Contrasting biotic and abiotic drivers of adaptive evolution in a host-pathogen conflict

宿主与病原体冲突中适应性进化的生物和非生物驱动因素对比

• 批准号: 10230445
• 负责人: Michelle Hays
• 金额: $ 6.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230445
• 关键词: Address; Affect; Alleles; Biological; Biological Models; Capsid; Cells; Communicable Diseases; Communities; Complex; Conflict (Psychology); Data; Disease; Dissection; Double Stranded RNA Virus; Elements; Environment; Eukaryota; Evolution; Experimental Designs; Foundations; Generations; Genes; Genetic; Genome; Genomics; Genotype; Health; Host Defense; Host resistance; Human; Human Genome; Immunity; Killer Cells; Learning; Life; Maintenance; Malignant Neoplasms; Metabolic; Microbe; Modeling; Molecular; Mutation; Natural Immunity; Organism; Other Genetics; Outcome; Parasites; Phenotype; Plasmids; Polymerase; Population; Prevalence; Process; Production; Proteins; RNA Viruses; Race; Recurrence; Research; Research Proposals; Resistance; Route; Saccharomyces cerevisiae; Saccharomycetales; Seeds; Selfish Genes; Shapes; Structure; System; Testing; Therapeutic; Time; Toxic Environmental Substances; Toxin; Viral; Viral Genome; Virus; Work; Yeasts; acquired immunity; addiction; alpha Toxin; antitoxin; arm; cancer cell; cell killing; cost; experimental study; fitness; genetic variant; human microbiota; innovation; killer factor; novel; parasitism; pathogen; pressure; theories; tool; virus genetics

Project Summary/Abstract To be successful, organisms must adapt to both abiotic (e.g. environmental pressures) as well as biotic (e.g. parasites) selection pressures. Although both of these pressures can drive evolutionary innovation, theory predicts that antagonistic relationships may drive recurrent episodes of adaptation. Dissecting these selective pressures has implications for understanding treatment of both human infectious disease and cancers, where both pathogens and clonally dividing malignant cells are adapting to both host immunity (biotic) and environmental (abiotic) therapeutics. Additionally, the human microbiota is a complex and dynamic community containing competing microbes in the context of both host immunity and gut environment. These complex co- evolution scenarios are challenging to study and disentangling the respective contributions of various selective pressures and fitness tradeoffs can be confounding. I propose to use RNA viruses of yeast as a model system to study the evolutionary consequences of both abiotic and biotic selective pressures of genome evolution in the presence of genetic conflict. RNA viruses of yeasts encode a “Killer” toxin-antitoxin addiction system, which protects virus-bearing Killer cells but kills virus-lacking sensitive cells. As a result, these RNA viruses can be maintained in host populations despite imposing a metabolic cost to their host. In my research proposal, I will study adaptation in the face of both abiotic (toxin) and biotic (virus) selective pressures. Killer itself requires multiple viral genomes for toxin production as well as host cellular components. With sensitive cells in the environment, this system is a four-party genetic conflict, with competing fitness tradeoffs. In spite of this complexity, budding yeast is one of the best-supported model eukaryote systems with many genetic and molecular tools. This makes this model system supremely experimentally tractable, even while maintaining the biological complexity of a naturally occurring system. I will identify beneficial mutations that arise in populations of competing killer and sensitive cells (Aim 1), in sensitive cells that evolve resistance to toxins in the absence of virus (Aim 2), and determine which genomes adapt to regain competitive fitness in a molecular arms race (Aim 3). Together, these aims will uncover how intricate biotic systems co-evolve and constrain one another and reveal the evolutionary dynamics imposed by antagonistic coevolution, versus abiotic adaptation. Understanding how genomes evolve, and specifically how genetic conflict (antagonistic co-evolution) drives adaptation, is fundamental for understanding and treating many processes that shape and drive disease. By exploring host-parasite coevolution from first principles, we can develop a foundation towards understanding the impact of these processes on human health and disease. This proposed work will benefit many fields by experimentally addressing fundamental questions about how biotic and abiotic selection drives and constrains evolutionary outcomes.

项目概要/摘要 为了成功，生物体必须适应非生物（例如环境压力）和生物 （例如寄生虫）选择压力虽然这两种压力都可以推动进化创新，但理论。 预测对抗关系可能会导致反复出现的选择性适应。 压力对于理解人类传染病和癌症的治疗具有影响，其中 病原体和克隆分裂的恶性细胞都在适应宿主免疫（生物）和 此外，人类微生物群是一个复杂且动态的群落。 在宿主免疫和肠道环境中含有竞争性微生物。 进化情景的研究和理清各种选择性的各自贡献具有挑战性 我建议使用酵母 RNA 病毒作为模型系统。 研究基因组进化的非生物和生物选择压力的进化后果 酵母RNA病毒的遗传冲突编码了一种“杀手”毒素-抗毒素成瘾系统。 保护携带病毒的杀伤细胞，但杀死缺乏病毒的敏感细胞。因此，这些 RNA 病毒可以被杀死。 尽管给宿主带来了代谢成本，但在我的研究提案中，我将维持在宿主群体中。 研究杀手本身面对非生物（毒素）和生物（病毒）选择性压力时的适应。 需要多个病毒基因组来产生毒素以及宿主细胞成分。 尽管与环境有关，但该系统是一个四方遗传冲突，具有相互竞争的适应性权衡。 由于复杂性，芽殖酵母是支持最好的真核生物模型系统之一，具有许多遗传和 这使得该模型系统在实验上极其容易处理，即使在保持 自然发生系统的生物复杂性。 我将识别竞争性杀伤细胞和敏感细胞群体中出现的有益突变（目标 1），在没有病毒的情况下进化出对毒素的抵抗力的敏感细胞（目标2），并确定哪些 基因组适应以在分子军备竞赛中恢复竞争能力（目标 3）。 揭示复杂的生物系统如何共同进化和相互制约，并揭示进化过程 对抗性共同进化所施加的动力学，与了解基因组如何适应。 进化，特别是遗传冲突（对抗性共同进化）如何驱动适应，是生物进化的基础。 通过探索宿主寄生虫来了解和治疗许多形成和驱动疾病的过程。 从第一原理开始共同进化，我们可以为理解这些影响奠定基础 这项拟议的工作将通过实验使许多领域受益。 解决有关生物和非生物选择如何驱动和限制进化的基本问题 结果。