Sequence divergence of B2m alleles of wild Mus musculus and Mus spretus implies positive selection

Mouse β₂-microglobulin (β₂m) is polymorphic. Sequences of five allelic wild mouse B2m genes have been determined from the large exons of genomic DNA using the polymerase chain reaction. Relative to the standard B2m^a allele, the products of four alleles of Mus musculus origin (w2, w3, w4, and w5), differ by only one or two amino acids. w5 has a single nucleotide change, Asp85 → Val, and is identical to the c allele. w2 differs at Arg81 → Thr and w4 at His34 → Gln, and they share the Asp85 → Val change with B2m^c and B2m^w5.w5 and c cells are lysed by S19.8, a monoclonal antibody specific for β2m^b (Ala85), in a complement-mediated cytotoxicity assay, whereas w4 cells are not. Thus, distant changes appear to introduce subtle conformational effects on β2m structure. Five independent isolates of Mus spretus (w1) differ the most from B2m^a, with 12 amino acid changes and only one silent substitution. Replacements predicted from the nucleotide sequence occur in loops of the molecule facing away from the class I heavy chain and not in regions where β2m associates with class 1 α3 domains. Concordantly, the w1 - 5 allelic forms of β2m associate well with H-2 heavy chains. The many amino acid changes in the spretus sequence and the paucity of silent substitutions suggest that B2m has been subject to positive selection.