Strain resolved metagenomics for medical microbiology

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A great diversity of microbes, live on or in the human body. In particular, the human gut contains hundreds or thousands of species, what is more every individual's microbiota is different. The exact composition of species varies from one person to another. We now realise that this microbiome plays a key role in many aspects of human health including providing nutrients and protection against disease. They have even been implicated in mental health. To study the microbiome in its entirety we sequence the DNA of all members of the community simultaneously, the metagenome. The challenge is then to reconstruct, or assemble, the individual genomes of the community members particularly when the fragments of DNA obtained, the sequence reads, are short, and similar strains of the same species can co-occur.This proposed project will develop a new software tool for resolving genomes from metagenomes. It will better exploit two sources of information that have been under-utilised previously. The first is time series information where multiple samples are available from the same community and the members of the community are fluctuating in abundance. This signal can be used to link small scale differences between very similar strains in the community and resolve genomes to high resolution. The second are long reads that are being generated by new sequencing technologies such as Nanopore. These are noisy but they can be used to determine large scale differences in genome structure unambiguously.The resulting (bioinformatics) tools will enable the research community to understand microbiome composition at high resolution. This could have major implications for our understanding of the microbiome in human health. For example, we will use it to resolve changes in the gut microbiota of children with Crohn's disease when they undergo treatment with a therapeutic diet. Crohn's disease is an inflammatory condition of the gut, where the microbiome exhibits a disturbed or dysbiotic state. If we can resolve exactly which strains increase or decrease in abundance in children who get better when they are treated, then we should be able to understand how the diet works and develop better diets that are personalised to the very different microbiotas of the individual children. This is just one example, these methods could result in a fundamental improvement in our understanding of the microbiome in other inflammatory bowel diseases, e.g. ulcerative colitis, and their treatment with methods such as fecal microbiome transplants. Furthermore, microbial communities (MCs) are important in multiple other areas in addition to human health, including agriculture and biotechnology. These methods will be a major step forward in our ability to study these communities.