Tracking evolution of myoglobin stability in cetaceans using experimentally calibrated computational methods that account for generic protein relaxation

Abstract

The evolution of cetaceans (whales, dolphins, and porpoises) from land to water is one of the most spectacular events in mammal evolution. It has been suggested that selection for higher myoglobin stability (∆G of folding) allowed whales to conquer the deep-diving niche. The stability of multi-site protein variants, including ancient proteins, is however hard to describe theoretically. From a compilation of experimental ∆∆G vs. ∆G we first find that protein substitutions are subject to large generic protein relaxation effects. Using this discovery, we develop a simple two-parameter model that predicts multi-site ∆∆G as accurately as standard methods do for single-site mutations and reproduces trends in contemporary myoglobin stabilities. We then apply this new method to the study of the evolution of Mb stability in cetaceans: With both methods the main change in stability (about 1kcal/mol) occurred very early, and stability was later relaxed in dolphins and porpoises, but was further increased in the sperm whales. This suggests that single proteins can affect whole organism evolution and indicates a role of Mb stability in the evolution of cetaceans. Transition to the deep-diving niche probably occurred already in the ancestor of contemporary baleen and toothed whales. In summary, we have discovered generic stability relaxation effects in proteins that, when incorporated into a simple model, improves the description of multi-site protein variants.

Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

“…The summed of ∆∆G values was computed to be 9.0 and 5.1 kcal/mol for I-Mutant and Popmusic for the first branch towards Haplorhini, and 4.5 and 1.1 kcal/mol for the branch towards great apes. Note that these values are too large and upper bounds to the true stability effect, whereas the average values in Figure 4 are lower bounds, as explained recently [44]. Therefore, only the sign direction has been noted but the numerical change is more substantial (and thus significant) than shown in Figure 4.…”

“…Such "protein-explicit phylogeny" was previously applied to myoglobin of diving cetaceans [43] and involves mapping specific protein orthologs onto established species trees to deduce the ancestors of the evolved protein, enforced by the species phylogeny. Subsequently, the ancient proteins are studied to identify protein properties that have changed during evolution [43] [44]. This approach reveals insight into the molecular causes and types of recent selection pressure on genes.…”

Adaptive strategies of aquatic mammals: Exploring the role of the HIF pathway and hypoxia tolerance

“…Shifts in the distribution of selection pressure are often associated with large biological transitions, such as the transition from land to water, which can lead to phenotypic plasticity and adaptive changes ( Lahti et al , 2009 ). In the case of lipid metabolism gene CYP8B1 , for example, signs of relaxation of selection pressure were observed in the common ancestor of cetaceans ( Shinde et al , 2019 ), while the MB gene showed relaxation of constraints, reflected in the protein stability, in shallow-diving cetacean species ( Holm et al , 2016 ). The RAG1 gene also showed a relaxation of selective pressure in cetaceans ( Dias and Nery, 2020 ).…”

Not just fat: investigating the proteome of cetacean blubber tissue

“…This work is based on the notion that known proteins from other organisms can help to identify cetacean proteins by homology. While there may be subtle differences in both protein structure and function, cetacean myoglobin compared to myoglobin from terrestrial species for example ( Holm et al , 2016 ), it was assumed that the proteins within the tissue could be positively identified based on regions of sequence identity with known proteins from vertebrate species within the NCBI database. However, due to the adaptation of marine mammals to an aquatic environment, the potential for protein structural modification could be high for some proteins.…”