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

NSFDEB-BSF：合作研究：HIV 基因组中每个单一突变的适应成本

• 批准号: 1655211
• 负责人: Robert Shafer
• 金额: $ 8.67万
• 依托单位: Stanford 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 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1655211&HistoricalAwards=false
• 关键词: NSFDEB; BSF; Collaborative; Research; fitness

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.

该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。他们的目标是利用新的实验室技术和新的统计方法确定人类免疫缺陷病毒（HIV）基因组中所有可能突变的适应成本。突变是遗传变异的最终来源，也是进化的燃料。但特定突变是否持续存在并导致种群内的变异取决于其适应度成本。与适应度成本低或没有适应度成本的突变相比，适应度成本高的突变很可能会从群体中被消除。突变适应性的知识是进化生物学中许多基本问题的核心，但也具有重要的实际应用，例如，用于预测抗生素、抗病毒药物和杀虫剂耐药性的进化。尽管如此重要，估计适应度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来自 75 名 HIV B 亚型和 C 亚型患者的临床样本。由此产生的数据最终将使他们能够推断出艾滋病毒基因组中每个单点突变的适应成本。该项目包括为 STEM 领域代表性不足群体的本科生提供强化指导和研究机会。这些学生还将获得国际经验。将开发一门关于向公众传播科学的新研究生课程。公众宣传将通过视频、公开讲座和参观当地学校进行。 HIV是研究体内健康成本的理想模型系统：遗传多样性在每个宿主中快速积累，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成本。研究人员有三个主要目标。 1) 开发从突变频率推断适应度成本的统计方法。 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) 推断全球最流行的两种亚型 HIV-1 B 和 C 亚型的高分辨率健身成本图，并量化与环境相关的健身效果。实现这些目标将导致基因组适应性成本的首次完整体内分布。这些创新方法的开发也将推广到任何存在独立群体下一代测序（NGS）数据的系统。该奖项由国际科学与工程办公室共同资助。

项目成果

Analysis of unusual and signature APOBEC-mutations in HIV-1 pol next-generation sequences

HIV-1 pol 下一代序列中异常和特征性 APOBEC 突变的分析

• DOI: 10.1371/journal.pone.0225352
• 发表时间: 2020
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Tzou, Philip L.;Kosakovsky Pond, Sergei L.;Avila-Rios, Santiago;Holmes, Susan P.;Kantor, Rami;Shafer, Robert W.
• 通讯作者: Shafer, Robert W.