Experimental Models of Viral Genome Evolution

病毒基因组进化的实验模型

• 批准号: 6622157
• 负责人: JAMES J BULL
• 金额: $ 20.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622157
• 关键词: bacteriophage T7; chromosome aberrations; environmental adaptation; evolution; gene deletion mutation; gene rearrangement; genetic mapping; genetic regulation; molecular biology; nucleic acid sequence; polymerase chain reaction; population genetics; site directed mutagenesis; virus genetics

DESCRIPTION (provided by applicant): An experimental system is proposed for studying viral evolution in response to major changes in its genome: deletions, gene rearrangements, gene additions, and wholesale changes in regulation. Many of these genome changes will cause major drops in viral fitness. Can these modified viruses evolve back to high fitness, just as viruses have been extremely versatile in evolving resistance to drugs? The work will use the bacteriophage T7, which is amenable to a wide scope of genomic alterations and for which the supporting molecular genetics and biochemistry is extensive enough to develop a predictive framework for evolution and to interpret the evolutionary mechanisms. The three specific aims are: 1) Characterize regulatory evolution in viruses with modified, complete genomes; 2) Determine whether viruses with engineered deletions can evolve to recover original fitness levels; 3) Observe the evolution of viral genomes with new genes. Genome alterations will be performed, the altered viruses will be grown extensively to allow improvement through evolution, and the evolved genomes will be analyzed by sequencing, mapping beneficial changes, and site-directed mutation to test the effects of different mutations. The combined studies will yield an understanding of the mechanisms by which viral genomes evolve and maintain high fitness across a variety of genome modifications. The work developed here will have relevance to the development of live, attenuated vaccines, the improvement of phages as antibacterial agents (phage therapy), and to assess the long-term consequences of any viruses engineered to perform specific functions.

描述（由申请人提供）：提出了一个实验系统 研究病毒进化以响应其基因组的重大变化：删除， 基因重排、基因添加和调控的大规模变化。许多 这些基因组变化将导致病毒适应性大幅下降。这些可以吗 修改后的病毒进化回高度适应性，就像病毒一样 在不断发展的药物耐药性方面是否具有广泛的用途？该作品将使用 噬菌体 T7，可进行广泛的基因组改变， 其支持分子遗传学和生物化学是广泛的 足以开发进化的预测框架并解释 进化机制。这三个具体目标是： 1) 表征 具有修饰的完整基因组的病毒的调控进化； 2）确定 带有工程删除的病毒是否可以进化以恢复原始状态 健身水平； 3）观察带有新基因的病毒基因组的进化。 将进行基因组改变，改变的病毒将被生长 广泛地允许通过进化和进化的基因组进行改进 将通过测序、绘制有益变化和定点分析来分析 突变来测试不同突变的效果。合并研究将 了解病毒基因组进化的机制 在各种基因组修饰中保持高适应性。工作 这里开发的将与活的、减毒的开发相关 疫苗、噬菌体作为抗菌剂的改进（噬菌体疗法）、 并评估任何被设计用于执行任务的病毒的长期后果 具体功能。