Deciphering the mechanisms and dynamics of proto-gene evolution

破译原基因进化的机制和动力学

• 批准号: 8618664
• 负责人: Anne-Ruxandra Carvunis
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618664
• 关键词: Address; American; Applications Grants; Award; Binding; Bioinformatics; Biological; Biological Process; Biology; Birth; California; Cell model; Cessation of life; Code; Communities; Complement; Creativeness; Data; Data Set; Educational process of instructing; Environment; Event; Evolution; Fission Yeast; Foundations; Frequencies; Gene Duplication; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Hereditary Disease; Human; Human Genome; Institution; International; Investigation; Journals; Junk DNA; Knowledge; Laboratories; Lead; Link; Manuscripts; Maps; Mediating; Mentors; Modeling; Natural Selections; Nature; Organism; Phase; Phenotype; Plastics; Population; Population Genetics; Positioning Attribute; Prevalence; Process; Productivity; Proteins; Public Health; Publications; Race; Research; Research Personnel; Ribosomes; Risk; Saccharomycetales; Science; Series; Shapes; Students; Supervision; Surveys; Systems Biology; Technology; Testing; Training; Transcript; Transcriptional Regulation; Translating; Translational Regulation; Translations; Universities; Virulent; Wit; Work; Writing; Yeasts; arm; biological research; cancer cell; career; design; fitness; fly; gene function; genome analysis; genome sequencing; genome-wide; improved; innovation; insight; medical schools; next generation sequencing; novel; overexpression; pathogen; pleasure; polypeptide; programs; protein function; public health relevance; research study; response; skills; trait; vector control; yeast genome

DESCRIPTION (provided by applicant): Overarching scientific challenge. The quest to model the genetic determinants of normal and diseased phenotypes has been at the core of biological research for the past century. However, genotype-phenotype relationships remain poorly understood. The central tenet of systems biology is that intricate networks of dynamic molecular interactions mediate genotype-phenotype relationships, while that of evolutionary biology is that genotype-phenotype relationships are governed by natural selection. I propose to establish an integrative research program aimed at deciphering how evolution shapes the organization of biological networks, in order to improve understanding of genotype-phenotype relationships. Current research goals. I aim to determine how the emergence of new genes contributes to the evolution of new traits and to the adaptation of species confronted with changing environments. I recently proposed that novel protein-coding genes can emerge de novo through transitory "proto-genes" generated by widespread translation of non-canonical transcripts (Carvunis et al., Nature 2012). This evolutionary model suggests a direct link between translational regulation and evolutionary adaptation. My current research aims at testing these predictions and investigating the dynamics and mechanisms underlying proto-gene evolution. Candidate and mentoring plan. With six first or co-first author publications in journals including Nature and Science, I have an impeccable track record of research productivity and creativity. Under the supervision of Prof. Vidal at Harvard Medical School, I have acquired superb training in all bioinformatics aspects involved in the annotation and evolutionary analysis of genomes and protein interaction networks. I have participated in large international collaborative projects, co authored review manuscripts and have had the pleasure to mentor many students. However, if I am to pursue my chosen research direction to its full potential, I need to develop a series of new skills in the next two years. I recently moved to the University of California in order to work wit an exceptional mentoring team. Together, Profs. Ideker (UCSD) and Weissman (UCSF) will i) teach me how to design and execute traditional and cutting-edge genomic experiments, ii) complement my computational training with integrative systems biology and next-generation sequencing bioinformatics skills, iii) help me plan and evaluate my own research, iv) train me in grant writing and laboratory management skills, and v) guide me during the transition to independence. I will also participate in formal training opportunities offered by the Office for Postdoctoral Scholar Affairs at UCSD and seek attendance at renowned Cold Spring Harbor Laboratory technical courses for intense experimental training. Proposed scientific plan for the mentored phase of the award. During the mentored phase of the award, I will investigate the translational regulation and adaptive potential of canonical protein-coding genes, which remain poorly understood. These research directions will improve modeling of cellular networks, gene expression and evolutionary adaptation, while allowing me to acquire new biological knowledge, establish experimental and computational pipelines, and acquire preliminary data, which I will subsequently exploit as an independent researcher. Proposed scientific plan for the independent phase of the award. With my strong background and the relevant training and data obtained during the mentored phase, I will be in a unique position to develop my original research as an independent investigator in one of the top American research institutions. I will have all the required expertise and maturity to successfully address the following questions. How large and how dynamic is the proto-gene reservoir? How do proto-genes influence fitness? Is the proto-gene model universal? This proto-gene research promises to reveal fundamental aspects of protein functions and to open exciting avenues of investigation in the fields of systems biology, genomics and evolution. I expect it will lay the foundation for subsequent grant applications and be the start of a productive independent research career. Determining whether the human genome contains proto-genes, as I strongly suspect, will be of great significance for public health.

描述(申请者提供)：最重要的科学挑战。在过去的一个世纪里，对正常和疾病表型的遗传决定因素进行建模的探索一直是生物学研究的核心。然而，基因-表型之间的关系仍然知之甚少。系统生物学的中心原则是复杂的动态分子相互作用网络调节基因-表型关系，而进化生物学的核心原则是基因-表型关系受自然选择的支配。我建议建立一个综合研究计划，旨在破译进化如何塑造生物网络的组织，以提高对基因-表型关系的理解。目前的研究目标。我的目标是确定新基因的出现如何有助于新特征的进化，以及如何帮助物种适应不断变化的环境。我最近提出，新的蛋白质编码基因可以通过广泛翻译非规范转录本而产生的短暂“原基因”从头出现(Carvunis等人，“自然”，2012)。这一进化模型表明，翻译调控和进化适应之间存在直接联系。我目前的研究旨在验证这些预测，并调查原始基因进化背后的动力和机制。候选人和指导计划。我在包括《自然》和《科学》在内的期刊上发表了六篇第一或联合第一作者的论文，在研究生产率和创造力方面有着无可挑剔的记录。在哈佛医学院维达尔教授的指导下，我在基因组和蛋白质相互作用网络的注释和进化分析所涉及的所有生物信息学方面获得了出色的培训。我曾参与过大型国际合作项目， 撰写了审稿，并有幸指导了许多学生。然而，如果我要追求我选择的研究方向的全部潜力，我需要在接下来的两年里发展一系列新的技能。我最近搬到了加州大学，以便在一个出色的指导团队中工作。在一起，教授们。Ideker(UCSD)和Weissman(UCSF)将教我如何设计和执行传统的和尖端的基因组实验，ii)用综合系统生物学和新一代测序生物信息学技能补充我的计算培训，iii)帮助我计划和评估我自己的研究，iv)培训我撰写拨款和实验室管理技能，以及v)在向独立的过渡期间指导我。我还将参加加州大学伯克利分校博士后学者事务办公室提供的正式培训机会，并寻求参加著名的冷泉港实验室技术课程，进行密集的实验培训。为该奖项的指导阶段提出科学计划。在奖项的指导阶段，我将研究规范蛋白质编码基因的翻译调节和适应潜力，这些基因仍然知之甚少。这些研究方向将改进细胞网络、基因表达和进化适应的建模，同时使我能够获得新的生物学知识，建立实验和计算管道，并获得初步数据，随后我将作为独立研究员加以利用。为奖项的独立阶段提出了科学计划。凭借我雄厚的背景以及在指导阶段获得的相关培训和数据，我将处于独特的地位，能够作为美国顶级研究机构之一的独立研究员发展我的原创研究。我将拥有成功解决以下问题所需的所有专业知识和成熟度。原基因库的规模有多大，活力有多大？原基因是如何影响健康的？原基因模型是通用的吗？这项原基因研究有望揭示蛋白质功能的基本方面，并在系统生物学、基因组学和进化领域开辟令人兴奋的研究途径。我希望这将为随后的拨款申请奠定基础，并成为富有成效的独立研究生涯的开始。正如我强烈怀疑的那样，确定人类基因组是否包含原基因将对公共卫生具有重要意义。