Evolution of regulatory sequences and systems

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“We propose that evolutionary change in regulatory systems accounts for evolution at and beyond the anatomical level”--Wilson et al. Proc. Nat. Acad. Sci. USA, July 1974Increasing understanding of the mechanisms of development and physiology and, more recently, the identification of specific regulatory changes that are associated with phenotypic differences between species has provided detailed support for Wilson et al.'s proposal. However, since many phenotypes are determined by groups of genes organized in regulatory networks and signaling pathways, we must consider how changes in genes and regulatory sequences affect function in context. Functional genomic technologies have begun to allow systematic characterization of the evolution of regulatory mechanisms and have identified thousands of potential regulatory changes. It is yet unknown which (of any) of these were the result of natural selection, or neutral changes fixed by genetic drift. My research program addresses challenges in two major areas:First, we apply novel and existing statistical methods to functional genomics data to study evolution of regulatory systems at the transcriptional and posttranslational levels. Among the thousands of putative changes in transcription factor binding or post-translational modification sites identified in high-throughput molecular experiments, we aim to identify which (if any) of these changes are the results of natural selection. In this proposal we aim to apply ideas from quantitative genetics to regulatory system evolution.Second, we test hypotheses about regulatory system evolution in the lab directly using budding yeast as a model organism, for which we can combine genetic engineering and quantitative fitness measurements. These experiments allow us to go beyond inference to empirically test models of how evolution actually happens. In this proposal we aim to test the effects of spontaneous mutations and artificial selection on signaling pathways, and study the evolution of pulsing in the calcium signaling pathway.This research will address basic questions about the evolutionary forces that cause changes in regulatory sequences and systems, and how these molecular changes affect the cellular processes that regulatory systems control. Understanding the mechanisms of evolution helps us explain how the diversity of living things arises. The tools and techniques in my lab are interdisciplinary: we will employ classical methods from molecular evolution including comparative sequence analysis, population genetics modeling and tests for selection, as well as systems biology regulatory network simulations, and molecular biology experiments in budding yeast, such as site-specific mutagenesis and fluorescence-based fitness assays.