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Abstract
VH replacement occurs through RAG-mediated secondary recombination between a rearranged VH gene and an upstream unrearranged VH gene. Due to the location of the cryptic recombination signal sequence (cRSS, TACTGTG) at the 3′ end of VH gene coding region, a short stretch of nucleotides from the previous rearranged VH gene can be retained in the newly formed VH–DH junction as a “footprint” of VH replacement. Such footprints can be used as markers to identify Ig heavy chain (IgH) genes potentially generated through VH replacement. To explore the contribution of VH replacement products to the antibody repertoire, we developed a Java-based computer program, VH replacement footprint analyzer-I (VHRFA-I), to analyze published or newly obtained IgH genes from human or mouse. The VHRFA-1 program has multiple functional modules: it first uses service provided by the IMGT/V-QUEST program to assign potential VH, DH, and JH germline genes; then, it searches for VH replacement footprint motifs within the VH–DH junction (N1) regions of IgH gene sequences to identify potential VH replacement products; it can also analyze the frequencies of VH replacement products in correlation with publications, keywords, or VH, DH, and JH gene usages, and mutation status; it can further analyze the amino acid usages encoded by the identified VH replacement footprints. In summary, this program provides a useful computation tool for exploring the biological significance of VH replacement products in human and mouse.
Highlights
Antibodies are the effective molecules in the adaptive immune system to recognize specific antigens and combat bacterial and viral infections, as well as malignant cells [1]
AN OVERVIEW OF THE VH replacement footprint analyzer-I (VHRFA-I) PROGRAM AND FUNCTIONAL MODULES As shown in the workflow of the VHRFA-I program (Figure 1), the VHRFA-I program consists of multiple functional modules for the analysis of Ig heavy chain (IgH) genes and for the identification and analysis of VH replacement products in published or newly generated IgH gene sequences from human or mouse
We can determine the distribution of VH replacement products in IgH genes derived from different diseased subjects
Summary
Antibodies are the effective molecules in the adaptive immune system to recognize specific antigens and combat bacterial and viral infections, as well as malignant cells [1]. V(D)J recombination is catalyzed by the recombination activating gene products (RAG1 and RAG2) that recognize recombination signal sequences (RSS) [3,4,5]. Functional RSS consists of a heptamer (CACTGTG), a nonamer (GGTTTTTGT), and a non-conserved spacer region of 12 or 23 base pairs in between [6, 7]. During V(D)J recombination, the RAG1 and RAG2 complexes first nick between the heptamer and the coding sequence, leaving a blunt signal end and a hairpin sealed DNA coding end [7,8,9]. Nontemplate nucleotides (N-regions) can be added by the terminal deoxynucleotidyl transferase (TdT), whose expression is restricted to early lymphoid cells during active V(D)J recombination. TdT has a preference for adding G residues, which results in generally GC-rich N-regions [7,8,9]
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