Deciphering the mechanisms and dynamics of proto-gene evolution

描述（由申请人提供）：全面的科学挑战。在过去的世纪，对正常和患病表型的遗传决定因素建模的探索一直是生物学研究的核心。然而，基因型-表型关系仍然知之甚少。系统生物学的核心原则是动态分子相互作用的复杂网络介导基因型-表型关系，而进化生物学的核心原则是基因型-表型关系由自然选择控制。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，以提高对基因型-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性状的进化和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由非经典转录物的广泛翻译产生的临时“原基因”从头出现（Carvunis et al.，Nature 2012）。这种进化模型表明，翻译调节和进化适应之间的直接联系。我目前的研究旨在测试这些预测，并调查原基因进化的动力学和机制。候选人和指导计划。我在《自然》和《科学》等期刊上发表了六篇第一作者或共同第一作者的论文，在研究生产力和创造力方面有着无可挑剔的记录。在哈佛医学院Vidal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都获得了极好的培训。我曾参与大型国际合作项目， 撰写评论手稿，并有幸指导许多学生。然而，如果我想追求我选择的研究方向，充分发挥其潜力，我需要在未来两年内开发一系列新技能。我最近搬到了加州大学，以便与一个出色的指导团队一起工作。在一起，教授。Ideker（UCSD）和Weissman（UCSF）将i）教我如何设计和执行传统和尖端的基因组实验，ii）用综合系统生物学和下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）培训我的赠款写作和实验室管理技能，v）在向独立过渡期间指导我。我还将参加加州大学圣地亚哥分校博士后学者事务办公室提供的正式培训机会，并参加著名的冷泉港实验室技术课程，进行密集的实验培训。奖励指导阶段的拟议科学计划。在该奖项的指导阶段，我将研究经典蛋白质编码基因的翻译调控和适应潜力，这仍然知之甚少。这些研究方向将改善细胞网络，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人员利用这些数据。为奖励的独立阶段提出科学计划。凭借我强大的背景和在指导阶段获得的相关培训和数据，我将在一个独特的位置，发展我的原创研究作为一个独立的研究者在美国顶级研究机构之一。我将具备成功解决以下问题所需的所有专业知识和成熟度。原始基因库有多大，有多大活力？原始基因如何影响健康？原始基因模型是否具有普遍性？这种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，并成为一个富有成效的独立研究生涯的开始。确定人类基因组中是否包含原始基因，正如我强烈怀疑的那样，将对公共卫生具有重大意义。

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.