Mechanism and explanation in molecular evolution: reconstructing the biochemical histories of a transcription factor family

17 November 2017

Joe Thornton
Departments of Human Genetics & Ecology and Evolution
University of Chicago


More than a half-century ago, Ernst Mayr justified the separation of evolutionary and molecular biology/biochemistry by ascribing to each field a unique mode of scientific explanation: molecular mechanisms provide the proximate explanations of biological systems – how they work – whereas evolutionary mechanisms represent ultimate explanations, revealing why those systems work as they do. Now is a good time for us to shed this way of thinking, because it is conceptually unsound, scientifically limiting, and unnecessary in practice: indeed, we can now productively explore a large research territory that Mayr's duality concealed at the direct interface of evolutionary and molecular biology. I will illustrate the necessity and potential of work at this interface by discussing my lab's work to explicitly trace the molecular history of the steroid hormone receptors, a biologically essential family of ligand-activated transcription factors. By reconstructing, genetically manipulating, and experimentally characterizing ancient proteins, we have shown how specific ancient changes in amino acid sequence altered protein structure and, in turn, modified biological function – namely, specificity for different ligands and DNA binding sites. We have also used deep mutational scanning to examine alternative histories that could have occurred, but did not. This approach has illuminated fundamental questions about evolutionary processes, revealed how the physical architecture of the protein shaped its evolutionary trajectory, identified sequence-structure-function determinants that drive the behavior of present-day steroid hormone receptors, and explained why these proteins have these properties. I will discuss the limitations of this approach and the conceptual implications for the various disciplines of studying biological systems by probing their molecular mechanisms' histories.

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