PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS

项目4-概要 环境-基因组相互作用 它所编码的基因组和分子电路并不是单独行动的，而是嵌入在一个相互作用的网络中 与环境因素和刺激，如营养素，激素，药物，毒素和其他化学物质 化合物.在这个项目中，我们将采用多方面的方法来系统地研究相互作用， 生物体和环境之间的关系，目的是开发基因-环境的大型地图 互动和分析这些地图，以利用基本原则和互动规则， 用于预测。我们将使用两种互补的网络映射方法， 另一种是基于高密度化学遗传学筛选平台。 该项目有三个具体目标。目的1是基于保护性突变模式的原则， 当基因组暴露于有毒的小分子生长抑制剂时， 用于同时探索蛋白质-蛋白质相互作用和研究生物体的基因组如何相互作用 在这种环境下。我们不使用代表整个基因组的敲除菌株系统， 当暴露于小分子时，将允许基因组自适应变化，然后对其进行分析 系统地在本试验中，将在酵母菌中检测总计60种药物。这些研究将反映在 一个单倍体人类细胞系，进行小规模的全基因组测序研究， 远离抗癌药物目标2将采用互补遗传图谱方法， 发展基因网络，提供对环境干扰的抵抗力。利用一个 新的高通量6144菌落筛选格式，我们将筛选125种化合物的库， 单倍体S.过表达或表达不足的完整基因的酿酒酵母菌株，模拟结构 暴露于环境毒素的基因组发生的变化。然后我们将测试其中的一个子集 人癌细胞中正向同源基因间的相互作用空间在第三个目标中，我们建议将 来自进化抗性（Aim 1）和全基因组的化学-遗传相互作用图 文库（目标2）与大量的各种各样的先验知识，以建立一个跨物种的药物基因模型 互动该模型的目标是学习如何从不同的基因中预测人类药物-基因相互作用。 信息包括药物基因相互作用在另一个物种的地图。 总的来说，这些目标将大大提高我们对全球基因网络的认识， 控制着细胞如何产生抗药性。这些努力是由两个系统中的先驱共同领导的 传染病生物学：伊丽莎白·温泽勒博士，她于2011年12月12日正式加入SDCSB教师队伍。 更新，和Sumit Chanda博士，目前SDCSB研究员。该项目利用酵母基因 Trey Ideker博士建立的筛选平台和计算分析专业知识，以及 两名SDCSB初级研究员Hannah Carter博士和Jason Kreisberg博士的参与。

PROJECT 4 – SUMMARY ENVIRONMENT-GENOME INTERACTIONS The genome and molecular circuitry it encodes do not act alone, but are embedded in a web of interactions with environmental factors and stimuli such as nutrients, hormones, drugs, toxins and other chemical compounds. In this project, we will apply a multifaceted approach to systematically study the interactions between the organism and the environment, with the aim of developing large maps of gene-environment interactions and analyzing these maps to exploit fundamental principles and rules of interaction that can be used predictively. We will use two complementary network mapping approaches, one based on sequencing of resistant isolates and another based on a high-density chemogenetic screening platform. The project has three Specific Aims. Aim 1 is based on the principle that patterns of protective mutations acquired within a genome, when the genome is exposed to a toxic small molecule growth inhibitor, can be used to simultaneously explore protein-protein interactions and study how the organism's genome interacts with this environment. Instead of using a system of knockout strains that represent the entire genome, we will allow the genome to adaptively change when exposed to a small molecule and then analyze it systematically. A total of 60 drugs will be tested in yeast in this assay. These studies will then be mirrored in a haploid human cell line, to perform small-scale whole genome sequencing studies of how human cells mutate away from cancer drugs. Aim 2 will employ a complementary genetic mapping approach to further develop networks of genes that provide resistance to environmental perturbagens. Taking advantage of a new high-throughput 6144 colony screening format, we will screen a library of 125 chemical compounds in haploid S. cerevisiae strains that over-express or under-express complete genes, modeling the structural changes that develop in genomes exposed to environmental toxins. We will then test a subset of this interaction space among orthologous genes in human cancer cells. In the third aim, we propose to integrate the chemical-genetic interaction maps derived from evolutionary resistance (Aim 1) and genome-wide libraries (Aim 2) with a vast assortment of prior knowledge to build a cross-species model of drug-gene interaction. The goal of this model will be to learn how to predict human drug-gene interactions from diverse information including maps of drug-gene interactions in another species. Collectively, these aims will significantly advance our knowledge of the global gene networks that govern how cells become resistant to drugs. These efforts are led jointly by two pioneers in the systems biology of infectious disease: Dr. Elizabeth Winzeler, who formally joins the SDCSB faculty as of this renewal, and Dr. Sumit Chanda, a current SDCSB investigator. The project leverages the yeast genetic screening platform and computational analysis expertise established by Dr. Trey Ideker, as well as involvement from two SDCSB junior investigators, Dr. Hannah Carter and Dr. Jason Kreisberg.