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

项目总结： 人畜共患疾病是由于病原体从动物宿主向人类的溢出而引起的. 接触接触动物或动物产品据估计，60%的已知传染病和 高达75%的新发传染病起源于人畜共患病。尽管如此，相对而言， 已知在高度封闭的人中人类微生物组的变化 与农场里的动物接触。我们建议进行一项研究，以了解致病性和非致病性 高度接触家畜的致病效应。我们将使用鸟枪式元基因组学 为了调查在人畜共患病暴露后哪些细菌在人体肠道内定植，哪些细菌是 被殖民者击败，以及哪种细菌适应。以实现与以下各项的比较 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 假设所有基因组都被无误地观察到，这种情况对于元基因组来说很少发生。 组装基因组(MAG)。例如，MAG可能会省略真正存在于 靶基因组或MAG可能包含错误观察到的基因。要解决以下限制 目前的方法，我们将开发统计方法，以调整不同的质量在 元基因组组装后基因组的基因水平比较。此外，我们还将开发 基于最大化功率的猎枪测序实验设计导则 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 共同之处，并提出了广泛适用的基本比较方法 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.