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.

项目摘要 许多物种的发展特征在特定的环境环境中具有自适应性，但会被认为 人类或密切相关的谱系中的病理。仅在南极鱼类中就有进化的损失 红细胞（贫血），低骨骼密度（骨质减少），甘油三酸酯（代谢疾病）的积累， 肾小球（肾脏疾病）和心脏增大（心脏肿大）的丧失。这些特征如何发展， 以及如何克服与这些表型极端相关的有害权衡？到 补充传统的前进和人群遗传方法，以鉴定疾病修饰剂，我 实验室一直在开发工具和资源，以分析富含物种的自然变异。 这些工具使我们能够跟踪系统发育中的蛋白质编码和基因调节演化的模式 评估先前并遵循特定特征进化的特定实例的基因组和宏观进化趋势。 在接下来的五年中，我们将利用这些资源专注于两个主要研究领域：1）识别 与疾病相关性状的进化和发展的基础的遗传机制和2）发现 在体验季节性萎缩和恢复活力的器官中组织可塑性的分子机制。 我的实验室将集中于一系列趋同发展的特征，这些特征反复出现在分类学中 发散的鱼谱系，包括骨骼密度降低，有形脂质含量增加和动态 肾脏中肾小球的季节性萎缩。要解决这些问题，我们将整合比较 自然系统中的OMIC方法通过我们在斑马鱼中发现的实验建模。我们寻求 评估性状进化和疾病弹性的基本基因组基础，包括蛋白质的影响 编码和基因调节变体，基因组偏差的变异模式，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 与案例研究在单细胞分辨率下组织可塑性的分析，以分离分子机制 组织结构和功能适应环境变化。该研究计划一起发现 极端性状的系统基因组性，通过环境相互作用修改性状表现来识别基因， 将探索有机体对病理的弹性。