Abstract
BackgroundFunctional antibody genes are often assembled by VDJ recombination and then diversified by somatic hypermutation. Identifying the combination of sourcing germline genes is critical to understand the process of antibody maturation, which may facilitate the diagnostics and rapid generation of human monoclonal antibodies in therapeutics. Despite of successful efforts in V and J fragment assignment, method in D segment tracing remains weak for immunoglobulin heavy diversity (IGHD).ResultsIn this paper, we presented a D-sensitive mapping method called DSab-origin with accuracies around 90% in human monoclonal antibody data and average 95.8% in mouse data. Besides, DSab-origin achieved the best performance in holistic prediction of VDJ segments assignment comparing with other methods commonly used in simulation data. After that, an application example was explored on the antibody response based on a time-series antibody sequencing data after influenza vaccination. The result indicated that, despite the personal response among different donors, IGHV3–7 and IGHD4–17 were likely to be dominated gene segments in these three donors.ConclusionsThis work filled in a computational gap in D segment assignment for VDJ germline gene identification in antibody research. And it offered an application example of DSab-origin for studying the antibody maturation process after influenza vaccination.
Highlights
Functional antibody genes are often assembled by VDJ recombination and diversified by somatic hypermutation
DSab-origin algorithm and performance validation DSab-origin algorithm construction Since the variable region of antibody heavy chain consists of variable V, diversity D, and joining J gene segments with imprecise nucleotide additions adjacent to the D gene segment, the query is artificially divided into three parts: V block, NDN block, and J block
To separate these three parts, we first identified the germline V and J gene hits with the human IGHV and IGHJ germline repertoires obtained from IMGT [25] via performing BLAST searches [17]
Summary
Functional antibody genes are often assembled by VDJ recombination and diversified by somatic hypermutation. Antibody undergoes genetic recombination and somatic hypermutation to achieve the diversity of immune repertoires during the maturation. The diversity of the immunoglobulin is firstly generated by the recombination of variable V, diversity D, and joining J gene segments with imprecise junctions formed by palindromic and non-templated nucleotides [1, 2]. Somatic hypermutation creates further diversity by introducing point mutations into the rearranged immunoglobulin variable domain to enhance the affinity between the antibody and antigen [3]. Due to the VDJ gene recombination, palindromic and non-templated nucleotide additions, and somatic hypermutation implemented during the process of antibody maturation, it is difficult to trace VDJ gene segments back to the germline, especially for D gene segments
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