Mechanisms of evolution by gene duplication: The origins of corticosteroid signaling

Gene duplication underlies the evolution of many protein functions and is a known stimulus for molecular innovation. Many models exist to explain the maintenance of duplicate genes in the genome and the dynamics that drive the evolution of novel protein functions; few if any of these models, however, incorporate knowledge of how protein structures and functions actually evolve. A growing body of work on the historical mechanisms of molecular evolution and the ways in which proteins evolve in the lab has provided profound insights into the ways in which proteins respond to mutation, selection, and drift. Evolutionary models of duplicate gene evolution could greatly benefit from the knowledge gained from these mechanistic studies of protein evolution.;My dissertation seeks to address this gap in knowledge by reconstructing the process by which novel steroid signaling pathways evolved after gene duplication. I focus specifically on a class of hormones called corticosteroids---critical regulators of the stress response, metabolism, and immunity---and the mineralocorticoid and glucocorticoid receptors that mediate the steroid response. Both the enzymes that synthesize corticosteroids and the hormone receptors are the result of ancient gene duplication events, and I make use of methods in phylogenetics, molecular biology, and structural biology to reconstruct the mechanisms and dynamics by which they evolved.;This dissertation comprises three separate but complementary studies that illuminate the origins of corticosteroid signaling. In the first project, I show how lineage-specific steroid signaling arose in elasmobranchs as a novel hormone exploited the structural promiscuity of preexistent receptors. Next, I describe how degenerative and stabilizing mutations defined the divergence of the glucocorticoid receptor after gene duplication. And finally, I use phylogenetic and functional analyses to reconstruct the origins of corticosteroid synthesis with the duplication of enzymes in the steroid synthesis pathway. Together, I provide a comprehensive reconstruction of the evolution of corticosteroid signaling. This work also highlights specific evolutionary mechanisms---molecular exploitation, structural and functional promiscuity, degenerative mutations, and stabilizing mutations---that could drive the evolution of novel protein functions after gene duplication.;This dissertation includes both previously published and unpublished co-authored materials.