Testing evolutionary hypotheses for the long-term maintenance of balanced immunogenetic polymorphisms in a wildlife model

在野生动物模型中测试长期维持平衡免疫遗传多态性的进化假设

• 批准号: NE/Y000900/1
• 负责人: Barbara Tschirren
• 金额: $ 104.83万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NE%2FY000900%2F1
• 关键词: Testing; evolutionary; hypotheses; long; term

Infectious diseases are a major cause of morbidity and mortality in humans, livestock and wild animals. Although the immune system has evolved as a defence against infection and plays a key role in influencing host health and survival, it is not perfect, and substantial genetic variation in disease vulnerability is typically observed among hosts. To date it is not well understood why and how genetic variation in immune function is preserved over extended (i.e. evolutionary) timescales. Understanding the factors that maintain genetic variation in immune function within a species will tell us why vulnerability to infectious diseases is not eliminated by selection, why some populations are more susceptible to infectious diseases than others, and how environmental change and newly emerging diseases influence the costs and benefits associated with different immune gene variants, and thus affect immune system evolution. In our project we will use wild bank voles, an exceptionally tractable wild rodent model that shows a distinct genetic polymorphism at an immune receptor involved in the defence against bacterial pathogens, to test why and how genetic variation in immune function is maintained in populations. Hosts are typically exposed to a wide range of pathogens simultaneously. If being resistant to one pathogen comes at the cost of being susceptible to another, these diverse pathogen communities can maintain immune gene variation in host populations. Using next-generation sequencing technology, we will characterise entire microbial communities within voles to test if their genetic makeup influences pathogen-specific infection, either directly or indirectly by affecting their commensal microbes. Alternatively, immune gene variation may be maintained because of a resistance - 'harm-to-self' trade-off. Although powerful immune responses are required to prevent or clear an infection, they may act as a double-edged sword and also cause 'harm-to-self'. To date it is not known if immune gene variants differ in the amount of collateral damage they cause when they are activated. By experimentally activating the immune system of voles that differ in their genetic makeup, we will test if immune gene variants that confer pathogen resistance also cause more collateral damage to the host. Ultimately, these trade-offs can maintain genetic variation in immune function because they ensure that immune gene variants are not absolutely good or bad, but that their costs and benefits are dependent on either the host's external environment, or on intrinsic host characteristics, such as sex. We will experimentally test this by manipulating population density and pathogen infection risk in large outdoor enclosures and quantify survival and reproduction of males and females with different genetic makeup. This will allow us to test if the fitness outcomes of genetic variants are context-dependent. The outcome of the project will be an improved understanding of the mechanisms and selective forces that contribute to the maintenance of genetic variation in immune function and disease vulnerability in natural populations, with broad cross-disciplinary implications for evolutionary biology, disease ecology, wildlife conservation, and human and animal health.

传染病是人类，牲畜和野生动物发病率和死亡率的主要原因。尽管免疫系统已经发展为防御感染的防御，并且在影响宿主健康和生存方面起着关键作用，但它并不完美，并且通常在宿主之间观察到疾病脆弱性的实质遗传变异。迄今为止，尚不清楚为什么以及如何在扩展（即进化）时间尺度上保存免疫功能的遗传变异。了解某个物种中免疫功能的遗传变异的因素将告诉我们为什么选择脆弱性无法通过选择来消除感染性疾病的脆弱性，为什么某些人群比其他人更容易感染感染疾病，而环境变化以及新出现的疾病如何影响与不同的免疫基因变异物质，以及影响免疫系统的不同成本和收益。在我们的项目中，我们将使用野生银行田鼠（野生银行田鼠（Wild Bank Pores），这是一种非常可触犯的野生啮齿动物模型，该模型在涉及防御细菌病原体的免疫受体下显示出明显的遗传多态性，以测试人群中免疫功能的遗传变异以及如何在人群中保持遗传变异。宿主通常同时暴露于多种病原体。如果对一种病原体有抵抗力，以易于另一种病原体易感，那么这些多样化的病原体群落可以维持宿主种群中的免疫基因变异。使用下一代测序技术，我们将表征田鼠中的整个微生物群落，以测试其遗传构成是否通过影响其共生微生物直接或间接影响病原体特异性感染。另外，由于抗性 - “伤害自我”的权衡，可以保持免疫基因变异。尽管需要强大的免疫反应来预防或清除感染，但它们可能充当双刃剑，也会引起“伤害自我”。迄今为止，尚不清楚免疫基因变异在激活时造成的附带损害量是否有所不同。通过实验激活其基因组成不同的田鼠免疫系统，我们将测试是否赋予病原体耐药性的免疫基因变体也会对宿主造成更大的附带损害。最终，这些权衡可以维持免疫功能的遗传差异，因为它们确保免疫基因变体不是绝对好或坏的，但是它们的成本和收益取决于宿主的外部环境或内在的宿主特征，例如性别。我们将通过操纵大型室外外壳中的种群密度和病原体感染风险，并量化具有不同基因组成的男性和女性的生存和繁殖，从而实验测试。这将使我们能够测试遗传变异的适应性结果是否取决于上下文。该项目的结果将是对自然种群中免疫功能和疾病脆弱性遗传变异的机制和选择性力量的改进，对进化生物学，疾病生态保存，野生动植物保存以及人类和动物健康具有广泛的跨学科影响。