Genetic Transmission of Componenets of the Human Gut Microbiome

项目摘要 生活在人体内的微生物被视为我们生物学中不可或缺的组成部分， 微生物组的可变性已被发现导致疾病易感性的差异。建议数 研究将开发和应用各种方法来推断人类基因组的变异是如何调节的 肠道微生物群的组成和功能。为了实现这一目标，我们将实施四项具体措施 旨在分析已从TwinsUK项目获得的全基因组SNP基因数据，以 确定微生物组组成的遗传决定因素。对于特定的目标1，我们将使用完整- 这对双胞胎的基因组序列数据以及他们肠道的深层元基因组测序 用更高分辨率的分类学推断遗传力和基因特异性关联的微生物群 数据，以及b)细菌群落的代谢属性。这些数据已经掌握，并提供了 剖析人类基因组变异调节肠道的独特机会 微生物组特性。对于特定的目标2，我们将推断肠道微生物群中的单个菌株 从元基因组数据中，利用我们的测序深度足以识别 最常见的~50种细菌的克隆单倍型。特定菌株的生物学影响 可能变化很大，这种针对菌株的分析可能通过提高特异性而提供高度的信息。 以及宿主基因和微生物组组成之间的关联的准确性。针对具体目标3，我们 将对最初的TwinsUK微生物群调查中的1000人进行重新采样，并使用这一 识别肠道微生物群随时间稳定的属性的信息，并测试 微生物组中微生物的遗传力与稳定性的关系。对于具体目标4，我们将 利用灵知生菌小鼠实验系统解剖可遗传细菌的影响 微小克里斯滕森杆菌对肠道功能也有一定的整体生理学作用。这样做的结果 研究将被用来建立人类基因组区域和人类基因组组成之间的联系 微生物组。这项研究的结果有可能揭示人类基本的宿主-微生物 相互作用可能适用于慢性炎症性疾病的预防和治疗。

Project Summary The microbes that inhabit the human body are viewed as an integral component of our biology, and microbiome variability has been found to result in differences in disease predisposition. The proposed research will develop and apply methods to infer how variation in the human genome mediates composition and function of the gut microbiome. To achieve this objective, we will pursue four specific aims in an analysis of genome-wide SNP genotype data already available from the TwinsUK project to identify genetic determinants of microbiome composition. For Specific Aim 1, we will use whole- genome sequence data of the twins along with deep metagenomic sequencing of their gut microbiomes to infer heritability and gene-specific associations with a) greater resolution taxonomic data, and b) metabolic attributes of the bacterial community. These data are already in hand, and provide unique opportunities to dissect the means by which variation in the human genome mediates gut microbiome properties. For Specific Aim 2, we will infer individual strains in the gut microbiomes from the metagenomics data, making use of the fact that our sequencing depth is sufficient to identify clonal haplotypes of the most common ~50 bacterial species. The biological impacts of specific strains can vary widely, and this strain-specific analysis is likely to be highly informative by improving specificity and accuracy of associations between host genes and microbiome composition. For Specific Aim 3, we will resample 1000 individuals from the original TwinsUK microbiome survey, and use this information to identify attributes of the gut microbiome that are stable over time, and to test the relationship between heritability and stability of microbes in the microbiome. For Specific Aim 4, we will use the gnotobiotic mouse experimental system to dissect the effects of the heritable bacterium Christensenella minuta on gut function as well has whole-organism physiology. The results of this research will be used to establish links between regions of the human genome and composition of the microbiome. The results of this study have the potential to reveal fundamental human host-microbe interactions that may be applicable to the prevention and treatment of chronic inflammatory diseases.