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

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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.