Formation of ultralong DH regions through genomic rearrangement
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RESEARCH ARTICLE
Open Access
Formation of ultralong DH regions through genomic rearrangement Brevin A. Smider1 and Vaughn V. Smider1,2*
Abstract Background: Cow antibodies are very unusual in having exceptionally long CDR H3 regions. The genetic basis for this length largely derives from long heavy chain diversity (DH) regions, with a single “ultralong” DH, IGHD8–2, encoding over 50 amino acids. Many bovine IGHD regions have sequence similarity but have several nucleotide repeating units that diversify their lengths. Genomically, most DH regions exist in three clusters that appear to have formed from DNA duplication events. However, the relationship between the genomic arrangement and long CDR lengths is unclear. Results: The DH cluster containing IGHD8–2 underwent a rearrangement and deletion event in relation to the other clusters in the region corresponding to IGHD8–2, with possible fusion of two DH regions and expansion of short repeats to form the ultralong IGHD8–2 gene. Conclusions: Length heterogeneity within DH regions is a unique evolutionary genomic mechanism to create immune diversity, including formation of ultralong CDR H3 regions. Keywords: Bovine immunoglobulin, DH region, Ultralong CDR3, Cow antibody, Antibody diversity, Immunoglobulin repertoire, CDR3 length
Background Adaptive immunity arose in vertebrates through the ability to somatically alter antigen receptor (antibody and Tcell receptor) genes to form diverse repertoires which are selected to bind and neutralize invading pathogens. A key component of this system is the ability to perform recombination of variable (V), diversity (D), and joining (J) gene segments through the process of V(D)J recombination [1–3]. A diversity of V, D, and J elements, along with imprecise joining at the V-D and D-J junctions enables different amino acids to be encoded in key paratopic regions which impact antigen binding. The third complementary determining region of the heavy chain (CDR H3) is particularly important in antibody molecules as it contains the greatest diversity and also usually makes the most extensive contact with * Correspondence: [email protected] 1 The Applied Biomedical Science Institute, San Diego, CA 92127, USA 2 The Scripps Research Institute, La Jolla, CA 92037, USA
antigen. Long CDR H3 regions are often found in broadly neutralizing antibodies targeting human immunodeficiency (HIV), influenza, and polio viruses [4–8], and are also thought to be important in binding challenging antigens like G-protein coupled receptors and protease active sites [9, 10]. Thus, genetic mechanisms to form long CDR H3s may be very important in immune responses against key antigens. In most organisms, the antibody CDR H3 forms a loop of 10–15 amino acids in length, and is encoded by the DH gene and associated recombinational junctions that form through VDJ recombination. Unusually long CDR H3s, such as those in rare broadly neutralizing anti-HIV antibodies from infected patients, are often over 20 amino acids in length [4, 11–13]. The major de
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