Regulatory Morif Discovery in the Human Genome Using Comparative Genomics

描述（由申请人提供）：为了实现人类基因组计划的承诺，我们不仅需要所有基因的部分列表，还需要全面了解它们如何协同工作。除了基因之外，我们的基因组还包含了控制基因表达以应对环境和发育刺激所必需的所有信号。这些调控过程是由短序列基序控制的，负责在每个水平上调节基因的使用。尽管它们普遍存在，但由于它们的长度很短，并且它们可以起作用的距离不同，因此识别调控基序尤其具有挑战性。鉴于它们的非凡重要性，对它们的系统理解仍然是现代生物学的主要挑战之一。在本研究中，我们利用多种哺乳动物的比较基因组学，基于人类基因组的进化保守性，系统地识别和表征了人类基因组中的调控基序。我们开创了一种新的强大的方法，利用全基因组保护来发现从头开始的基序，并成功地将其应用于4个酵母基因组，12个苍蝇基因组，以及人类启动子和3'- utr。在这里，我们将这种方法扩展到在整个人类基因组中进行基序发现：(1)我们开发了使用数十种哺乳动物物种进行基序发现和表征的方法；(2)识别出重要的母题组合和语法，揭示其功能角色；(3)发现基序聚类的功能区，研究基序在确定增强子功能中的作用。考虑到NHGRI的测序工作现在已经涵盖了30多种哺乳动物基因组，特别是为了了解人类，这项工作是及时的。此外，大规模的系统实验正在提供必要的功能信息，以告知和验证我们的发现。通过揭示控制基因使用的潜在序列模式，我们补充了这些正在进行的努力，并为人类基因调控的具体构建块提供了途径。这将使世界各地的研究人员能够通过它们的共同调节将通路中的新基因联系起来，阐明非编码snp在调节性疾病中的作用，并为现代医学带来新的测试和治疗方法。调控基序的全球地图为全面理解调控、发展和疾病提供了必要的知识基础。

DESCRIPTION (provided by applicant): To realize the promise of the human genome project, we need not only the parts list of all the genes, but also a comprehensive understanding of how they function together. Along with genes, our genome contains all the signals necessary for controlling gene expression in response to environmental and developmental stimuli. These regulatory processes are governed by short sequence motifs, responsible for modulating gene usage at every level. Despite their prevalence, regulatory motifs have been particularly challenging to identify, due to their short length and the varying distances at which they can act. Given their extraordinary importance, their systematic understanding still remains one of the major challenges of modern biology. In the proposed work, we use comparative genomics of multiple mammals to systematically identify and characterize regulatory motifs in the human genome based on their evolutionary conservation. We have pioneered a new powerful approach for de novo motif discovery by using genome-wide conservation, and successfully applied it in four yeast genomes, twelve fly genomes, and human promoters and 3'-UTRs. Here we expand this methodology to undertake motif discovery across the entire human genome: (1) we develop methods that use dozens of mammalian species for motif discovery and characterization; (2) we identify significant motif combinations and grammars and reveal their functional roles; and (3) we discover functional regions of motif clustering and study motif role in specifying enhancer function. The proposed work is timely, given that NHGRI's sequencing efforts now encompass more than 30 mammalian genomes, specifically for understanding the human. Moreover, large-scale systematic experimentation is providing the functional information necessary to inform and validate our findings. By revealing the underlying sequence patterns that govern gene usage, we complement these ongoing efforts and provide access to the concrete building blocks of human gene regulation. This will enable researchers world-wide to link new genes in pathways by their co-regulation, elucidate the role of non- coding SNPs in regulatory diseases, and lead to new tests and therapeutics for modern medicine. A global map of regulatory motifs constitutes a necessary knowledge infrastructure towards a comprehensive understanding of regulation, development, and disease.