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

生物学的进步往往是两个不同学科研究成果综合的结果。该项目结合了20年来在两个领域的研究：遗传物质如何表达以构建生物体，以及DNA序列的突变变化如何随着时间的推移导致特定特征的变化。该项目将来自实验酵母种群的数据与进化和数量遗传学的理论结合起来，测量新突变对基因表达的影响。这项工作的综合将提供一个更完整的理解基因表达差异是如何产生并随着进化时间的推移而持续存在的。这一综述将在一篇学术评论论文中发表，预计将对该领域产生重大影响。它还将构成一个计算模型的基础，该模型将使跨学科工作的新领域成为可能。最后，突变作为物种内部和物种之间差异的起源的重要性将在与密歇根大学自然历史博物馆合作开发的互动博物馆展览中向公众展示。最终，这项研究提供了对有关监管差异如何产生和持续的一般生活规则的洞察，并对农业、医药和其他社会利益领域的各种问题提供了潜在的洞察。基因表达受顺式和反式调控序列的共同控制。这两种类型的差异导致了物种内和物种之间的表达差异。至于所有性状，基因表达的这种变化既反映了通过突变引入的表型变化(“适者生存”)，也反映了通过自然选择(“适者生存”)对这种变化的过滤。该项目将利用实验室对新的调控突变的性质进行系统研究并与在自然种群中发现的调控变异的性质进行比较所产生的数据。这些比较既揭示了监管演变方面可能发生的事情，也揭示了已经发生的事情。更具体地说，影响局部基因(酿酒酵母TDH3基因)表达的顺式和反式调控突变的相对频率、效应、显性、可塑性、基因与环境的相互作用、多效性和上位性都已经被经验地测量过。此外，改变TDH3表达的适合度效应也在多个环境中被确定，并且最近从野外分离的酿酒酵母菌株之间的顺式和反式调节变异已经被表征。综合这些数据并将它们与进化理论相结合，将产生比任何其他定量试验更完整的进化过程图景。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.