Phylogenomic mechanisms of trait evolution and resilience to disease

项目摘要 许多物种都进化出了适应特定环境的特征， 在人类或密切相关的谱系中是病理性的。仅在南极鱼类中， 红细胞减少（贫血）、低骨骼密度（骨质减少）、甘油三酯蓄积（代谢疾病）， 肾小球丧失（肾脏疾病）和心脏增大（心脏肥大）。这些特征是如何进化的 以及物种如何克服与这些极端表型相关的有害权衡？到 补充传统的前瞻性和群体遗传学方法在确定疾病修饰，我 实验室一直在开发工具和资源，用于分析物种丰富的数据集之间的自然变异。 这些工具使我们能够跟踪蛋白质编码和基因调控进化的模式， 评估基因组和宏观进化的趋势，之前和之后的性状进化的具体情况。 在未来五年，我们将把这些资源集中在两个主要研究领域：1）识别 疾病相关性状的进化和发展的遗传机制; 2）发现 在经历季节性萎缩和再生的器官中，组织可塑性的分子机制。 我的实验室将专注于一套趋同进化的特征，这些特征在分类学上反复出现， 不同的鱼类谱系，包括减少骨骼密度，增加皮质脂质含量，和动态 肾脏肾小球的季节性萎缩。为了解决这些问题，我们将结合比较 自然系统中的组学方法与我们在斑马鱼中的发现的实验建模。我们寻求 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 编码和基因调控变体，基因组中变异的偏向模式，基因流的贡献， 以及历史偶然性对性状进化的影响。此外，我们将整合比较基因组学， 分析与个案研究组织可塑性在单细胞分辨率分离的分子机制， 组织结构和功能适应环境的变化。这项研究计划将发现 研究极端性状的基因组起源，通过环境相互作用确定基因，改变性状的呈现， 将探索生物体对病理学的适应能力。

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.