Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

Background. Elevated blood O₂affinity enhances survival at low O₂pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O₂affinity of the hemoglobin (Hb) molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG), or by suppressing the sensitivity of Hb to these physiological cofactors. Results. Here we report that strictly fossorial eastern moles (Scalopus aquaticus) have evolved a low O ₂affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the -type -globin chain (136GlyGlu) of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with 82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl^-, lactate and DPG (the latter of which is virtually absent from the red cells of this species) at 82Lys, thereby markedly reducing competition for carbamate formation (CO₂binding) at the -chain N-termini. Conclusions. We propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO ₂carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation.