CAREER: Modeling Missense Mutation

职业：错义突变建模

• 批准号: 0845275
• 负责人: Rachel Karchin
• 金额: $ 61.89万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0845275&HistoricalAwards=false
• 关键词: CAREER; Modeling; Missense; Mutation

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). This is a CAREER award to support the research of Dr. Rachel Karchin, who holds appointments in the Department of Biomedical Engineering, Department of Computer Science, Institute for Computational Medicine, Whiting School of Engineering, Johns Hopkins University and Institute of Genetic Medicine, Johns Hopkins School of Medicine. She is a third-year, tenure-track Assistant Professor. High-throughput genome sequencing has resulted in vast amounts of data on amino acid residue sequence variation (i.e. missense mutations). This has presented the opportunity to increase our understanding of how protein sequence, structure, and function are inter-related. Further in order to understand the role of the interactions between individual mutations, accurate modeling methods are needed. This will bring the field closer towards understanding the genetic basis of natural protein evolution and to improve efforts to evolve proteins in the laboratory. This project is developing computational methods for missense mutant function prediction. These models are resulting in the ability to explore the importance of biological context in protein response to missense mutation (such as loss or gain of activity), the generalizability of such responses among different proteins, and the relative importance of biophysics and phylogeny at these predictions. Further, an experimental verification of these model predictions is being tested in a directed evolution system in Escherichia coli. The work will contribute to computational research in public health (genetic components of disease), agriculture, and ecology (plant and animal susceptibility to pathogens and parasites, resistance to herbicides and insecticides, response to fertilizers). As part of her CAREER plan Dr. Karchin will introduce high school students from groups underrepresented in science, particularly disadvantaged young women, to computational biology. A unique approach to this activity is a molecular evolution computer game designed by the PI for high school students in which an agent-based model is employed to evolve a highly fit population of toy proteins in a virtual environment. Further information on the products of this award and how to access them will be found at the PI's lab web site at http://karchinlab.org/.

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。这是一个职业奖，以支持博士的研究。Rachel Karkin博士在约翰霍普金斯大学怀汀工程学院生物医学工程系、计算机科学系、计算医学研究所和约翰霍普金斯医学院遗传医学研究所任职。她是一个第三年，终身制轨道助理教授。高通量基因组测序已经产生了大量关于氨基酸残基序列变异（即错义突变）的数据。这为我们提供了一个机会，让我们进一步了解蛋白质序列、结构和功能是如何相互关联的。此外，为了理解个体突变之间相互作用的作用，需要精确的建模方法。这将使该领域更接近理解天然蛋白质进化的遗传基础，并改善在实验室中进化蛋白质的努力。这个项目正在开发错义突变功能预测的计算方法。这些模型能够探索蛋白质对错义突变的反应（如活性的丧失或获得）中生物背景的重要性，不同蛋白质之间这种反应的普遍性，以及生物物理学和遗传学在这些预测中的相对重要性。此外，这些模型预测的实验验证正在测试中的定向进化系统在大肠杆菌。这项工作将有助于公共卫生（疾病的遗传成分），农业和生态学（植物和动物对病原体和寄生虫的易感性，对除草剂和杀虫剂的抗性，对肥料的反应）的计算研究。作为她职业生涯计划的一部分，Karkin博士将向来自科学领域代表性不足的群体的高中生，特别是弱势年轻女性介绍计算生物学。这项活动的一个独特方法是PI为高中生设计的分子进化计算机游戏，其中采用基于代理的模型在虚拟环境中进化出高度适合的玩具蛋白质群体。有关该奖项的产品以及如何访问它们的更多信息，请访问PI实验室网站http://karchinlab.org/。