due to somatic hypermutation and analysis of the junctional mechanism have been ignored.MethodsHere we analyzed 9,340 human and 6,657 murine unique productive sequences of immunoglobulin (IG) variable heavy (VH) domains derived from IMGT/LIGM-DB database to understand how VH CDR3 AA compositions significantly differed between human and mouse. These sequences were identified and analyzed by IMGT/HighV-QUEST (http://www.imgt.org), including gene usage, number of AA changes due to somatic hypermutation, AA length distribution of VH CDR3, AA composition, and junctional diversity.ResultsAnalyses of human and murine IG repertoires showed significant differences. A higher number of AA changes due to somatic hypermutation and more abundant N-region addition were found in human compared to mouse, which might be an important factor leading to differences in VH CDR3 amino acid composition.ConclusionsThese findings are a benchmark for understanding VH repertoires and can be used to characterize the VH repertoire during immune responses. The study will allow standardized comparison for high throughput results obtained by IMGT/HighV-QUEST, the reference portal for NGS repertoire.
Highlights
Immunoglobulin (IG) complementarity determining region (CDR) includes variable heavy (VH) CDR1, VH CDR2, VH Complementarity determining region 3 (CDR3), VL CDR1, VL CDR2 and VL CDR3
Due to its key role in antigen binding, the VH CDR3 has become a target for the introduction of hypervariability in synthetic antibody libraries [10,11], which can be used for engineering therapeutic antibodies [12]
Sequences were considered effective because that came from the IMGT/LIGM-DB, we still removed some deemed invalid by IMGT/HighV-QUEST
Summary
Immunoglobulin (IG) complementarity determining region (CDR) includes VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3. Three major mechanisms are involved in the formation of the VH repertoire: germline gene rearrangement, junctional diversity and somatic hypermutation. Features of the generation mechanisms of VH repertoire in humans and mice share similarities while VH CDR3 amino acid (AA) composition differs. Previous studies have mainly focused on germline gene rearrangement and the composition and structure of the CDR3 AA in humans and mice. The variable domain at the N-terminal end of each chain is generated by the rearrangement of a variable (V) gene, a diversity (D) gene (for the VH) and a joining (J) gene. The third complementaritydetermining region of the IG heavy chain (VH CDR3) functions as the center of the classical antigen-binding site and it often influences how the specificity and affinity of the antibody is determined [6,7,8,9]. VH CDR3 is more diverse than any of the other five CDRs [13,14], which is generated by deletion and insertion of random nucleotides (nts) during joining (junctional diversity) [15]
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