INACTIVATION OF E(ALPHA) AND E(BETA) EXPRESSION IN INBRED AND WILD MICE BY MULTIPLE DISTINCT MUTATIONS, SOME OF WHICH PREDATE SPECIATION WITHIN MUS SPECIES

The H-2 MHC of mice encodes two functional class II heterodimeric prot eins: A(alpha)A(beta) (A) and E(alpha) E(beta) (E), While failure to e xpress the A protein has not been reported, a significant proportion o f of H-2 haplotypes in both inbred and wild mice do not express E prot eins, We and others have previously characterized the molecular basis for defective E expression in haplotypes from Mus domesticus (b, f, q, s, from inbred strains) and M. castaneus (w17, wild-derived) species, identifying six distinct defects in the genes for E(alpha) or E(beta) . In this report we have extended these studies to other E(-) haplotyp es, including several from t-haplotype-bearing M, domesticus mice (w29 , w57, w302) and one derived from the Asian species M, bactrianus (w30 1), Analyses at the protein, RNA and DNA levels were employed to ident ify the defects in the genes for Ea and Eb. At least one new defect wa s identified that prevents E(beta) expression in a t-associated H-2 ha plotypes (w57), bringing the number of distinct mutations causing the E(-) phenotype to seven. Another t-associated haplotype, w302, was fou nd to share the same E(beta) defect with mice of the inbred q haplotyp e and of the w17 haplotype from M. castaneus, while its Ea gene contai ns the deletion carried also by the inbred b and s haplotypes and by a number of wild haplotypes, The mutations in the Ea and Eb genes of th e w301 haplotype from M, bactrianus were found to be identical to thos e of the inbred f haplotype, This indicates that the origin of the mut ations in the Eb genes of the q, w17 and w302 haplotypes and in the Ea and Eb genes of the f and w301 haplotypes, predated speciation within Mus,thought to have occurred -0.35-1 million years ago, Their mainten ance in mouse populations suggests that in certain conditions the fail ure to express E(alpha) E(beta) proteins may be advantageous and selec ted for.