Abstract
BackgroundCow 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.ResultsThe 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.ConclusionsLength heterogeneity within DH regions is a unique evolutionary genomic mechanism to create immune diversity, including formation of ultralong CDR H3 regions.
Highlights
Cow antibodies are very unusual in having exceptionally long complementarity determining region (CDR) H3 regions
The heavy chain diversity region (DH) regions at the heavy chain locus are divided into “clusters” that arose from duplication events through evolution
The IMGT naming nomenclature for DH regions includes numerical designations for the family and cluster of each gene; for example, IGHD3–2 is in family 3 and located in cluster 2 [16, 31,32,33]
Summary
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. 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 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. Long CDR H3 regions are often found in broadly neutralizing antibodies targeting human immunodeficiency (HIV), influenza, and polio viruses [4,5,6,7,8], and are thought to be important in binding challenging antigens like G-protein coupled receptors and protease active sites [9, 10]. Genetic mechanisms to form long CDR H3s may be very important in immune responses against key antigens
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