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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

基本信息

批准号：
10361186
负责人：
Michelle Hays
金额：
$ 3.23万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361186
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 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 antagonist antitoxin arms race cancer cell cell killing cost experimental study fitness genetic variant human microbiota innovation killer factor novel parasitism pathogen pressure theories tool virus genetics

项目摘要

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.

项目总结/摘要为了取得成功，生物体必须适应非生物（例如环境压力）和生物 (e.g.寄生虫）选择压力。尽管这两种压力都能推动进化式创新，预测对抗关系可能会导致适应的反复发生。解剖这些选择性的压力对理解人类传染病和癌症的治疗都有影响，病原体和克隆分裂的恶性细胞都适应宿主免疫（生物）和环境（非生物）疗法。此外，人体微生物群是一个复杂而动态的社区。在宿主免疫和肠道环境的背景下含有竞争微生物。这些复杂的共同- 进化情景是具有挑战性的研究和解开各自的贡献，各种选择性的压力和健康的权衡可能是令人困惑的。我建议使用酵母的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，基因冲突的存在。酵母RNA病毒编码一种“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病毒可以维持在宿主种群中，尽管对它们的宿主施加代谢成本。在我的研究计划中，我将研究面对非生物（毒素）和生物（病毒）选择压力的适应性。凶手本身需要多个病毒基因组用于毒素生产以及宿主细胞组分。敏感细胞在环境，这个系统是一个四方的遗传冲突，与竞争的健身权衡。尽管如此复杂性，芽殖酵母是最受支持的模型真核生物系统之一，具有许多遗传和分子工具这使得该模型系统在实验上非常容易处理，即使在保持自然发生系统的生物复杂性。我将确定在竞争性杀伤细胞和敏感细胞群体中出现的有益突变（Aim 1），在不存在病毒的情况下进化出对毒素的抗性的敏感细胞中（目的2），并确定基因组在分子军备竞赛中重新获得竞争力（Aim 3）。总之，这些目标将揭示复杂的生物系统是如何共同进化和相互制约的，并揭示进化的过程。对抗性共同进化与非生物适应所施加的动力学。了解基因组如何进化，特别是遗传冲突（对抗性共同进化）如何驱动适应，是至关重要的，了解和治疗许多形成和驱动疾病的过程。通过探索宿主-寄生物从第一原则的共同进化，我们可以建立一个基础，了解这些影响，对人类健康和疾病的影响。这项工作将有利于许多领域的实验解决生物和非生物选择如何驱动和限制进化的基本问题结果。