Resources for Teleost Gene Duplicates and Human Disease

描述(申请人提供)：硬骨鱼为了解人类健康和疾病提供了重要的模型。其中包括癌症和肿瘤发生、人类发育和婴儿健康、心血管疾病、眼疾、骨病、环境毒理学、衰老以及基因组结构和调控的模型。由于硬骨鱼有共同的基因组扩张史，很可能是由于基因组复制，它们通常有两个拷贝的单拷贝人类基因。在复制的硬骨鱼基因拷贝之间划分祖先基因亚功能有助于分析与人类共享的祖先基因功能。这项拟议工作的长期目标是提供与复制硬骨基因相关的资源，以极大地扩展现有硬骨模型在人类发育、器官功能、健康和疾病方面的用途。目标1是开发TelGen，这是一种软件资源，用于自动识别和分析硬骨鱼测序基因组中重复基因的系统发育。目标2是使用新的软件来识别、调查并在TelGen2数据库中公开访问，这是在拟议的射线-鳍基因组复制事件中出现的一组基因重复。目标3是确定最近分化的、复制前的射线鳍谱系，并提供可获得的有形基因组资源，包括大插入基因组克隆和cDNA文库，以及这些序列的数据库OldFish。最后，目标4是创建TelExDB，这是人类疾病基因的两个硬骨副本的基因表达数据来源，并研究硬骨基因副本功能进化的一般原理。这些资源和研究将通过提供对硬骨鱼之间重复基因差异的一般理解来提高硬骨鱼模型的连接性和实用性。此外，在单拷贝哺乳动物基因的早期基本功能掩盖了后来的功能的情况下，它们还有助于分析。分析复制的硬骨基因可以更容易地发现候选的组织特异性调控元件和蛋白质结构基序，这些可能是副作用较少的药物的靶点。

DESCRIPTION (provided by applicant): Teleost fish provide important models for understanding human health and disease. These include models for cancer and tumorigenesis, human development and infant health, cardiovascular disease, eye disease, bone disease, environmental toxicology, aging, and genome structure and regulation. Because teleost fish share a history of genome expansion, likely due to genome duplication, they often have 2 copies of single copy human genes. The partitioning of ancestral gene subfunctions between duplicated teleost gene copies facilitates analysis of ancestral gene functions shared with humans. The long-term objective of the proposed work is to provide resources related to duplicated teleost genes to greatly expand the utility of existing teleost models for human development, organ function, health, and disease. Aim 1 is to develop TelGen, software resources to automate the identification and phylogenetic analysis of duplicated genes in the sequenced genomes of teleost fish. Aim 2 is to use the new software to identify, investigate, and make publicly accessible in the TelGen2 database, the set of gene duplicates that arose in the proposed ray-fin genome duplication event. Aim 3 is to identify the most recently diverging, pre-duplication ray-fin lineage, and make available tangible genomic resources, including large insert genomic clones and cDNA libraries, and OldFish, a database for these sequences. Finally, Aim 4 is to create TelExDB, a resource of gene expression data for both copies of teleost duplicates of human disease genes, and to investigate general principles for the evolution of function in teleost gene duplicates. These resources and studies will improve connectivities and utility of teleost models by providing a general understanding of duplicate gene divergence across teleosts. In addition, they facilitate analysis in cases where the early essential function of a single copy mammalian gene obscures a later function. Analysis of duplicated teleost genes can ease discovery of candidate tissue-specific regulatory elements and protein structural motifs that may be targets for drugs with fewer side effects.