Strain resolved metagenomics for medical microbiology

多种多样的微生物，生活在人体上或人体内。特别是，人类肠道包含数百或数千种物种，更重要的是每个人的微生物群都是不同的。物种的确切组成因人而异。我们现在意识到，这种微生物组在人类健康的许多方面发挥着关键作用，包括提供营养和预防疾病。它们甚至与心理健康有关。为了研究整个微生物组，我们同时对群落所有成员的DNA进行测序，即宏基因组。因此，我们面临的挑战是重建或组装群落成员的个体基因组，特别是当获得的DNA片段（序列读段）很短，并且同一物种的相似菌株可以共存时。这个拟议的项目将开发一种新的软件工具，用于从宏基因组中解析基因组。它将更好地利用以前未充分利用的两个信息来源。第一种是时间序列信息，其中可从同一社区获得多个样本，社区成员的数量在波动。该信号可用于连接社区中非常相似的菌株之间的小规模差异，并将基因组解析到高分辨率。第二种是由新的测序技术（如Nanopore）生成的长读段。这些是嘈杂的，但它们可以用来确定基因组结构的大规模差异明确。由此产生的（生物信息学）工具将使研究界能够以高分辨率了解微生物组的组成。这可能对我们理解人类健康中的微生物组产生重大影响。例如，我们将使用它来解决克罗恩病儿童在接受治疗性饮食治疗时肠道微生物群的变化。克罗恩病是一种肠道炎症性疾病，其中微生物组表现出紊乱或生态失调状态。如果我们能够准确地解决哪些菌株在治疗后变得更好的儿童中增加或减少，那么我们应该能够了解饮食是如何工作的，并开发出更好的饮食，这些饮食是针对个别儿童非常不同的微生物群而个性化的。这只是一个例子，这些方法可以从根本上改善我们对其他炎症性肠病（例如溃疡性结肠炎）中微生物组的理解，以及用粪便微生物组移植等方法治疗它们。此外，微生物群落（MC）在人类健康以外的多个其他领域也很重要，包括农业和生物技术。这些方法将是我们研究这些社区能力的一个重大进步。

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.