Resources for Teleost Gene Duplicates and Human Disease

描述（由申请人提供）：NIH支持人类疾病的鱼类模型研究，因为硬骨鱼，包括斑马鱼，可以快速有效地利用资源来探索有脊椎动物发育和功能的基本问题。本提案描述了促进从硬骨鱼医学模型到人类生物学的功能信息翻译的资源。大多数硬骨鱼基因与人类基因有一对一的关系，但由于基因组复制事件，硬骨鱼具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。硬骨鱼的人类基因副本经常共享相应的哺乳动物单拷贝基因的功能（亚功能化），并且经常比单拷贝更快地进化出新的功能（新功能化）。问题是：硬骨鱼基因的哪些功能是由于从最后一个共同的人类/鱼类祖先遗传而来的，哪些是由于硬骨鱼基因组复制后的进化而来的？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通性对于将硬骨鱼研究转化为人类生物学至关重要。最近分化的非复制鳍鱼为连接复制的硬骨鱼基因组和非复制的人类基因组提供了一座桥梁。斑点gar （Lepisosteus oculatus）是硬骨鱼谱系中一个不重复的外群，是一个方便的基因组、基因表达和基因功能分析系统。目的1是利用创新的下一代基于序列的基因分型方法构建斑点雀的高分辨率遗传连锁图谱。目标2是为gar构建一个表达序列标签（est）资源，并开发生物信息学，将est分配给链接图上的数千个标记。目标3是使用一种包括遗传连锁图谱上所有标记的新方法构建平铺bac（细菌人工染色体）资源，并发展生物信息学将bac与个体est联系起来。目标4是开发生物信息学工具，将遗传标记，est和平铺克隆整合到人类和硬骨鱼的比较基因组学的保守合成图中。目的5是通过使用gar序列检测在转基因斑马鱼中起作用的非编码元件，测试亚功能化和新功能化作为基因重复功能进化机制的假设预测。意义：实现这些目标将提供资源，促进硬骨鱼和人类基因组的连接，从而将硬骨鱼生物学转化为人类生物医学。琼脂、硬骨鱼和人类基因组的比较图将注意力集中在琼脂基因组中包含与硬骨鱼生物医学基因复制对应的单子的区域，并发现这些不复制基因的功能。硬骨鱼研究人员可以利用这些知识来区分祖先和衍生的基因结构和功能，这是硬骨鱼到人类转化研究的关键问题。

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. PUBLIC HEALTH RELEVANCE: Fish biomedical models allow rapid and efficient analysis of human disease mechanisms. Most model fish species, however, possess a duplicated genome that often disrupts the one-to-one relationship between human and fish genes. Proposed work will provide genomic resources for an unduplicated fish genome that will better link model fish and human genomes and thus will more effectively translate research on fish biomedical models to human health and disease.