Alignments of representative α1 and β1 domain sequences. Representative teleost fish DA, DB and DE group sequences are compared with MHC class II of primitive fish and tetrapods. Shown sequences correspond with single exons, while residue numbers above alignments relate to mature HLA-DR molecules . c: cartilaginous fish classical-type class II. t: tetrapod lineage classical-type class II. Dashes: gaps made for the alignment. Blue frame: the DAA-lineage specific GCSDXDG (or similar) motif. Downward triangles: peptide-backbone interacting residues based on mammalian studies , with red triangles for the positions α62, α69, β81 and β82 (see also Additional file 6: Table S3). Various color shadings represent as follows. Purple: cysteines confirmed or predicted to form a disulfide bridge. Rose: DM-specific cysteine. Green: conserved N-glycosylation motifs. Red: α62 N, α69 N, β81H and β82 N. Yellow: typical residues shared between spotted gar 501 A2 and teleost DAA and DBA sequences. Gold: tryptophan residues at the position 43 of α1 domain. Black: highly conserved residues among jawed vertebrates. Blue in β1: ray-finned fish specific residues. Lime green: DE group specific residues. Gray: residues shared by DE group and class II in cartilaginous fish and tetrapods. Brown: cartilaginous fish residues that appear to be ancestral. Dark and light blue in α1: single and two residues deletion compared to class II consensus, respectively. Italic font: human DR and DM secondary structures with solid frames for the β-strands S1-S4, dotted frames for 310 helices, and dashed frames for the α -helices according to PDB structures 3PDO and 2BC4. At the site of non-capital font “nd” in salmon DBA α1 the stretch SNTCLIA was deleted for lay-out reasons, and at the site “fe” of medaka M16A α1 this was FKANLS (Additional file 10: Text S4A). Sequences are referenced in Additional file 7: Text S1; Additional file 8: Text S2; Additional file 10: Text S4.