Evolutionary and Functional Properties of a Two-Locus β-Globin Polymorphism in Indian House Mice

Abstract

Abstract Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative β-globin haplotypes, Hbbd and Hbbp, are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct β-globin paralogs, HBB-T1 (which encodes the β-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the β-chains of the minor Hb isoform). The Hbbd and Hbbp haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (dminor and pminor) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbbd/Hbbp polymorphism we conducted a population genetic analysis of the duplicated β-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbbd and Hbbp haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated β-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbbd and Hbbp haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (dminor and pminor) are associated with different O2-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both β-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O2-equilibrium curves revealed no discernible functional differences between red cell lysates containing the dminor and pminor Hb isoforms. If the dminor and pminor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.