Effects of genetic background on adaptive evolution

遗传背景对适应性进化的影响

• 批准号: 10615639
• 负责人: Peter Andolfatto
• 金额: $ 32.96万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615639
• 关键词: ATP phosphohydrolase; Address; Amino Acid Substitution; Amino Acids; Animals; Behavior; Biology; CRISPR/Cas technology; Cardiac Glycosides; Chromosome Mapping; Cre lox recombination system; Data; Dependence; Development; Disease; Drosophila genus; Drosophila melanogaster Proteins; Drug Targeting; Eating; Engineering; Evolution; Exhibits; Fertility; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Genetic Drift; Genetic Engineering; Genetic Epistasis; Genetic Variation; Genome; Genome engineering; Genomics; Glycosides; Homeostasis; Human; Human Biology; In Vitro; Individual; Insecta; K ATPase; Learning; Link; Maps; Modeling; Molecular; Molecular Genetics; Mutation; Natural Selections; Nature; Neurologic; Organism; Outcome; Phenotype; Physiological; Plants; Population; Population Genetics; Process; Property; Proteins; Quantitative Trait Loci; Recurrence; Resistance; Role; Shapes; Site; Steroids; System; Technology; Time; Toxic effect; Toxin; Variant; Vertebrates; Work; comparative genomics; experience; fitness; genetic analysis; genetic architecture; genome editing; genome wide association study; human disease; in vivo; inhibitor; innovation; insight; model organism; novel; pathogenic bacteria; pathogenic virus; permissiveness; protein function; tool; trait; whole genome

Project Summary To what extent is adaptive evolution predictable? Despite its importance in understanding the biology of human diseases, including the evolution of viral and bacterial pathogens, the dynamics of genetic adaptation are still poorly understood. In particular, few examples yet exist that have been dissected to the molecular level. Examples of adaptations from natural systems and the use of model organisms are powerful tools that can be combined to make progress on this difficult question. We have employed instances of “parallel evolution”, involving assemblages of species experiencing a common regime of natural selection, to evaluate multiple outcomes of the process of adaptation. With this information, we can learn about recurrent features of adaptation and infer constraints and regularities in the adaptive process. Our work focused on the biomedically-important interaction between Na+,K+-ATPases and their regulatory steroidal-glycosides that a large variety of plants and animals use as toxins to defend themselves from being eaten. Using a diverse set of animals that have independently evolved resistance to steroidal-glycoside toxicity, including insects and vertebrates, we discovered these diverse species most often evolve resistance via a small number of possible options (i.e. involving only three of 41 possible sites in the protein that could be modified to confer resistance). These findings suggest that adaptive evolution is often path-dependent, implying that the individual components of an adaptation must evolve in a prescribed, and ultimately predictable, order. They also raise numerous questions about the nature of this path dependency, including the extent to which it emerges from interactions among residues within a protein, or from the genomic background of the species; whether it similarly constrains adaptation over short and longer time scales, and how generally it applies in adaptive protein evolution. Here we propose three aims that address these questions, by combining approaches from evolutionary genomics and molecular genetics. In Aim 1, we will use genome engineering in Drosophila to elucidate the path dependence of the steroidal-glycoside resistance adaptation both at the level of its primary target (Na+,K+-ATPase) and at the level of the whole genome. In Aim 2, we will determine which and how many genomic factors contribute to naturally occurring variation within Drosophila populations. This information will reveal the relationship between within- population and between-species genetic variation underlying the same trait, connecting short- and long-term dynamics of the adaptive process. In Aim 3, we will use principles learned from molecular adaptation at Na+,K+-ATPase to computationally predict and use genome engineering to functionally validate path dependent adaptation dynamics in Drosophila for a diverse group of proteins, many of which (like Na+,K+-ATPase) have important roles in neurological development and homeostasis. Together this work will greatly increase our understanding of the constraints on adaptive protein evolution and the predictability of the genetic changes by which novel phenotypes emerge.

项目摘要 适应性进化在多大程度上可以预测？尽管它在理解人类疾病的生物学方面很重要，但 包括病毒和细菌病原体的进化，遗传适应的动力学仍然很少了解。在 特别是，很少有示例已剖析到分子水平。自然改编的例子 系统和模型生物的使用是强大的工具，可以合并以在这一困难上取得进展 问题。我们曾在“平行进化”的实例中工作，涉及经历常见的物种的组合 自然选择的制度，以评估适应过程的多种结果。有了这些信息，我们可以 了解适应性的经常性特征，并在自适应过程中推断约束和规律性。我们的工作 专注于Na+，K+-ATPases及其调节性型糖苷之间的生物医学重要相互作用，这些相互作用 各种各样的动植物用毒素来捍卫自己免于被食用。使用一组动物 具有独立发展对类固醇 - 糖苷毒性的抗性，包括绝缘和脊椎动物，我们 发现这些潜水员最常通过少数可能的选择来发展抵抗（即仅涉及 蛋白质中的41个可能位点中有3个可以修改以赋予抗性）。这些发现表明自适应 进化通常是依赖路径的，这意味着适应的个体组成部分必须在规定的规定中进化， 并最终可预测，秩序。他们还提出了有关此道路依赖性的性质的许多问题，包括 它来自蛋白质中残留物之间的相互作用的程度，或从基因组背景中 物种;它是否类似地限制了短期和更长的时间尺度的适应，以及它通常如何应用 自适应蛋白的进化。在这里，我们提出了三个通过结合方法来解决这些问题的三个目标 进化基因组学和分子遗传学。在AIM 1中，我们将使用果蝇中的基因组工程来阐明 类固醇 - 糖苷耐药性适应的路径依赖性在其主要靶标水平（Na+，K+-ATPase）上 以及整个基因组的水平。在AIM 2中，我们将确定哪些基因组因素有助于 果蝇种群中自然发生的变化。这些信息将揭示内部之间的关系 种群和种类之间的遗传变异是相同特征的基础，连接了短期和长期动态 自适应过程。在AIM 3中，我们将使用从Na+，K+-ATPase的分子适应中学到的原理 计算预测和使用基因组工程来在功能上验证路径依赖性适应动力学 果蝇针对潜水蛋白的果蝇，其中许多（例如Na+，K+-ATPase）在神经学中具有重要作用 发展和体内稳态。这项工作将大大增加我们对自适应限制的理解 蛋白质进化和遗传变化的可预测性出现。