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

Abstract

The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated b-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbb d and Hbb p haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (d minor and p minor ) are associated with different O 2 -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 b-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O 2 -equilibrium curves revealed no discernible functional differences between red cell lysates containing the d minor and p minor Hb isoforms. If the d minor and p minor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.B ALANCING selection at a particular locus is expected to produce elevated levels of nucleotide diversity and linkage disequilibrium (LD) due to the partitioning of sequence variation between unusually long-lived allele classes (Hudson and Kaplan 1988;Charlesworth et al. 2003;Charlesworth 2006). Although elevated levels of nucleotide polymorphism at a particular gene may provide suggestive evidence for a history of balancing selection, conclusive inferences regarding the selective maintenance of allelic polymorphism ultimately require experimental evidence that the alternative alleles are functionally distinct. The well-characterized b-globin polymorphism in house mice (genus Mus) represents a system where it is possible to integrate evolutionary and functional approaches to evaluate the role of balancing selection in maintaining protein polymorphism.The two tandemly duplicated b-globin genes of house mice, HBB-T1 and HBB-T2, encode the b-chain subunits of adult hemoglobin (Hb) (Petras 1967; Selander et al. 1969a,b;Selander and Yang 1969;Berry and Murphy 1970;Wheeler and Selander 1972;Myers 1974;Berry and Jakobson 1975;Berry and Peters 1975, 1977Berry et al. 1978;Sage 1981;Petras and Topping 1983;Sage et al. 1986). This striking uniformity of two-locus haplotype frequencies has led a number of authors to conclude that the polymorphism may be maintained by some form of balancing selection Sequence data from this article have been deposited in GenBank under accession nos. GU057161-GU057256. (Hutton et al. 1962;Gilman 1972Gilman , 1974Whitney 1977 /Hbbp polymorphism we conducted a population genetic analysis of the HBB-T1 and HBB-T2 genes in a natural population of M. castaneus from northern India. In conjunction with this evolutionary analysis of sequence variation, we also conducted an experimental study of Hb function in inbred strains of mice that carry each of the alternative two-locus b-globin h...

Genetic differences in hemoglobin function between highland and lowland deer mice

“…These values are similar to those for other vertebrate Hbs (Antonini and Brunori, 1971;Weber, 1992;Hofmann et al, 1995) and are close to the Cl -concentration normally present in the vertebrate red blood cell (0.1moll -1 ). A relatively greater allosteric effect of Cl -ions than of DPG on Hb-O 2 affinity has also been reported for house mice Mus musculus (Runck et al, 2010), and may be a feature shared by other rodents. Larger allosteric effects of Cl -ions than of DPG have also been reported in select lineages of artiodactyls, carnivores, and prosimian primates which, unlike deer mice, possess Hbs with intrinsically low O 2 affinities (Bunn, 1971;Bunn et al, 1974).…”

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

“…In the presence of the physiological anionic effectors Cl -and DPG at pH7.4, Hb-O 2 affinities of the six sciurid species that we examined were appreciably higher than those of muroid rodents measured under identical experimental conditions. In the presence of allosteric effectors (DPG and Cl -), P 50 values for the sciurid Hbs ranged from 9.3 to 11.9Torr (where 1Torr≈133Pa), with thirteen-lined ground squirrel Hb from a single individual reaching 13.1Torr (Table1), whereas those for three species of house mice (Mus caroli, M. domesticus and M. musculus) ranged from 16.9 to 17.5Torr (Runck et al, 2010;Storz et al, 2012;) and those for deer mice (Peromyscus maniculatus) ranged from 11.7 to 15.8Torr (Storz et al, 2010a). Similarly, intrinsic Hb-O 2 affinities, as indexed by P 50 values for stripped hemolysates of the sciurids, ranged from 5.2 to 7.1Torr (Table1), whereas comparable measurements for house mice and deer mice were 7.6-8.8Torr (Storz et al, 2012) and 7.4-7.9Torr (Storz et al, 2010a), respectively.…”

Phenotypic plasticity in blood-oxygen transport in highland and lowland deer mice

“…However, given that the optimal blood-O 2 affinity is a non-linear function of ambient P O2 (Turek et al, 1973;Eaton et al, 1974;Bencowitz et al, 1982;Willford et al, 1982), empirical performance curves are needed to evaluate whether hypoxia-induced reductions in the DPG/Hb ratio are advantageous or disadvantageous at a given altitude. As changes in the DPG/Hb ratio also affect intracellular pH and Cl -concentration, and as the adult Hbs of deer mice and other muroid rodents have ligand affinities that are more strongly modulated by Cl -ions than by DPG (Storz et al, 2009;Storz et al, 2010a;Storz et al, 2012b;Runck et al, 2010), the net effects on blood-O 2 affinity are difficult to predict. Moreover, if deer mice have a hyperventilatory response to hypoxia, as in other mammals, the resultant increase in plasma pH (respiratory hypocapnia) may effectively counterbalance the inhibitory effects of DPG on Hb-O 2 affinity (Mairbäurl and Weber, 2012).…”