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NSFDEB-BSF: Collaborative Research: RUI: The fitness cost of every single mutation in the HIV genome

NSFDEB-BSF：合作研究：RUI：HIV 基因组中每个单一突变的适应成本

基本信息

批准号：
1655212
负责人：
Pleuni Pennings
金额：
$ 61.23万
依托单位：
San Francisco State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1655212&HistoricalAwards=false
关键词：
NSFDEB BSF Collaborative Research RUI

项目摘要

This collaborative project involves two early career female researchers, one from the U.S. and the other from Israel. Their goal is to determine the fitness cost of all possible mutations in the human immunodeficiency virus (HIV) genome using new laboratory techniques and new statistical methods. Mutations are the ultimate source of genetic variation and the fuel of evolution. But whether a particular mutation persists and contributes to variation within a population is determined by its fitness cost. Mutations with high fitness costs will likely be eliminated from the population versus those with little or no fitness costs. Knowledge of mutational fitness is central to many basic questions in evolutionary biology, but also has critical practical application, for example, for predicting evolution of resistance to antibiotics, antiviral drugs, and pesticides. Despite this importance, estimating fitness costs remains one of the key challenges in modern evolutionary genomics. The researchers will analyze clinical samples from a combination of 75 HIV subtype B and subtype C patients using innovative genomic and computational methods. Resulting data will ultimately allow them to infer the fitness cost of every single point mutation in the HIV genome. The project includes intensive mentoring and research opportunities for undergraduate students from underrepresented groups in STEM fields. These students will also gain international experiences. A new graduate level course on communicating science to the public will be developed. Public outreach will occur via videos, public lectures, and visits to local schools. HIV is an ideal model system for studying in vivo fitness costs: Genetic diversity accumulates quickly in every host, and samples from different patients can be treated as independent replicate populations. Fitness costs can then be inferred by using the theory of mutation-selection balance and averaging mutation frequencies across patients. The researchers have three primary objectives. 1) Develop statistical methods for inferring fitness costs from mutation frequencies. 2) Develop highly accurate next generation sequencing approaches for low biomass samples, and use these to sequence HIV from patient samples and infer mutation frequencies. 3) Infer high-resolution maps of fitness costs in HIV-1 subtypes B and C, the two most prevalent subtypes across the globe, and quantify context-dependent fitness effects. Accomplishing these objectives will lead to the first complete in vivo distribution of fitness costs for a genome. Development of these innovative methods will also be generalizable to any system for which next generation sequencing (NGS) data exist for independent populations. This award is co-funded by the Office of International Science and Engineering.

这个合作项目涉及两名早期职业女性研究人员，一名来自美国，另一名来自以色列。他们的目标是使用新的实验室技术和新的统计方法来确定人类免疫缺陷病毒（HIV）基因组中所有可能突变的适应性成本。突变是遗传变异的最终来源，也是进化的燃料。但是，一个特定的突变是否持续存在并导致种群内的变异，取决于它的适应度成本。具有高适应性成本的突变可能会从群体中被淘汰，而那些具有很少或没有适应性成本的突变则会被淘汰。突变适应度的知识是进化生物学中许多基本问题的核心，但也有关键的实际应用，例如，用于预测对抗生素，抗病毒药物和杀虫剂的抗性的进化。尽管如此重要，估计健身成本仍然是现代进化基因组学的关键挑战之一。研究人员将使用创新的基因组和计算方法分析75名HIV亚型B和亚型C患者的临床样本。由此产生的数据最终将使他们能够推断出HIV基因组中每个点突变的适应性成本。该项目包括为来自STEM领域代表性不足的群体的本科生提供密集的指导和研究机会。这些学生也将获得国际经验。将开发一个关于向公众传播科学的新的研究生课程。公共宣传将通过视频，公开讲座和访问当地学校进行。HIV是研究体内适应性成本的理想模型系统：遗传多样性在每个宿主中迅速积累，来自不同患者的样本可以被视为独立的复制群体。然后可以通过使用突变选择平衡理论和平均患者的突变频率来推断适应性成本。研究人员有三个主要目标。1)开发统计方法，从突变频率推断适应性成本。2)为低生物量样本开发高度准确的下一代测序方法，并使用这些方法对患者样本中的HIV进行测序并推断突变频率。3)推断HIV-1亚型B和C（地球仪上最流行的两种亚型）的适应性成本的高分辨率地图，并量化环境依赖的适应性效应。实现这些目标将导致第一个完整的体内分布的基因组的健身成本。这些创新方法的开发也将推广到任何系统，其中存在独立群体的下一代测序（NGS）数据。该奖项由国际科学与工程办公室共同资助。