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

拟议的项目解决的问题是重建祖先基因组和基因组的进化历史，可能偏离基因内容，造成基因组重排以及基因复制和删除进化事件。它将缩小测序基因组数量稳步增长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软件将采用多断点图框架，该框架将被扩展以解决基因组具有不相等基因内容所带来的新算法挑战。由于这些挑战中的一些可能是困难的，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融入其中，PI将让模型变得灵活和问题驱动。在PRUGC开发过程中，PI计划解决以下特别重要的生物学问题（按复杂性增加的顺序排列）：哺乳动物进化中的灵长类-啮齿类-食肉类分裂之争（具有相对少量的重复）;多种酵母基因组的系统发育分析，包括经历全基因组重复的基因组;以及植物进化中的进化问题，这些问题富含节段复制。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为特定基因序列的功能意义提供见解，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，并允许测试有关其机制和对塑造基因组架构的影响的假设。需要强调的是，PRUGC软件将有广泛的应用，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10 K”和“i5 k”等项目中的各种基因组研究。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，供生物学家使用。 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拥有实践经验的机会，帮助培养新一代的生物信息学研究人员。一个本科生，两个博士生。学生将在本项目的支持下招募，PI将指导这些学生，并为他们在学术界或工业界建立职业生涯做好准备。PI将尽一切努力帮助学生获得生物学的第一手经验，包括短期访问我们的地方，国家和国际合作者。这样的经验还将帮助学生发展和提高与其他领域研究人员沟通的能力，这是跨学科研究的一项重要技能。 该项目还将为计算机科学专业的学生提供一个极好的机会，了解生物信息学跨学科领域的实验和理论研究。多个基因组比较的整个过程的详细解释将完全适合生物信息学课程的时间框架。PI计划在南卡罗来纳州大学为本科生和研究生提供的生物信息学课程CSCE 555中讲授此材料。作为生物信息学教育联盟开发“生物学家的生物信息学”（B4 B）教科书的成员，PI与编辑协调，为下一版B4 B准备了新的章节模块和基于网络的教育材料，这将扩展当前关于基因组重排的章节，并说明其在PRUGC项目中的一些生物学问题的应用。

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.