Computational models, algorithms and methods for comparative genomics, applied to pathogens and anopheles mosquitoes genomes

基因组重排是一种罕见的进化事件，它会改变基因沿染色体的顺序。它们可能与病原体的毒力发展、新物种的出现或对新的环境条件或生态位的适应有关。在过去的10年里，我和我的合作者以及其他团队在开发已经广泛适用的方法来推断基因顺序进化场景和祖先基因顺序方面取得了重大进展。 我提议的研究计划的主要目标是扩大现有的方法语料库，以重建祖先基因序列，以解决一些剩余的挑战。我将开发一套全面的数学模型、计算算法、软件、数据分析程序和管道，为生命科学家提供有效和相关的工具，以研究相关物种群体的结构基因组(基因含量、基因顺序)的进化。为了与大规模比较基因组学项目相关，这些工具将在一般进化模型中开发，包括基因复制和丢失、水平基因转移和导入以及基因组重排。此外，为了处理由不同完成程度的基因组组成的数据集，我将开发使用各种测序数据的方法，并在一个综合框架内联合重建基因家族进化、祖先基因顺序和改进的现存和古代基因组支架。 虽然这些方法将适用于许多大规模数据集，但我将深入研究疟疾寄生虫的媒介--按蚊的18个基因组的数据集。特别是，我将补充上面描述的通用方法，以便处理与按蚊(和一般昆虫)进化有关的一些非常具体的问题，例如多态倒置和导入。这将改进按蚊基因组的基因组组合、基因树和祖先基因序列的数据集，这些数据集将成为蚊子生物界的宝贵资源。 第二个将被研究的应用领域是鼠疫的病原体--鼠疫耶尔森氏菌。鼠疫耶尔森菌是一种研究病原体基因组重排的有趣物种，由于最近对历史上大流行(查士丁尼鼠疫和黑死病)涉及的几种古代菌株进行了测序，因此特别令人感兴趣。我的目标是利用这个古老的和现存的测序基因组的独特数据集来开发将DNA整合到病原体比较基因组学中的新方法，并应用于完善我们对高度动态的人类病原体在历史时间尺度上的进化的理解。

Genome rearrangements are rare evolutionary events that alter the order of genes along chromosomes. They can be related to the development of virulence in pathogens, the emergence of new species or the adaptation to new environmental conditions or ecological niches. Over the last 10 years, my collaborators and I, as well as other groups, have made significan t advances in the development of already widely applicable methods for inferring gene order evolution scenarios and ancestral gene orders. The primary goal of my proposed research program is to expand the existing corpus of methods to reconstruct ancestral gene orders to address some of the remaining challenges. I will develop a comprehensive suite of mathematical models, computational algorithms, software, and data analysis procedures and pipelines, providing to life scientists efficient and relevant tools to investigate the evolution of the structural genome (gene content, gene order) of related groups of species. To be relevant to large--scale comparative genomics projects, these tools will be developed within a general evolutionary model, that includes gene duplication and loss, horizontal gene transfer and introgression, and genome rearrangements. Moreover, to handle data sets composed of genomes available in various levels of completion in terms of assemblies, I will develop methods that use sequencing data of various kinds and reconstruct jointly, in an integrative framework, gene family evolution, ancestral gene order and improved extant and ancient genome scaffolds. While these methods will be applicable to many large--scale data sets, I will study in depth a data set of eighteen genomes of Anopheles mosquitoes, the vector of the malaria parasite. In particular, I will complement the generic approaches described above in order to handle some very specific issues related to Anopheles (and insects in general) evolution, such as polymorphic inversions and introgression. This will result in improved data sets of genome assemblies, gene trees and ancestral gene orders of Anopheles genomes that will be valuable resources for the mosquito biology community. The second field of application that will be investigated is the pathogen Yersinia pestis, the agent of the bubonic plague. Yersinia pestis is an interesting species for studying genome rearrangement in pathogens, and is of particular interest due to the recent sequencing of several ancient strains involved in historical pandemics (the Justinian Plague and the Black Death). My goal is to take advantage of this unique data set of ancient and extant sequenced genomes to develop novel methods integrating aDNA in pathogen comparative genomics, with an application to refine our understanding of the evolution of a highly dynamic human pathogen at a historical time--scale.