Yeast as a model for understanding gene expression adaptation

酵母作为理解基因表达适应的模型

• 批准号: 9353830
• 负责人: Hunter B Fraser
• 金额: $ 31.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-05 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353830
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Alleles; Amaze; Amino Acid Sequence; Amphotericin B; Anabolism; Antifungal Agents; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cells; Chromosome Mapping; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Data Set; Databases; Demography; Down-Regulation; Drug resistance; Emerging Communicable Diseases; Environment; Enzymes; Ergosterol; Evolution; Future; Gene Expression; Genes; Genetic; Genetic Drift; Genome Scan; Genotype; Goals; Health; Human; Hybrids; Immune; Individual; Investigation; Lead; Life; Loss of Heterozygosity; Measures; Methods; Mitotic Recombination; Modeling; Molecular; Mutation; Natural Selections; Pathogenicity; Pathway interactions; Patients; Pattern; Phenotype; Population; Process; Proteins; Quantitative Trait Loci; Repression; Resistance; Role; Shapes; Site; Specific qualifier value; Technology; Testing; Toxin; UV response; Variant; Work; Yeasts; base; darwinism; fitness; follow-up; gene discovery; genetic variant; genome-wide; innovation; pathogen; precise genome editing; promoter; protein complex; protein expression; rapid technique; species difference; tool; trait; transcription factor

Project Summary Adaptation via natural selection is the process by which the incredible fit between every species and its environment has evolved. Despite its importance, we still have little understanding of which genetic variants have been adaptive in any species, and how these variants act at the molecular level. One classic question is whether most adaptations involve changes in protein sequences, or in cis- regulatory elements; another fundamental question is whether adaptations typically involve single mutations of large effect, or many mutations of small effect. Historically, most studies pinpointing the genetic basis of polymorphic traits have focused on protein sequence changes of large effect, because these have been the simplest to identify. However recent work has suggested that polygenic cis-regulatory adaptations may actually be far more common. Unfortunately these have traditionally been almost impossible to identify, due to the very small individual effect of each variant on the selected trait. Over the past five years, we have developed a method to find these polygenic adaptations from genome-wide data, based on the idea of a “sign test”. The goal is to identify cases where selection has led to up- or down-regulation of multiple genes via independent mutations. Using this test in yeast, we have identified gene expression adaptations involving toxin resistance, ergosterol biosynthesis, and pathogenicity. Overall, our applications of the sign test have identified several hundred genes involved in cis-regulatory adaptations, including the first examples of gene expression adaptation occurring at the level of pathways and protein complexes; the first known cases of regulatory adaptations affecting behavior and pathogenicity; and the first examples of polygenic gene expression adaptations of any kind in house mice and humans. In this project we have two major goals. First, we will develop computational and experimental tools based on CRISPR/Cas9 technology that will make characterizing cis-regulatory variants far more practical in a wide range of species. Second, we will develop methods for high-throughput mapping of genes contributing to divergence in fitness, the key phenotype for natural selection. This project will also lay the groundwork for future investigations into facets of gene expression evolution important to human health, such as how gene expression evolves in both humans and their pathogens.

项目概要 通过自然选择的适应是每个物种之间令人难以置信的适应的过程 它的环境也发生了变化。尽管它很重要，但我们仍然对其知之甚少 遗传变异在任何物种中都具有适应性，以及这些变异如何在分子水平上发挥作用。 一个经典的问题是，大多数适应是否涉及蛋白质序列或顺式序列的变化。 监管要素；另一个基本问题是适应是否通常涉及单一 大影响的突变，或小影响的许多突变。 历史上，大多数查明多态性状遗传基础的研究都集中在 蛋白质序列的变化影响很大，因为这些是最容易识别的。然而 最近的研究表明，多基因顺式调节适应实际上可能更为常见。 不幸的是，由于它们非常小，传统上几乎不可能识别 每个变体对所选性状的个体影响。在过去的五年里，我们开发了 基于“标志”的思想，从全基因组数据中找到这些多基因适应的方法 测试”。目标是识别选择导致多种基因上调或下调的案例。 基因通过独立突变。通过在酵母中进行此测试，我们已经确定了基因表达 适应涉及毒素抗性、麦角甾醇生物合成和致病性。总体而言，我们的 符号测试的应用已经鉴定出数百个参与顺式调控的基因 适应，包括发生在水平上的基因表达适应的第一个例子 途径和蛋白质复合物；第一个已知的监管调整影响案例 行为和致病性；以及任何多基因基因表达适应的第一个例子 对家鼠和人类都有好处。 在这个项目中，我们有两个主要目标。首先，我们将开发计算和实验 基于 CRISPR/Cas9 技术的工具将使顺式调控变异的表征更加容易 适用于多种物种。其次，我们将开发高通量绘图方法 导致适应性差异的基因，这是自然选择的关键表型。该项目将 也为未来研究基因表达进化的重要方面奠定了基础 人类健康，例如人类及其病原体的基因表达如何进化。