OPUS: CRS Integrating data and theory to understand the evolution of gene expression

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Advances in biology are often the result of synthesizing findings from two different disciplines of research. This project combines 20 years of research in two areas: how genetic material is expressed to build organisms and how mutational changes in DNA sequence lead to changes in specific traits over time. The project combines data from experimental yeast populations measuring the effects of new mutations on gene expression with theory in evolutionary and quantitative genetics. The synthesis of this work will provide a more complete understanding of how differences in gene expression arise and persist over evolutionary time. This synthesis will be presented in a scholarly review paper expected to have a major influence on the field. It will also form the basis of a computational model that will enable new areas of interdisciplinary work. Finally, the importance of mutation as the origin of differences within and between species will be presented to the general public in an interactive museum exhibit developed in collaboration with the University of Michigan's Natural History Museum. Ultimately, this research provides insight into the general rules of life regarding how regulatory variation arises and persists, with potential insights into diverse problems in agriculture, medicine and other areas of societal interest. Gene expression is controlled by both cis- and trans-regulatory sequences. Variation in both types contributes to expression differences seen within and between species. As for all traits, this variation in gene expression reflects both the introduction of phenotypic variation by mutation (the "arrival of the fittest") as well as filtering of this variation by natural selection (the "survival of the fittest"). This project will take advantage of data produced by the laboratory's systematic study of properties of new regulatory mutations and comparisons with the properties of regulatory variants found in natural populations. These comparisons reveal both what can happen and what has happened in terms of regulatory evolution. More specifically, the relative frequency, effects, dominance, plasticity, gene-by-environment interactions, pleiotropy, and epistasis of cis- and trans-regulatory mutations affecting expression of a focal gene (the Saccharomyces cerevisiae TDH3 gene) have all been measured empirically. In addition, the fitness effects of changing TDH3 expression have also been determined in multiple environments, and cis- and trans-regulatory variation among strains of S. cerevisiae recently isolated from the wild have been characterized. Synthesizing these data and integrating them with evolutionary theory will result in a more complete picture of the evolutionary process than available for any other quantitative trait.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.