Genomic Basis of Vertebrate Diversity

描述：本项目的长期目标是了解脊椎动物表型多样性的基因组机制。基因组学的快速发展已经为几种生物提供了几乎完整的序列。比较分析表明，许多基本的途径和基因网络在生物体之间是保守的。然而，不同物种的形态、生理和行为却有着明显而深刻的差异。产生这些关键差异的机制是什么？独特的性状是由少数还是许多基因变化控制的？什么样的变化？当生物体适应新环境时，是否有特定的基因和机制被反复使用？更好地理解这些机制是否有助于解释群体之间也存在的疾病易感性的巨大差异？斯坦福大学CEGS将在鱼类、小鼠和人类中使用创新的方法组合，以确定脊椎动物自然种群中主要表型变化的分子基础。具体目标包括：1）杂交棘鱼，并开发染色体、基因和突变的全基因组图谱，这些染色体、基因和突变在自然环境中控制着广泛的新形态、生理和行为特征; 2）测试哪些群体遗传指标提供最可靠的“选择特征”周围的基因，已知已作为基础的平行适应性变化，在世界各地的许多不同的自然种群; 3）组装棘鱼原Y染色体，并测试性别或常染色体重排是否在产生表型多样性中起重要作用，或者在控制表型变化的基因组区域中富集; 4）测试特定基因和机制是否重复用于控制许多不同脊椎动物的表型变化。初步数据表明，被确定为自然鱼类种群适应性变化基础的机制可能广泛预测包括人类在内的大量动物的适应性机制。假设在人类中被选择的遗传区域将与在鱼类中被选择的遗传区域进行比较。预测在自然人类变异和疾病易感性中发挥重要作用的区域将在小鼠中建模，产生新的模型系统，用于确认从人类群体遗传学和比较基因组学预测的功能变异。

DESCRIPTION: The long-term goal of this project is to understand the genomic mechanisms that generate phenotypic diversity in vertebrates. Rapid progress in genomics has provided nearly complete sequences for several organisms. Comparative analysis suggests many fundamental pathways and gene networks are conserved between organisms. And yet, the morphology, physiology, and behavior of different species are obviously and profoundly different. What are the mechanisms that generate these key differences? Are unique traits controlled by few or many genetic changes? What kinds of changes? Are there particular genes and mechanisms that are used repeatedly when organisms adapt to new environments? Can better understanding of these mechanisms help explain dramatic differences in disease susceptibility that also exist between groups? The Stanford CEGS will use an innovative combination of approaches in fish, mice, and humans to identify the molecular basis of major phenotypic change in natural populations of vertebrates. Specific aims include: 1) cross stickleback fish and develop a genome wide map of the chromosomes, genes, and mutations that control a broad range of new morphological, physiological, and behavioral traits in natural environments; 2) test which population genetic measures provide the most reliable "signatures of selection" surrounding genes that are known to have served as the basis of parallel adaptive change in many different natural populations around the world; 3) assemble the stickleback proto Y chromosome and test whether either sex or autosomal rearrangements play an important role in generating phenotypic diversity, or are enriched in genomic regions that control phenotypic change; 4) test whether particular genes and mechanisms are used repeatedly to control phenotypic change in many different vertebrates. Preliminary data suggests that mechanisms identified as the basis of adaptive change in natural fish populations may be broadly predictive of adaptive mechanisms across a surprisingly large range of animals, including humans. Genetic regions hypothesized to be under selection in humans will be compared to genetic regions under selection in fish. Regions predicted to play an important role in natural human variation and disease susceptibility will be modeled in mice, generating new model systems for confirming functional variants predicted from human population genetics and comparative genomics.