A statistical framework for the evaluation and comparison of complex networks and its application to microbiome research

在过去的十年中，测序技术的进步已经从包括原核生物和真核生物在内的无数生物中产生了大量的序列，并且不断降低成本，增加了序列读取的数量和长度。此外，宏基因组学目前正直接从环境或组织样本中提供前所未有的丰富DNA序列，可用于通过复杂网络详细描述生物系统的巨大多样性。***网络通常是指一组离散实体及其在多维空间中的相互作用的基于数学图的表示。网络是分析生物系统及其组成部分之间复杂关系的有用概念工具；它们可以应用于基因组和宏基因组数据，其中个体实体（节点）可以用序列、个体、物种、地理位置或此类组织水平的任何组合来表示。连接这些节点的链接（边）可以表示系统发育距离、遗传和功能相似性或地理距离。如何从这样的网络中提取有用的信息是研究人员非常感兴趣的问题。然而，我们缺乏一个适当的统计框架来识别和比较这些网络。本提案的目标有两个方面：首先，我将开发一系列统计和图形理论方法，使用基于网络的方法有效地分析大型基因组和宏基因组数据集。其次，我将应用这些技术来表征和比较各种微生物组项目中产生的网络。也就是说，提案被分解为五个活动。在活动1中，我将根据路径长度分布的新分类公式开发一个统计框架来评估网络。在活动2中，我将开发新的指标来比较基于图形主题的网络，并为此开发一个统计程序。在活动3中，我将通过比较病毒组和微生物组网络，应用这些新工具来评估蝙蝠中新发疾病的风险。在活动4中，我将应用相同的技术来评估受白鼻综合征影响的蝙蝠物种的皮肤微生物组和真菌组之间的联系。在活动5中，我将研究一种濒危蝾螈物种的皮肤微生物组，以测量杂交事件对受壶菌病影响的同域和异域种群的影响。**

During the last decade, advances in sequencing technologies have generated an enormous volume of sequences from a myriad of organisms including both prokaryotes and eukaryotes, and have done so with continuous cost reduction and increased numbers and lengths of sequence reads. In addition, metagenomics is currently providing an unprecedented richness of DNA sequences directly from environmental or tissue samples that can be used to describe in detail the enormous diversity of biological systems using complex networks. ***Networks generally refer to mathematical graph-based representations of a set of discrete entities and their interactions in multidimensional space. Networks are useful conceptual tools for analyzing biological systems and the complex relationships among their constituents; they can be applied to genomic and metagenomic data in which individual entities (nodes) can be represented by sequences, individuals, species, geographic locations, or any combination of such levels of organization. The links (edges) connecting such nodes can represent phylogenetic distances, genetic and functional similarities, or geographic distances. How to extract useful information from such networks is a question of acute interest for researchers. Yet we lack a proper statistical framework to identify and compare these networks.***The goal of this proposal is two fold: First, I will develop a series of statistical and graph-theoretical methods to efficiently analyze large genomic and metagenomic datasets using network-based approaches. Second, I will apply such techniques to characterize and compare networks generated in a variety of microbiome projects. Namely, the proposal is broken down in five activities. In activity 1, I will develop a statistical framework to evaluate networks based on a new categorical formulation of path length distributions. In activity 2, I will develop new metrics to compare networks based on graph motifs and a statistical procedure for doing so. In activity 3, I will apply these new tools to assess the risk of emerging diseases in bats by comparing virome and microbiome networks. In activity 4, I will apply the same techniques to evaluate the link between the skin microbiome and mycobiome in bat species affected by the white nose syndrome. In activity 5, I will study the skin microbiome of a threatened salamander species to measure the impact of hybridization events in sympatric and allopatric populations affected by chytridiomycosis. **