CAREER: Comparative Genomics and Biological Signal Discovery in the Human Genome

职业：人类基因组中的比较基因组学和生物信号发现

• 批准号: 0644282
• 负责人: Manolis Kellis
• 金额: $ 128.21万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0644282&HistoricalAwards=false
• 关键词: CAREER; Comparative; Genomics; Biological; Signal

Massachusetts Institute of Technology researcher Manolis Kellis is awarded a Faculty Early Career Development award to develop comparative genomics methods that can maximally use mammalian sequences for biological signal discovery and to systematically interpret the human genome. In Aim 1 comparative methods for ortholog identification will be developed that can scale to dozens of complete mammals, can account for the complex phylogenies relating them, gene duplication and loss, and varying rates of divergence across gene families, and across species. In a second aim a classification framework for gene identification will be constructed. Beyond the simple use of comparative genomics to recognize conserved regions, evolutionary signatures will be defined specific to protein-coding regions, based on patterns of insertion and deletion, codon mutational biases, and motif abundance in proximity of exons. Finally, phylogenetically-informed tools for motif discovery and enhancer identification will be developed. The study of rates of motif gain and loss will allow them to derive parameters for every lineage based on the information content of each motif. These parameters will then be used to discover motifs at the genome scale, tolerating motif movement and loss, based on a likelihood ratio of motif conservation over a branch length within a given window of tolerated movement. Further research will develop methods for identifying functional motif combinations, and use these to identify regions of motif clustering, and relate them with experimentally identified enhancer elements and other regions of regulatory importance. Functional information of expression, regulator binding, and chromatin structure from human tissues and cell lines, across the entire genome and in selected ENCODE regions, will provide training data for our methods, and validate datasets for the predictions. Two key model organisms will be the yeast Saccharomyces cerevisiae, and the fruit fly Drosophila melanogaster, which provide unique models for the computational and experimental efforts. Both benefit from large phylogenetic trees with many completely sequenced relatives, compact genomes, and extensive experimental information, which can inform the power of the methods. The ability to work with multiple model organisms will allows the study of each aspect of human biology at the appropriate scale of complexity, from yeast, to fly, mouse, and human, by virtue of the early shared ancestry of our common biology. The education plan involves developing new courses and curricula and a computational biology textbook. The tools produced by the project will be distributed freely. Already strong efforts to include underrepresented groups will continue along outreach activities, such as lectures at museums or working with high school teachers in the Boston area.

麻省理工学院研究员马诺利斯·凯利斯 (Manolis Kellis) 荣获学院早期职业发展奖，以开发比较基因组学方法，最大限度地利用哺乳动物序列发现生物信号并系统地解释人类基因组。在目标 1 中，将开发用于直系同源鉴定的比较方法，该方法可以扩展到数十种完整的哺乳动物，可以解释与它们相关的复杂系统发育、基因复制和丢失，以及跨基因家族和跨物种的不同分化率。第二个目标是构建基因识别的分类框架。除了简单地使用比较基因组学来识别保守区域之外，还将根据插入和缺失的模式、密码子突变偏差和外显子附近的基序丰度来定义特定于蛋白质编码区域的进化特征。最后，将开发用于基序发现和增强子识别的系统发育工具。对基序增益和损失率的研究将使他们能够根据每个基序的信息内容推导出每个谱系的参数。然后，这些参数将用于在基因组规模上发现基序，根据给定的容许移动窗口内的分支长度上基序保守的似然比，容忍基序的移动和丢失。进一步的研究将开发识别功能基序组合的方法，并使用这些方法来识别基序聚类区域，并将它们与实验识别的增强子元件和其他具有监管重要性的区域联系起来。来自人类组织和细胞系、整个基因组和选定编码区域的表达、调节器结合和染色质结构的功能信息将为我们的方法提供训练数据，并验证预测的数据集。两个关键的模型生物是酿酒酵母和果蝇，它们为计算和实验工作提供了独特的模型。两者都受益于大型系统发育树，其中包含许多完全测序的亲属、紧凑的基因组和广泛的实验信息，这些信息可以告诉我们方法的力量。凭借我们共同生物学的早期共同祖先，使用多种模型生物的能力将允许以适当的复杂程度研究人类生物学的各个方面，从酵母到苍蝇、小鼠和人类。该教育计划涉及开发新课程和课程以及计算生物学教科书。该项目产生的工具将免费分发。我们将继续大力努力将代表性不足的群体纳入其中，并继续开展外展活动，例如在博物馆举办讲座或与波士顿地区的高中教师合作。