Resources for Teleost Gene Duplicates and Human Disease

描述(由申请人提供)：NIH支持人类疾病鱼类模型的研究，因为硬骨鱼，包括斑马鱼，允许快速和有效地利用资源来探索对有脊骨的动物的发育和功能至关重要的问题。该提案描述了促进将硬骨鱼医学模型的功能信息转换为人类生物学的资源。大多数硬骨鱼基因与人类基因具有一对一的关系，但由于基因组复制事件，硬骨鱼拥有许多人类基因的两个副本，特别是控制发育和生理机制的基因。人类基因的硬骨复制体通常在它们之间共享相应的哺乳动物单拷贝基因的功能(亚功能化)，并且通常比单一个体更快地进化出新的功能(新功能化)。问题是：硬骨基因的哪些功能是由于从最后一个共同的人类/鱼类祖先那里遗传来的，哪些是由于硬骨基因组复制以来的进化？这个问题的解决方案很重要，因为硬骨鱼和人类基因组的连接对于将硬骨鱼研究转化为人类生物学至关重要。最近分离的非复制放射鳍FISH提供了一座桥梁，将复制的硬骨鱼基因组连接到未复制的人类基因组。斑点GAR(Lesssteus Oculatus)是硬骨鱼谱系中一个不可复制的最近外群，是基因组、基因表达和基因功能分析的便捷系统。目标1是使用创新的基于下一代序列的基因分型方法构建斑点糖的高分辨率遗传连锁图谱。目标2是构建GAR的表达序列标签(EST)资源，并发展生物信息学，将EST分配给连锁图谱上的数千个标记。目的3是利用一种新的方法构建包含遗传连锁图谱上所有标记的平铺细菌人工染色体资源，并发展生物信息学将细菌人工染色体与单个EST相关联。目标4是开发生物信息学工具，将遗传标记、EST和平铺克隆整合到保守的同步性图谱中，用于人类和硬骨鱼的比较基因组学。目的5是通过使用GAR序列来检测转基因斑马鱼中的非编码元件，以检验亚功能化和新功能化假说作为基因重复功能进化机制的预测。意义：实现这些目标将提供促进硬骨鱼和人类基因组连接的资源，从而将硬骨鱼生物学转化为人类生物医学。GAR、硬骨鱼和人类基因组的比较图谱将注意力集中在GAR基因组中包含与硬骨鱼中复制的生物医学基因相对应的单倍体的区域，并发现这些非复制基因的功能。硬骨鱼研究人员可以利用这一知识来区分祖先和衍生的基因结构和功能，这是硬骨鱼到人类翻译研究的一个关键问题。

DESCRIPTION (provided by applicant): NIH supports research on fish models for human disease because teleost fish, including zebrafish, allow the rapid and efficient use of resources to explore problems fundamental to the development and function of animals with backbones. This proposal describes resources to facilitate the translation of functional information from teleost medical models to human biology. Most teleost genes have a one-to-one relationship with human genes, but due to a genome duplication event, teleosts have two copies of many human genes, especially genes controlling developmental and physiological mechanisms. Teleost duplicates of human genes have often shared between them the functions of the corresponding mammalian single-copy gene (subfunctionalization) and have often evolved new functions (neofunctionalization) more rapidly than singletons. The problem is: Which functions of teleost genes are due to inheritance from the last common human/fish ancestor and which are due to evolution since the teleost genome duplication? Solutions to this problem are important because the connectivity of teleost and human genomes is crucial for translating teleost research to human biology. The most recently diverged unduplicated ray-fin fish provides a bridge to connect the duplicated teleost genome to the unduplicated human genome. Spotted gar (Lepisosteus oculatus) occupies an unduplicated recent outgroup to the teleost lineage and is a convenient system for genomic, gene expression, and gene function analyses. Aim 1 is to construct a high-resolution genetic linkage map for spotted gar using an innovative next-generation sequence-based genotyping methodology. Aim 2 is to construct a resource of expressed sequence tags (ESTs) for gar and to develop bioinformatics that assign ESTs to thousands of markers on the linkage map. Aim 3 is to construct a resource of tiled BACs (bacterial artificial chromosomes) using a novel method that includes all markers on the genetic linkage map, and to develop bioinformatics to associate BACs to individual ESTs. Aim 4 is to develop bioinformatic tools to integrate genetic markers, ESTs, and tiled clones into conserved synteny maps for comparative genomics of humans and teleosts. Aim 5 is to test predictions of the hypotheses of subfunctionalization and neofunctionalization as mechanisms for the functional evolution of gene duplicates by using gar sequences to detect non-coding elements that function in transgenic zebrafish. Significance: Achieving these aims will provide resources that facilitate the connectivity of teleost and human genomes, thereby translating teleost biology to human biomedicine. Comparative maps of gar, teleost and human genomes focus attention on regions of the gar genome that contain singletons corresponding to duplicated biomedical genes in teleosts and to discover the functions of these unduplicated genes. Teleost researchers can exploit this knowledge to distinguish ancestral from derived gene structure and function, a critical question for teleost-to-human translational research.