Research

My lab studies multiple molecular networks including those involved in mitochondria, but currently the most prominent focus is on the Insulin/Insulin-like Signaling (IIS) network. The IIS network is a collection of hormones, receptors, and intracellular signaling proteins that regulates many aspects of life-history — reproduction, growth, stress response and aging — that vary across natural population of animals and across species. Comparative analyses of IIS have been largely been limited to invertebrates and mammals. Our initial work on this network identified that one of the key hormones regulating this network (IGF1) was evolving rapidly in reptiles. In collaboration with a team of researchers we conduct an extensive evolutionary analysis of the IIS network across 66 amniotes, including 18 RNA-seq transcriptomes from non-avian reptiles that we generated (McGaugh et al 2015). We uncovered rapid and extensive molecular evolution such that (i) the IIS network exhibited divergent evolutionary rates between reptiles and mammals, with reptiles generally having faster evolutionary rates; and (ii) positive selection IIS receptors and hormones has shaped the extracellular network in reptile- and mammal-specific manner. With this study, we have exposed vast variation in the IIS network within and among amniotes. This provides a critical step to unlocking information that this signaling network may contain about vertebrate patterns of genetic regulation of metabolism, modes of reproduction, and rates of aging. The three projects below approach the understanding of this network from different angles. The first two use naturally occurring instances of the repeated evolution of traits across species.

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(i) The Functional Consequences of Divergent Selection on the IIS network among Anolis Lizards. Anolis lizards vary in the amino acid sequence of the IIS hormones, and previous work has demonstrated positive selection on the hormones and their receptors. We (PhD students Abby Beatty and Amanda Clark, and undergraduates Shawn Yates and Hannah Marshall) are exploring this sequence diversity of the hormones and the receptors through sequencing of the genes within and across anolis lizard species. To understand the functional consequences of the amino acid changes we are cloning, expressing and purifying the IGF hormones from different anolis species. We are use these purified hormones for comparative experiments in a captive colony of wild-caught lizards and in their cell cultures to determine the functional roles of the observed amino acid substitutions in binding the receptors and the consequences on cellular and organismal growth.

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(ii) The Role of the IIS network in the Repeated Evolution of Dwarfism in Reptiles on Islands.

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(iii) The Repeated Evolution of Placental Structures Across Reptile Species.

The placenta and live-birth are key traits associated with mammals. Less well known are the placental structures that have evolved independently hundreds of times in snake and lizard species. Beautiful work has elucidated the co-option of key elements of the IIS genetic network in the evolution of the placenta through the mammalian lineage. Because of its conserved role in growth and reproduction we would expect this network would be a target of selection in the repeated evolution of placental structures in reptiles. We (MS student Aundrea Westfall, AU collaborator Dr. Jamie Oaks) are using genomic techniques to test if genetic variants in the IIS network are associated with the repeated evolution of placental structures. Future work will involve comparative analysis of gene expression among reptile species and mammals to examine regulation of the IIS network during pregnancy and in facilitating the evolution of live birth. This work will bring new insights into the extent of variation in IIS network across a large group of species, and the different ways selection can manipulate this network.

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