Phylogenomic mechanisms of trait evolution and resilience to disease

性状进化和疾病恢复力的系统发育机制

• 批准号: 10713885
• 负责人: Jacob Michael Daane
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713885
• 关键词: Anemia; Animal Model; Antarctic; Area; Atrophic; Cardiomegaly; Case Study; Cells; Code; Comparative Genomic Analysis; Complement; Data; Data Set; Development; Disease; Environment; Erythrocytes; Evolution; Experimental Models; Fishes; Genes; Genetic; Genome; Genomics; Human; Human Genome; Kidney; Kidney Diseases; Laboratories; Lipids; Metabolic; Metabolic Diseases; Molecular; Organ; Osteopenia; Pathologic; Pathology; Pattern; Phenotype; Phylogeny; Population Genetics; Proteins; Regulator Genes; Rejuvenation; Research; Resolution; Resources; Seasons; Structure; System; Taxonomy; Tissues; Triglycerides; Variant; Zebrafish; comparative; density; experience; gene environment interaction; genetic approach; genome wide association study; human disease; human model; programs; resilience; skeletal; tool; trait; trend

PROJECT SUMMARY Many species have evolved traits that are adaptive in specific environmental contexts but would be considered pathological in humans or in closely related lineages. In Antarctic fishes alone there has been an evolved loss of red blood cells (anemia), low skeletal density (osteopenia), accumulation of triglycerides (metabolic disease), loss of the glomerulus (kidney disease) and enlargement of the heart (cardiomegaly). How do these traits evolve, and how to species overcome the deleterious trade-offs associated with these phenotypic extremes? To complement traditional forward and population genetic approaches at identifying disease modifiers, my laboratory has been developing tools and resources for analysis of natural variation across species rich datasets. These tools allow us to track the patterns of protein coding and gene regulatory evolution across a phylogeny to assess the genomic and macroevolutionary trends that precede and follow specific instances of trait evolution. Over the next five years, we will apply these resources to focus on two main research areas: 1) identification of genetic mechanisms underlying the evolution and development of disease-relevant traits and 2) discovery of the molecular mechanisms underlying tissue plasticity in organs that experience seasonal atrophy and rejuvenation. My lab will focus on a suite of convergently evolved traits that have repeatedly appeared in taxonomically divergent fish lineages, including reduced skeletal density, increased corporeal lipid content, and the dynamic seasonal atrophy of the glomerulus in the kidney. To approach these questions, we will integrate comparative omic approaches in natural systems with the experimental modeling of our findings in the zebrafish. We seek to assess the fundamental genomic basis of trait evolution and disease resilience, including the impact of protein coding and gene regulatory variants, biased patterns of variation across the genome, contributions of gene flow, and the influence of historical contingency on trait evolution. Additionally, we will integrate comparative genomic analyses with case studies tissue plasticity at single cell resolution to isolate the molecular mechanisms by which tissue structure and function adapts to changes in the environment. Together, this research program will discover the phylogenomic origins of extreme traits, identify gene by environment interactions modifying trait presentation, will explore organismal resilience to pathology.

项目概要 许多物种已经进化出适应特定环境背景的特征，但会被认为是 在人类或密切相关的谱系中是病理性的。仅在南极鱼类中就出现了进化损失 红细胞减少（贫血）、骨骼密度低（骨质减少）、甘油三酯积累（代谢性疾病）、 肾小球丧失（肾脏疾病）和心脏扩大（心脏肥大）。这些特征是如何进化的， 物种如何克服与这些极端表型相关的有害权衡？到 补充传统的前向和群体遗传学方法来识别疾病修饰因素，我的 实验室一直在开发工具和资源，用于分析跨物种丰富数据集的自然变异。 这些工具使我们能够跟踪整个系统发育中蛋白质编码和基因调控进化的模式，以 评估性状进化特定实例之前和之后的基因组和宏观进化趋势。 未来五年，我们将运用这些资源重点关注两个主要研究领域：1）识别 疾病相关性状进化和发展的遗传机制；2）发现 经历季节性萎缩和再生的器官中组织可塑性的分子机制。 我的实验室将重点研究一系列在分类学上反复出现的趋同进化特征 不同的鱼类谱系，包括骨骼密度降低、体内脂质含量增加以及动态变化 肾脏肾小球的季节性萎缩。为了解决这些问题，我们将综合比较 通过对我们在斑马鱼中的发现进行实验建模，在自然系统中采用组学方法。我们力求 评估性状进化和疾病恢复力的基本基因组基础，包括蛋白质的影响 编码和基因调控变异、整个基因组变异的偏差模式、基因流的贡献、 以及历史偶然性对特质进化的影响。此外，我们将整合比较基因组 在单细胞分辨率下对组织可塑性进行案例研究分析，以分离出组织可塑性的分子机制 组织结构和功能适应环境的变化。该研究计划将共同发现 极端性状的系统发育起源，通过改变性状呈现的环境相互作用来识别基因， 将探索机体对病理的恢复能力。