The coevolutionary dynamics of pleiotropic genetic architecture

多效性遗传结构的共同进化动力学

• 批准号: 10396659
• 负责人: Ann Thomas Tate
• 金额: $ 39.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396659
• 关键词: Animals; Autoimmunity; Complex; DNA Sequence Alteration; Data; Development; Disease; Evolution; Flour; Genes; Genetic; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunological Models; Immunologics; Innate Immune Response; Insecta; Light; Mediating; Modeling; Molecular; Natural Immunity; Natural Selections; Order Coleoptera; Outcome; Parasites; Pathway interactions; Physiological Processes; Plants; Play; Population Genetics; Process; Property; Proteins; Research; Role; Running; Sepsis; Shapes; Side; Source; Stress; Structure; System; Therapeutic; Translations; Tribolium; Ursidae Family; Work; antagonist; base; biological adaptation to stress; biological systems; design; expectation; experimental study; fitness; gene product; genetic analysis; genetic architecture; genome-wide; host-microbe interactions; human disease; human pathogen; immune function; improved; insight; mathematical model; pathogen; pleiotropism; pressure; response; side effect; system architecture; theories; trait; transcriptome

PROJECT SUMMARY/ABSTRACT The coevolution of hosts and parasites is mediated by genetic mutations that allow one side to gain an advantage over the other. As the host immune system bears the primary burden of responding to evolving parasites, it is expected to adapt or diversify in response to natural selection. However, recent population genetics analyses from a variety of animal taxa only partially bear out this hypothesis, revealing a paucity of adaptive evolution among innate immune gene repertoires relative to expectations. My recent work suggests that an appreciable proportion of genes associated with innate immune responses in taxa as broad as humans, insects and plants are pleiotropic, meaning that they also play unrelated roles in other organismal traits like development and the response to abiotic stress. This observation raises the possibility of temporal and evolutionary tension between the use of a gene product for developmental and immunological functions. Current coevolutionary theory largely fails to account for sources of genetic constraint on host defenses, impeding the translation of existing coevolutionary models into predictions for evolutionary dynamics at the molecular or system level. Moving forward, a major focus of research in my lab will be to explore the role of pleiotropic genetic architecture on the evolvability of host immune systems in response to parasite pressure. To tackle this long-term objective, my lab will employ several complementary approaches. Using transcriptome data, we will define the extent and dynamics of pleiotropy among developmental, stress, and immunological pathway genes in a variety of insect model species. We will perform genome-wide evolutionary genetics analyses in these insect species to quantify signatures of selection on pleiotropic and non-pleiotropic developmental, immunological, and stress response gene sets relative to null expectations. We will build mathematical models of immune pathway protein networks possessing different properties – modularity, redundancy, complexity, pleiotropy – and allow them to co-evolve with parasites, quantifying changes in fitness landscapes to better understand network structures that constrain or promote host adaptation. In parallel, we will run coevolution experiments using the flour beetle Tribolium castaneum and its natural parasites. We will manipulate the strength of pleiotropic antagonism among immunity and other processes in these experiments by limiting host-microbe interactions to a particular developmental stage or altering abiotic stress conditions, and then compare the evolutionary trajectories and genetic bases of host-microbe interaction outcomes. Together, these research avenues will provide insight into an array of fundamental questions about the extent of genetic pleiotropy among essential physiological processes, the influence of pleiotropy on coevolutionary dynamics, and the role of immune system architecture in host adaptation to parasite pressure. Gaining greater insight into the evolutionary forces that shape biological systems has important implications for predicting human pathogen evolution, understanding the origins of diseases like autoimmunity and sepsis, and designing therapeutic treatments that minimize side effects.

项目总结/摘要 宿主和寄生虫的共同进化是由基因突变介导的，基因突变允许一方获得对另一方的优势。 其他.由于宿主免疫系统承担着对进化中的寄生虫作出反应的主要负担，因此预期它会适应或 多样化是对自然选择的反应。然而，最近的群体遗传学分析，从各种动物类群， 部分证实了这一假设，揭示了先天免疫基因库中缺乏适应性进化。 到期望。我最近的研究表明，与先天免疫相关的基因中， 在人类、昆虫和植物等广泛的分类群中，反应是多效性的，这意味着它们也在 其他生物特征，如发育和对非生物胁迫的反应。这一观察提出了以下可能性： 基因产物用于发育和免疫功能之间的时间和进化紧张关系。 目前的共同进化理论在很大程度上未能解释宿主防御的遗传约束来源，阻碍了人类的进化。 将现有的共同进化模型转化为分子或系统水平上的进化动力学预测。 展望未来，我实验室的一个主要研究重点将是探索多效性遗传结构在人类遗传中的作用。 宿主免疫系统对寄生虫压力的反应。 为了实现这一长期目标，我的实验室将采用几种互补的方法。利用转录组数据，我们 将定义在一个发育，应激和免疫途径基因之间多效性的程度和动力学， 各种昆虫模式物种。我们将在这些昆虫物种中进行全基因组进化遗传学分析， 量化选择对多效性和非多效性发育、免疫和应激反应的影响 相对于零期望的基因集。我们将建立免疫途径蛋白质网络的数学模型 拥有不同的属性-模块性，冗余性，复杂性，多效性-并允许它们与 寄生虫，量化适应度景观的变化，以更好地了解限制或促进宿主的网络结构， 适应与此同时，我们将使用面粉甲虫赤拟谷盗（Tribolium castaneum）及其自然种群进行共同进化实验。 寄生虫我们将操纵免疫和其他过程中的多效性拮抗作用的强度， 通过将宿主-微生物相互作用限制在特定发育阶段或改变非生物胁迫条件的实验， 然后比较宿主-微生物相互作用结果的进化轨迹和遗传基础。 总之，这些研究途径将提供深入了解一系列基本问题的程度遗传 基本生理过程之间的多效性，多效性对共同进化动力学的影响，以及 免疫系统结构在宿主适应寄生虫压力中的作用。更深入地了解进化的力量 这对预测人类病原体的进化，理解人类的免疫系统， 疾病的起源，如自身免疫和败血症，并设计治疗方法，最大限度地减少副作用。