CAREER: PRUGC---Phylogenetic Reconstructions with Unequal Gene Contents

该项目旨在解决祖先基因组的重建问题，以及基因组重排以及基因复制和缺失进化事件可能导致基因含量偏离的基因组的进化史问题。它将缩小稳定增长的测序基因组数量与现有系统发育重建工具无法处理不同种类基因组之间的差距。新的PRUGC软件将采用多个断点图的框架，该框架将得到扩展，以解决由基因含量不相等的基因组引起的新算法挑战。由于这些挑战中的一些可能很难，并且没有计算上可行的解决方案，而不是专注于固定的进化模型并试图将生物学问题纳入其中，PI将使模型变得灵活和问题驱动。在PRUGC的发展过程中，PI计划解决以下特别重要的生物学问题（按复杂程度排序）：哺乳动物进化中灵长类-啮齿动物-食肉动物分裂的争议（具有相对较少的重复数量）；多种酵母基因组的系统发育分析，包括经历全基因组复制的基因组；植物进化中的进化问题主要是片段复制。这些问题的解决方案将有助于更好地理解各种基因组中染色体进化背后的机制。重建的祖先基因组将提供对特定基因序列的功能意义的见解，有助于严格估计不同生物体中基因组重排和基因复制/缺失的速率，并允许测试关于其机制和对形成基因组结构的影响的假设。需要强调的是，PRUGC软件将具有广泛的应用范围，而不仅仅局限于上述问题。PRUGC软件将有助于“生命之树”、“基因组10K”和“i5k”等项目中的各种系统基因组学研究。它将作为一个独立的开源工具和一个在线网络服务器应用程序发布，可供生物学家随时使用。该项目将支持PI研究实验室的研究活动。特别是，它将通过提供在计算机科学和生物学方面的实践经验的机会，帮助培养新一代的生物信息学研究人员。在该项目的支持下，将招募一名本科生和两名博士生，PI将指导这些学生，并为他们在学术界或工业界的职业生涯做好准备。PI将尽一切努力帮助学生获得第一手的生物学经验，包括短期访问我们的地方，国家和国际合作者。这样的经验也将帮助学生发展和提高他们与其他领域的研究人员交流的能力，这是跨学科研究的一项重要技能。该计划亦将为计算机科学专业的学生提供学习生物信息学跨学科领域的实验和理论研究的绝佳机会。详细解释多基因组比较的整个过程将完全符合生物信息学课程的时间框架。PI计划在南卡罗莱纳大学为本科生和研究生开设的生物信息学课程欧安会555中讲授这些材料。作为生物信息学教育联盟开发“生物学家的生物信息学”（B4B）教科书的成员，PI与编辑们协调，为B4B的下一版编写新的章节模块和基于网络的教育材料，这些材料将扩展当前关于基因组重排的章节，并说明它们在PRUGC项目中的一些生物学问题中的应用。

The proposed project addresses the problem of reconstruction of ancestral genomes and evolutionary history of genomes that may deviate in gene content, resulting from genome rearrangements as well as gene duplications and deletions evolutionary events. It will close the gap between steadily growing number of sequenced genomes and incapability of existing phylogenetic reconstruction tools to process diverse varieties of genomes.The new PRUGC software will employ the framework of multiple breakpoint graphs that will be extended to address new algorithmic challenges arising from genomes having unequal gene contents. As some of these challenges may be hard and have no computationally feasible solutions, instead of focusing on a fixed evolutionary model and attempting to fit biological problems into it, the PI will let the model be flexible and problem-driven. In the course of PRUGC development, the PI plans to address the following particularly important biological problems (listed in the order of growing complexity): the primate-rodent-carnivore split controversy in mammalian evolution (featuring relatively small number of duplications); phylogenetic analysis of a diverse variety of yeast genomes including genomes that undergone whole genome duplications; and evolutionary problems in plant evolution rich in segmental duplications. Solutions to these problems will help to better understand the mechanisms behind chromosome evolution across variety of genomes. The reconstructed ancestral genomes will provide insights to functional significance of particular gene orders, help to rigorously estimate the rate of genome rearrangements and gene duplications/deletions in different organisms, and allow testing hypotheses about their mechanisms and influence on shaping genomic architectures. It is important to emphasize that the PRUGC software will have a wide range of applications, not limited to the aforementioned problems. The PRUGC software will be helpful in various phylogenomic studies within projects like "Tree of Life", "Genome 10K", and "i5k". It will be released as both a standalone open-source tool and an online web-server application readily accessible for use by biologists. The project will support research activities in the PI's research lab. In particular, it will help to prepare a new generation of researchers in bioinformatics by providing the opportunities to have hands-on experiences in both computer science and biology. One undergraduate student and two Ph.D. students will be recruited with the support of this project, and the PI will mentor these students and prepare them for building their careers in academia or industry. The PI will make every effort to help the students gain first-hand experience of biology, including short-term visits to our local, national, and international collaborators. Such experience will also help the students to develop and enhance their ability to communicate with researchers in other areas, an important skill in interdisciplinary research. The project will also offer an excellent opportunity for computer science students to learn about experimental and theoretical research in the interdisciplinary area of bioinformatics. Detailed explanation of the whole process of multiple genomes comparison will perfectly fit into a timeframe of a bioinformatics course. The PI plans to lecture this material within the bioinformatics course CSCE 555 offered for undergraduate and graduate students at the University of South Carolina. As a member of the Bioinformatics Education Alliance developing "Bioinformatics for Biologists" (B4B) textbook, the PI coordinated with the editors preparation of a new chapter module and web-based educational materials for the next edition of B4B that will expand the current chapter on genome rearrangements and illustrate their applications with a number of biological problems within the PRUGC project.