Molecular Constraints and Predictability in the Convergent Evolution of Toxin Resistance

When species face new environmental challenges – habitat shifts, novel predators, or toxic prey – many evolve remarkably similar solutions. This pattern, called convergent evolution, has long been recognised in analogous phenotypic traits across unrelated species. The molecular era has revealed the mechanism: identical genetic changes emerging independently across different lineages. But these repeat outcomes are not universal. Other species, facing the same pressures, take different evolutionary paths – or fail to adapt. Why does evolution repeat in some cases, but not others?
Our central idea is that the repeatability of evolution, particularly convergent genetic change, is shaped not only by natural selection but also by biological constraints rooted in protein structure and evolutionary history. A mutation beneficial in one species might be ineffective or even harmful in another, depending on the molecular context of that species’ biology. A species’ evolutionary history can limit its future: once certain paths are taken, others may be closed off. Our project reframes adaptive evolution as a systems-level process shaped by interactions between ecological pressures, protein architecture, and evolutionary legacy, with real consequences for predicting how species adapt to changing environments.
We will test this paradigm through a global-scale study of resistance to cardiotonic steroids (CTSs) – natural toxins that, when consumed, disable a vital cellular pump (Na,K-ATPase). CTS resistance has evolved repeatedly across animals, through amino acid changes at two sites in the protein. Our foundational research, built on eight years of evolutionary and functional analyses, shows that these same changes do not always yield resistance. In some reptiles and mammals, mutations impair ATPase function rather than confer resistance. This variation in outcome challenges the classic view of convergence as a predictable outcome of selection, emphasising how molecular...