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A Highly Complex, MHC-Linked, 350 Million-Year-Old Shark Nonclassical Class I Lineage.

ABSTRACT: Cartilaginous fish, or Chondrichthyes, are the oldest extant vertebrates to possess the MHC and the Ig superfamily-based Ag receptors, the defining genes of the gnathostome adaptive immune system. In this work, we have identified a novel MHC lineage, UEA, a complex multigene nonclassical class I family found in sharks (division Selachii) but not detected in chimaeras (subclass Holocephali) or rays (division Batoidea). This new lineage is distantly related to the previously reported nonclassical class I lineage UCA, which appears to be present only in dogfish sharks (order Squaliformes). UEA lacks conservation of the nine invariant residues in the peptide (ligand)-binding regions (PBR) that bind to the N and C termini of bound peptide in most vertebrate classical class I proteins, which are replaced by relatively hydrophobic residues compared with the classical UAA. In fact, UEA and UCA proteins have the most hydrophobic-predicted PBR of all identified chondrichthyan class I molecules. UEA genes detected in the whale shark and bamboo shark genome projects are MHC linked. Consistent with UEA comprising a very large gene family, we detected weak expression in different tissues of the nurse shark via Northern blotting and RNA sequencing. UEA genes fall into three sublineages with unique characteristics in the PBR. UEA shares structural and genetic features with certain nonclassical class I genes in other vertebrates, such as the highly complex XNC nonclassical class I genes in Xenopus, and we anticipate that each shark gene, or at least each sublineage, will have a unique function, perhaps in bacterial defense.

SUBMITTER: Almeida T

PROVIDER: S-EPMC8454915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations.Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages.We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.

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A Highly Complex, MHC-Linked, 350 Million-Year-Old Shark Nonclassical Class I Lineage.

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