An Ancestral MHC Organization in Cartilaginous Fish: Reconstructing MHC origin and evolution.

Cartilaginous fish (sharks, rays, chimeras) comprise the oldest living jawed vertebrates with a mammalian-like adaptive immune system based on Immunoglobulins(Ig), T-cell receptors (TCR) and the Major Histocompatibility Complex (MHC). Here we show that the cartilaginous fish "adaptive MHC" is highly regimented and compact, containing: i) a classical MHC class I region (MHC-Ia) containing antigen processing (antigen peptide transporters, immunoproteasome) and presenting (MHC-Ia) genes; ii) an MHC class II region (MHC-II, with alpha and beta genes) with linkage to β-2-microglobulin (β2m) and bromodomain-containing 2 (brd2); iii) nonclassical MHC class I regions (MHC-Ib) with 450 million-year-old lineages; and iv) a complement C4 associated with the MHC-Ia region. No MHC-Ib genes were found outside of the Elasmobranch MHC. Our data suggest that both MHC-I and -II genes arose after the second round (2R) of whole genome duplication on a human chromosome (huchr) 6 precursor. Further analysis of MHC paralogous regions across early-branching taxa from all jawed vertebrate lineages revealed that Ig/TCR genes likely arose on a precursor of the huchr9/12/14 MHC paralog. The β2m gene is linked to the Ig/TCR genes in some vertebrates suggesting that it was present at 1R, perhaps as the donor of C1 domain to the primordial MHC gene. In sum, extant cartilaginous fish exhibit a conserved and prototypical MHC genomic organization with features found in various vertebrates, reflecting the ancestral arrangement for the jawed vertebrates.