Abstract
Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a ∼10–20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity of Mbs is not significantly different among mammals (with typical oxygenation constants of ∼0.8–1.2 µM−1), folding stabilities of cetacean Mbs are ∼2–4 kcal/mol higher than for terrestrial Mbs. Using ancestral sequence reconstruction, maximum likelihood and Bayesian tests to describe the evolution of cetacean Mbs, and experimentally calibrated computation of stability effects of mutations, we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. Overall, these sites contribute to Mb stabilization with a conditional probability of 0.8. We observe a correlation between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected sites that occur later act against other destabilizing mutations to maintain stability across the clade, except for the shallow divers, where late stability relaxation occurs, probably due to the shorter aerobic dive limits of these species. The three main positively selected sites 66, 5, and 35 undergo changes that favor hydrophobic folding, structural integrity, and intra-helical hydrogen bonds.
Highlights
Upon adapting to the aquatic environment, marine mammals acquired features that improved their diving skills such as increased blood volume and hematocrit, efficient modes of locomotion [1,2] and,10–20 times higher myoglobin (Mb) concentration (CMb) in the skeletal muscles contributing substantially to total body oxygen stores and aerobic dive limits [3,4]
Using an integrated Krogh model of the muscle cell, models of convective oxygen transport and aerobic dive limit (ADL), and thermodynamics of O2-binding, we recently showed that wild-type (WT) Mb is more efficient than mutants under severely hypoxic conditions, whereas low-affinity mutants are better transporters at intermediate oxygen pressure [5]
Concluding remarks This work suggests that in an important real case of protein evolution, folding stability could be selected for in response to speciation in a new habitat: Our results suggest that the evolution of cetacean Mbs concurred with a divergence of one phenotype – stability – while oxygenation properties remained similar
Summary
Upon adapting to the aquatic environment, marine mammals acquired features that improved their diving skills such as increased blood volume and hematocrit, efficient modes of locomotion (stroke-and-glide swimming) [1,2] and ,10–20 times higher myoglobin (Mb) concentration (CMb) in the skeletal muscles contributing substantially to total body oxygen stores and aerobic dive limits [3,4]. Based on amino acid chemical properties and comparative studies of known Mb sequences, some form of selection has been suggested in the evolution of mammalian Mb to favor retention of the conformational structure [10]. It has been shown that variable sites in cetacean Mbs are fewer in number but more prone to change than primate Mbs suggesting a probable shift in the function of Mb in cetaceans [11]. It is still unclear what drives Mb evolution, as are the specific sites potentially under positive selection and the changes in phenotype they might introduce. The stability difference can reach up to ,4.5 kcal/mol when goose-beaked whale is compared to pig [16]
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