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: 9175447
• 负责人: Hunter B Fraser
• 金额: $ 33.45万
• 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/9175447
• 关键词: Accounting; 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; Housing; Human; Hybrids; Immune; Individual; Investigation; Lead; Life; Loss of Heterozygosity; Maps; Measures; Methods; Mitotic Recombination; Modeling; Molecular; Mutation; Natural Selections; Pathogenicity; Pathway interactions; Patients; Pattern; Peptide Sequence Determination; Phenotype; Population; Process; Proteins; Quantitative Trait Loci; Repression; Resistance; Role; Shapes; Site; Specific qualifier value; Technology; Testing; Toxin; UV response; Up-Regulation; Variant; Work; Yeasts; base; fitness; follow-up; gene discovery; genetic variant; genome editing; genome-wide; innovation; pathogen; promoter; protein complex; protein expression; 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 elements21-23; another fundamental question is whether adaptations typically involve single mutations of large effect, or many mutations of small effect23-24. 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”3,32. 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 resistance33, ergosterol biosynthesis13,40, and pathogenicity15. 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 pathways13 and protein complexes15; the first known cases of regulatory adaptations affecting behavior14 and pathogenicity15; and the first examples of polygenic gene expression adaptations of any kind in house mice14 and humans16. 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.

项目摘要 通过自然选择的适应是每个物种之间令人难以置信的拟合的过程 它的环境发展了。尽管它的重要性，但我们仍然对哪个 遗传变异在任何物种中都具有自适应性，以及这些变体在分子水平上的作用。 一个经典的问题是，大多数适应性是否涉及蛋白质序列的变化，或 监管元素21-23;另一个基本问题是改编是否通常涉及单一 大效应的突变或许多小作用的突变23-24。 从历史上看，大多数研究指出了多态性特征的遗传基础的研究都集中在 蛋白质序列的变化很大，因为这些效果是最简单的识别。然而 最近的工作表明，多基因顺式调节的适应实际上可能更为普遍。 不幸的是，由于很小，这些传统上几乎无法识别这些 每个变体对所选特征的个体效果。在过去的五年中，我们已经开发了 根据“符号的想法”从全基因组数据中找到这些多基因适应的方法 测试“ 3,32。目标是确定选择导致多个导致上调或下调的情况 通过独立突变基因。在酵母中使用此测试，我们已经鉴定了基因表达 毒素抗性33，麦角固醇生物合成13,40和致病性的适应性15。总体而言，我们的 符号测试的应用已经确定了涉及顺式调节的几百个基因 适应，包括基因表达适应的第一个例子，发生在 途径13和蛋白质复合物15;监管适应的第一个已知案例影响 行为14和致病性15;以及任何多基因表达适应的第一个例子 善良的房屋小鼠14和人类16。 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性 基于CRISPR/CAS9技术的工具将使CIS调节变体更加多 在广泛的物种中实用。其次，我们将开发用于高通量映射的方法 有助于适应性差异的基因，这是自然选择的关键表型。这个项目将 还为将来的投资奠定了基础，以对基因表达的进化方面 人类健康，例如基因表达如何在人类及其病原体中演变。