Regulatory Morif Discovery in the Human Genome Using Comparative Genomics

描述（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件列表，还需要全面了解它们如何共同发挥作用。沿着基因，我们的基因组包含了控制基因表达所需的所有信号，以响应环境和发育刺激。这些调控过程由短序列基序控制，负责在各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，并且它们可以作用的距离不同，因此识别调控基序特别具有挑战性。鉴于它们的特殊重要性，系统地了解它们仍然是现代生物学的主要挑战之一。在拟议的工作中，我们使用多种哺乳动物的比较基因组学系统地识别和表征人类基因组中的调控基序的基础上，他们的进化保守性。我们开创了一种新的强大的方法，从头基序发现通过使用全基因组保守，并成功地将其应用于四个酵母基因组，十二苍蝇基因组，和人类启动子和3 '-UTR。在这里，我们扩展了这种方法，在整个人类基因组进行基序发现：（1）我们开发的方法，使用几十种哺乳动物的基序发现和表征;（2）我们确定显着的基序组合和语法，并揭示其功能作用;（3）我们发现功能区的基序聚类和研究基序在指定增强子功能的作用。鉴于NHGRI的测序工作现在包括30多个哺乳动物基因组，特别是为了了解人类，拟议的工作是及时的。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，并提供了人类基因调控的具体组成部分。这将使全世界的研究人员能够通过它们的共调节将新基因连接到通路中，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。一个全球性的监管图案地图构成了一个必要的知识基础设施，以全面了解监管，发展和疾病。

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.