Statistical pangenomics to study the effects of zoonotic exposure on the gut microbiome

项目摘要： 人畜共患疾病是由于病原体从动物宿主向人类扩散而引起的， 与动物或动物产品接触。据估计，60%的已知传染病和 高达75%的新发传染病是人畜共患疾病。尽管如此， 已知在与人类微生物高度接近的人中， 在农场接触动物。我们提出了一项研究，以了解致病性和非- 牲畜高度接触的致病作用。我们将使用鸟枪宏基因组学 为了研究哪些细菌在人畜共患病暴露后定植在人类肠道中， 被殖民者击败，以及哪些细菌适应。要启用与以下内容的比较，请执行以下操作： 毒力，有益的代谢途径和抗生素耐药性，我们将开发新的 细菌泛基因组学的统计方法。细菌泛基因组学的现有方法 假设所有的基因组都被观察到没有错误，这对于宏基因组来说是很少见的- 组装基因组（MAG）。例如，MAG可能会忽略真正存在于细胞中的基因。 靶基因组或MAG可能含有错误观察到的基因。为了解决 目前的方法，我们将开发统计方法，调整不同的质量， 宏基因组组装基因组的基因水平比较。此外，我们将开发 基于最大功效的鸟枪测序实验设计指南 测试与基因存在相关的假设。圆满完成这些目标 将增加我们对人畜共患病病原体传播机制的了解， 论文，并提出了广泛适用的基本方法，比较 细菌基因组

Project Summary: Zoonotic diseases result from the spillover of pathogens from animal reservoirs to humans due to contact with animals or animal products. An estimated 60% of known infectious diseases and up to 75% of emerging infectious diseases are zoonotic in origin. Despite this, relatively little is known about the alterations to the human microbiome in persons with a high degree of close contact with animals on farms. We propose a study to understand the pathogenic and non- pathogenic effects of a high degree of livestock exposure. We will use shotgun metagenomics to investigate which bacteria colonize the human gut after zoonotic exposure, which bacteria are outcompeted by colonizers, and which bacteria adapt. To enable comparisons with respect to virulence, beneficial metabolic pathways and antibiotic resistance, we will develop novel statistical methods for bacterial pangenomics. Existing methods for bacterial pangenomics assume that all genomes are observed without error, which rarely is the case for metagenome- assembled genomes (MAGs). For example, MAGs may omit genes that are truly present in the target genome, or MAGs may contain erroneously observed genes. To address limitations of current methods, we will develop statistical methodology that adjusts for differential quality in gene-level comparisons of metagenome-assembled genomes. Additionally, we will develop guidelines for the design of shotgun sequencing experiments based on maximizing power to test hypotheses about associations with gene presence. Successful completion of these aims will increase our understanding of the mechanisms of transmission of zoonotic pathogens and commensals, and advance broadly applicable and essential methodology for comparing bacterial genomes.