An Ancient MHC-Linked Gene Encodes a Nonrearranging Shark Antibody, UrIg, Convergent with IgG

Abstract

Gnathostome adaptive immunity is defined by the Ag receptors, Igs and TCRs, and the MHC. Cartilaginous fish are the oldest vertebrates with these adaptive hallmarks. We and others have unearthed nonrearranging Ag receptor-like genes in several vertebrates, some of which are encoded in the MHC or in MHC paralogous regions. One of these genes, named UrIg, was detected in the class III region of the shark MHC that encodes a protein with typical V and C domains such as those found in conventional Igs and TCRs. As no transmembrane region was detected in gene models or cDNAs, the protein does not appear to act as a receptor. Unlike some other shark Ig genes, the UrIg V region shows no evidence of RAG-mediated rearrangement, and thus it is likely related to other V genes that predated the invasion of the RAG transposon. The UrIg gene is present in all elasmobranchs and evolves conservatively, unlike Igs and TCRs. Also, unlike Ig/TCR, the gene is not expressed in secondary lymphoid tissues, but mainly in the liver. Recombinant forms of the molecule form disulfide-linked homodimers, which is the form also detected in many shark tissues by Western blotting. mAbs specific for UrIg identify the protein in the extracellular matrix of several shark tissues by immunohistochemistry. We propose that UrIg is related to the V gene invaded by the RAG transposon, consistent with the speculation of emergence of Ig/TCR within the MHC or proto-MHC.

An Ancestral Major Histocompatibility Complex Organization in Cartilaginous Fish: Reconstructing MHC Origin and Evolution

“…The assemblage of Ig/TCR genes in the proto-MHC/AgR was previously suggested by the presence of VJ genes in the MHC (e.g. NKp30 and PRARP ), but this hypothesis has recently been further supported by the discovery of a novel nonrearranging (VJ-C1) Ig-like gene, UrIg , in the class III region of the elasmobranch MHC ( Flajnik et al 2023 ). Thus, the presence of genes with nonsplit V exon in both descendant chromosomes of the proto-MHC/AgR places inception of AgR genes at 1R but postdating the split between jawless and jawed vertebrates ( Fig.…”

“…Indeed, genes with VJ and C1-like IgSF domains have been identified in protochordates, and it has been hypothesized that simple exon shuffling would provide the means to create the typical VJ-C1-IgSF structure of AgR genes ( Kasahara et al 2004 ). Several such VJ-C1-type genes have been identified in tetrapods, some of which are linked to MHC paralogous regions ( Kasahara et al 1996 ; Ohta et al 2019 ; Flajnik et al 2023 ) and are perhaps remnants of the original VJ and C1-type precursors in the PIC ( Fig. 5 ).…”