Patterns of Adaptive Evolution

适应性进化的模式

• 批准号: 9883006
• 负责人: Craig R Miller
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883006
• 关键词: Address; Affect; Amino Acid Sequence; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Back; Bacteriophages; Bioinformatics; Biological Models; Cell Culture Techniques; Codon Nucleotides; Communicable Diseases; Consumption; Disease Outbreaks; Engineering; Epidemic; Evolution; Future; Generations; Genes; Genome; Goals; Human; Immunization; Individual; Knowledge; Libraries; Measures; Methods; Modeling; Mus; Mutation; Nigeria; Oral Poliovirus Vaccine; Pathogenicity; Pathway interactions; Pattern; Poliomyelitis; Population; Population Sizes; Property; Recovery; Research; Russia; System; Testing; Time; Transcript; Translations; Vaccine Design; Vaccines; Variant; Viral; Viral Genes; Viral Genome; Viral Proteins; Virulence; Virus; attenuation; base; design; fight against; fighting; pathogen; prevent; rapid technique; skills; stem; success; tool; vaccine development; vaccine response

Project Summary/Abstract Vaccines are a remarkably effective way to stem the threat posed by infectious diseases. Methods that allow rapid development of vaccines are vital. Synonymous recoding of viral genomes is a recently developed, general, and highly promising strategy for producing live attenuated vaccines. From an antigenic perspective, the method is ideal because it leaves the amino acid sequence of the viral proteins identical to the circulating pathogenic form. A number of viruses have been attenuated by recoding with non-preferred codons or codon pairs, and at least eight studies have shown protective immunization of mice. Despite its demonstrated success, there are fundamental gaps in our knowledge: 1) no effort has been made to compare alternative recoding strategies within the same virus in the same study; 2) several potential methods of synonymous recoding have not been tested at all; 3) the way in which attenuation is affected by the combination of multiple recoded genes is not known; and 4) most importantly, it is unresolved whether viruses attenuated by synonymous recoding are robust to evolutionary recovery. This proposal tackles these gaps through three Specific Aims. Aim 1: Identify methods of synonymous recoding and associated sequence features that can be used to generate viral genomes with a targeted level of attenuation. This aim includes developing empirical measures of individual codon and codon pair effects on translation rate to guide attenuation. It will also test metrics that have not previously been used for synonymous recoding. Aim 2: Extend models of adaptive evolution to determine if the attenuating effects, within and among genes and transcripts, combine in additive or non-additive ways. Aim 3: Determine if some strategies of attenuation are more robust to recovery than others. This aim will focus on viruses attenuated in multiple regions and by multiple methods, and also determine if some recovery pathways are broadly beneficial. The project takes advantage of a bacteriophage model system with well-developed tools for genome manipulation and methods for rapid experimental evolution relative to eukaryotic viral systems (i.e., a hundred generations per day at very large population sizes). Achieving these three aims will yield approaches that can be applied to other systems for designing viruses with targeted levels of attenuation that are robust to evolutionary recovery. This research is a critical step toward the long-term goal of achieving a general strategy for fighting infectious diseases by precision design of live vaccines that do not re-evolve virulence when used in humans.

项目摘要/摘要 疫苗是阻止传染病造成的威胁的一种非常有效的方法。允许的方法 疫苗的快速开发至关重要。病毒基因组的同义重现是一个最近开发的，一般的， 以及生产活衰减疫苗的高度有希望的策略。从抗原的角度来看 是理想的，因为它留下了与循环致病性相同的病毒蛋白的氨基酸序列 形式。通过使用非脱脱二密码子或密码子对进行重新编码，已减弱了许多病毒，在 至少八项研究表明，小鼠的保护性免疫。尽管取得了成功，但仍有 在我们的知识上的基本差距：1）没有努力比较替代策略 在同一研究中的同一病毒中； 2）几种潜在的同义重新编码方法尚未 完全测试； 3）由多个重新编码基因组合影响衰减的方式不是 已知4）最重要的是，尚未解决是否通过同义重新编码减弱的病毒 进化恢复。该提议通过三个特定目标解决了这些差距。目标1：确定方法 具有代名词和相关的序列特征，可用于生成具有A的病毒基因组 目标衰减水平。该目标包括制定单个密码子和密码子的经验措施 对翻译率的成对影响指导衰减。它还将测试以前尚未使用的指标 用于同义重新编码。 AIM 2：扩展自适应演化模型，以确定是否衰减效应， 在基因和成绩单之内，以添加剂或非添加方式结合。目标3：确定是否有些 衰减的策略比其他人更强大。这个目标将重点放在衰减的病毒上 多个区域和多种方法，还确定某些恢复途径是否具有广泛的有益。 该项目利用了具有完善的基因组工具的噬菌体模型系统 相对于真核病毒系统的快速实验进化的操纵和方法（即一百个 每天几代人的人口大小）。实现这三个目标将产生可以 应用于其他系统，用于设计具有靶向衰减水平的病毒 进化恢复。这项研究是朝着实现一般战略的长期目标迈出的关键一步 通过精确设计现场疫苗的精确设计，这些疫苗在使用时不会再出现毒力 人类。