Comparative and Functional Genomics of Protein Kinases

描述（由申请人提供）： 项目概要：518种人类蛋白激酶调节约30%的所有蛋白质的活性，并且共同控制细胞的几乎所有复杂途径和决定。尽管对一些激酶进行了大量的实验分析，但我们对这个独特重要家族的大多数成员的详细功能知之甚少。我们建议使用基因组序列来挖掘数亿年的进化实验，以澄清激酶序列和生物功能之间的联系。我们将利用我们从人类和小鼠激酶组发现中获得的广泛知识来预测多达40种脊椎动物基因组中的所有激酶直系同源物。然后，我们将绘制每个激酶的每个残基的进化约束，并预测蛋白质的结构域，基序，磷酸化位点和其他功能区域，将激酶组目录扩展到前所未有的分辨率，并为实验测试产生丰富的假设。最后，我们将应用这些知识来预测SNPs和体细胞突变在癌症中的功能影响，为拟议的癌症基因组图谱提供有价值的预览。 通过使用激酶作为模型家族来探索比较基因组学的预测能力，我们将开发经过充分验证的工具和参数，然后可以应用于任何人类基因或基因家族。 相关性：蛋白激酶是细胞功能的关键控制者，是疾病和新药治疗开发中最重要的基因家族之一。通过探索人类激酶与其他脊椎动物激酶的差异，我们可以预测任何人类序列变化是否会导致疾病或改变药物反应，并可以区分肿瘤中的癌症驱动突变与背景突变。

DESCRIPTION (provided by applicant): Project Summary: 518 human protein kinases modulate the activity of -30% of all proteins, and collectively control almost all complex pathways and decisions of a cell. Despite tremendous experimental analysis on some kinases, we know little of the detailed function of most members of this uniquely important family. We propose to use genome sequences to tap hundreds of millions of years of evolutionary experimentation, in order to clarify the link between kinase sequence and biological function. We will use our extensive knowledge from the discovery of the human and mouse kinomes to predict all kinase orthologs in up to 40 vertebrate genomes. We will then map the evolutionary constraints on every residue of every kinase, and predict domains, motifs, phosphorylation sites, and other functional regions of proteins, extending the kinome catalog to unprecedented resolution and generating a wealth of hypotheses for experimental testing. Finally, we will apply this knowledge to predict the functional impact of both SNPs and somatic mutations in cancer, providing a valuable preview of the proposed cancer genome atlas. By using kinases as a model family to explore the predictive power of comparative genomics, we will develop well-validated tools and parameters which can then be applied to any human gene or gene family. Relevance: Protein kinases key controllers of cell function, are one of the most important gene families in disease and development of new drug therapies. By exploring how human kinases vary from those of other vertebrates, we can predict whether any human sequence change can predispose to disease or alter drug response, and can distinguish cancer-driving mutations in tumors from background mutations.