Resources for Teleost Gene Duplicates and Human Disease

硬骨鱼基因重复和人类疾病的资源

• 批准号: 8909260
• 负责人: JOHN H. POSTLETHWAIT
• 金额: $ 23.13万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-18 至 2016-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909260
• 关键词: Animals; Architecture; Attention; Bacterial Artificial Chromosomes; Base Sequence; Behavior; Biochemical; Bioinformatics; Biology; Cardiovascular system; Chromosome Mapping; Chromosomes; Cichlids; Development; Disease; Elements; Embryo; Endocrine system; Event; Evolution; Expressed Sequence Tags; Fishes; Functional RNA; Fundulus; Gasterosteidae; Gene Duplication; Gene Expression; Gene Order; Gene Structure; Genes; Genetic Markers; Genome; Genomics; Genotype; Guppy; Health; Human; Human Biology; Human Genome; Individual; Institutes; Knowledge; Learning; Link; Lobe; Mammals; Maps; Medical; Methodology; Methods; Modeling; N.I.H. Research Support; Organ; Organ Model; Orthologous Gene; Pathway interactions; Physiological; Physiology; Problem Solving; Process; Reproductive system; Research; Research Personnel; Research Support; Resolution; Resources; Salmonidae; Sister; Solutions; Spottings; Syntenic Conservation; System; Testing; Tetraodontidae; Toxic effect; Transgenic Organisms; Translating; Translational Research; Translations; United States National Institutes of Health; Vertebral column; Work; Zebrafish; base; comparative; comparative genomics; duplicate genes; experience; functional genomics; gastrointestinal system; gene function; genetic linkage; human disease; innovation; interest; next generation sequencing; novel; teleost; teleost fish; tool

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.

描述（由申请人提供）：NIH支持对人类疾病的鱼类模型的研究，因为斑马鱼在内的Teolost Fish允许快速有效利用资源来探索对具有主骨动物的动物发展和功能的问题。该建议描述了促进功能信息从硬骨骼医学模型转换为人类生物学的资源。大多数硬骨基因与人类基因有一对一的关系，但是由于基因组重复事件，硬骨鱼具有许多人类基因的两个副本，尤其是控制发育和生理机制的基因。人类基因的硬质重复物经常在它们之间共享相应的哺乳动物单拷贝基因（亚功能化）的功能，并且通常比单胎更快地进化了新功能（新功能化）。问题是：硬骨基因的哪些功能是由于最后一个共同的人/鱼类祖先的遗传而引起的，哪些是由于定权基因组重复以来的进化而引起的？解决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。最近有差异的未建立的射线鳍鱼提供了一座桥梁，将重复的硬骨基因组连接到未修复的人类基因组。 Spotted GAR（Lepisosteus oculatus）占据了硬骨谱系的最新外群，是基因组，基因表达和基因功能分析的方便系统。目的1是使用基于创新的下一代序列基因分型方法来构建一个高分辨率的遗传链接图。 AIM 2是为GAR构建一个表达序列标签（EST）的资源，并开发生物信息学，将EST分配给链接图上的数千个标记。 AIM 3是使用一种新方法来构建瓷砖BAC（细菌人造染色体）的资源，该方法包括遗传链接图上的所有标记，并开发生物信息学以将BAC与单个EST相关联。 AIM 4是开发生物信息学工具，以将遗传标记，EST和瓷砖克隆整合到保守的同义图中，以进行人类和定量的比较基因组学。 AIM 5是通过使用GAR序列检测转基因斑马鱼中功能的非编码元件来检验基因重复的功能演化的机制，以测试对基因重复的功能演化的假设的预测。意义：实现这些目标将提供促进硬骨料和人类基因组的连通性的资源，从而将死者生物学转化为人类生物医学。 GAR，TOLOST和人类基因组的比较图将注意力集中在GAR基因组的区域上，该区域包含对应于定量重复的生物医学基因的单例，并发现这些未造成的基因的功能。权力研究人员可以利用这一知识来区分祖先与衍生的基因结构和功能，这是Teolost到人类转化研究的关键问题。