Roder, Thomas (2023). Decoding Microbial Genomes: Novel User-Friendly Tools Applied to Fermented Foods. (Thesis). Universität Bern, Bern

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Abstract

Over the past two decades, the cost of DNA sequencing per base has significantly outpaced Moore's law. Many organizations and research groups have exploited this trend and generated large amounts of genomic data and made it possible to tackle new research questions. This growth also brings challenges, including the need for faster algorithms, more efficient ways to visualize and explore data, more automatized data processing, and systematic data management. For more than a century, Agroscope collects lactic acid bacteria (LAB) extracted from the Swiss dairy environment. Today, the collection comprises more than 10’000 strains and so far, for about 15% of the strains the genome was sequenced. The over-arching goal of this thesis is to find new ways of exploiting this genetic potential to design new fermented food products including potential additional health benefits, and to understand the underlying mechanisms. One compound with potential health benefits is indole. Previous experiments have shown that indole compounds modulate the gut immune system via the aryl hydrocarbon receptor (AhR). Our objective was to create a yoghurt enriched in indole metabolites through fermentation, and then to examine whether maternal consumption of this yoghurt would enhance gut immune system maturation in germ-free mice. To reduce the number of strains to test, I developed comparative genomics tools to pre-select strains from the strain collection. This led to the successful development of a yoghurt with significantly increased AhR activation activity. In germ-free mice, we could show the expected effect. Based on these comparative genomics tools, I developed the software OpenGenomeBrowser to enable biologists, who know their organisms of interest in great detail, to efficiently explore the genomic data by themselves, without bioinformatics skills or the need for a middleman bioinformatician. The foundation of OpenGenomeBrowser is a simple system for transparent data management of microbial genomes which makes the automation of common bioinformatics workflows possible. In addition, I built a user-friendly website based on modern web technologies to facilitate common bioinformatics workflows. Because of OpenGenomeBrowser's solid foundation, it is the first software of its kind that can be self-hosted and is dataset-independent, making it potentially useful for many similar genome datasets. During the project, we measured thousands of metabolites in yoghurts made using different strains. However, we experienced that no existing tools could adequately connect such a high-dimensional phenotypic dataset to the genomic information, i.e., presence-absence of orthogenes. Finding high-confidence causative links between these datasets is challenging because of the properties of microbial genomes. For instance, clonal reproduction leads to genome-wide linkage disequilibrium, which prohibits the use of techniques developed for human genome-wide association studies (hGWAS). To this end, I developed Scoary2, a complete rewrite and extension of the original microbial GWAS (mGWAS) software Scoary. The key improvements include an implementation of the core algorithm that is orders of magnitude faster and an interactive web-app that enables efficient data exploration of the output, which is crucial given the size of the dataset. With this software, we discovered two previously uncharacterized genes involved in the carnitine metabolism.

Item Type:	Thesis
Dissertation Type:	Cumulative
Date of Defense:	3 July 2023
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
Institute / Center:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 08 Faculty of Science > Department of Biology
Depositing User:	Hammer Igor
Date Deposited:	13 Jul 2023 14:40
Last Modified:	14 Jul 2023 06:21
URI:	https://boristheses.unibe.ch/id/eprint/4421

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