Systematic Vertebrate Functional Genomics

描述（由申请人提供）：脊椎动物基因组包含预测的20，000+个基因，许多基因的生物学作用未知。此外，这些分子中的大部分在不同的过程中具有不同的功能。基因的功能注释是理解脊椎动物基因组的主要步骤之一。事实上，尽管人类基因组工作已经完成了十多年，但正在进行积极研究的基因的多样性并没有发生实质性变化。我们已经开发了一系列基因断裂转座子（GBT）等位基因，用于使用杰出的非哺乳动物模式生物斑马鱼（斑马鱼）的脊椎动物基因组的表型注释。GBT代表了一种创新的方法，可以提出当前的问题，同时也可以作为新的科学查询的平台。 我们将使用我们正在进行的500个GBT收集作为评估脊椎动物表型的候选基因突变的平台。在这次竞争性更新中，我们将专注于生物功能的注释，以识别开发中的新参与者以及一组临床相关的生物过程。 我们将通过以下具体目标实现这一目标：具体目标一。我们将对500多个GBT品系进行斑马鱼胚胎和早期幼虫发育所需基因的表型注释。具体目标二。我们将进行表型注释的皮肤表达的蛋白质所需的珠被形成过程中的发展和基因所需的皮肤的伤口愈合反应。具体目标III：我们将鉴定心脏突变体，以注释心脏发生或成人心肌病中的基因功能。具体目标四。我们将确定消化器官形成，脂质代谢和脂质信号所需的基因。具体目的V.使用符合PATO的表型评估描述记录GBT基因功能注释，并整合到正在进行的斑马鱼功能数据库中，包括zfishbook和ZFIN。我们选择胚胎发育是因为斑马鱼外部发育的优势，心脏生物学和功能是因为心脏病在美国是导致死亡的主要原因，外皮生物学是因为皮肤病对三分之一的美国人的强烈影响，发育和生理学中的脂质生物学是因为它在发育、心脏病和肥胖中的关键作用。该项目将共同注释一组新基因，以更好地了解人类健康和疾病。

DESCRIPTION (provided by applicant): The vertebrate genome contains a predicted 20,000+ genes, many of unknown biological role(s). In addition, a large fraction of these molecules have distinct functions in diverse processes. The functional annotation of genes is one of the major next steps in understanding the vertebrate genome. Indeed, despite over a decade after the completion of the human genome effort, the diversity of genes undergoing active research has not substantially changed. We have developed a collection of gene-break transposon (GBT) alleles for use in phenotypic annotation of the vertebrate genome using the preeminent non-mammalian model organism, the zebrafish (Danio rerio). GBTs represent an innovative methodology to ask current questions while also serving as a platform for new scientific query. We will use our ongoing 500 GBT collection as a platform of candidate gene mutations for assessment of the vertebrate phenome. In this competitive renewal, we will focus on the annotation of biological function to identify new players in development as well as a set of clinically relevant biological processes. We will accomplish this goal through the following specific aims: Specific Aim I. We will conduct phenotypic annotation of 500+ GBT lines for genes required for zebrafish embryonic and early larval development. Specific Aim II. We will conduct phenotypic annotation of skin-expressed proteins required for formation of the integument during development and for genes required for the skin's wound healing response. Specific Aim III: We will identify cardiac mutants for annotation of gene functions in either cardiogenesis or adult cardiomyopathy. Specific Aim IV. We will identify genes required for digestive organ formation, lipid metabolism and lipid signaling. Specific Aim V. Recording of GBT gene function annotation using PATO-compliant phenotypic assessment description and integration into ongoing zebrafish functional databases including zfishbook and ZFIN. We selected embryonic development due to the advantages of external development of the zebrafish, cardiac biology and function due to the critical role of heart disease as the leading cause of death in the US, integument biology due to the strong impact of skin disease on one in three Americans, and lipid biology in development and physiology due to its critical role(s) in development, heart disease and obesity. Together, this project will annotate a panel of new genes for the better understanding of human health and disease.