Genetic Transmission of Components of the Human Gut Microbiome

人类肠道微生物组成分的遗传传播

• 批准号: 8532887
• 负责人: ANDREW G CLARK
• 金额: $ 39.45万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532887
• 关键词: American; Bacteria; Bioinformatics; Biological Markers; Biology; Biomedical Research; Candidate Disease Gene; Cataloging; Catalogs; Chronic; Chronic Disease; Classification; Communities; Complement; DNA; Data; Diabetes Mellitus; Diet; Diet Habits; Disease; Disease Outcome; Disease susceptibility; Dizygotic Twins; Family; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Models; Genetic Screening; Genome; Genomics; Genotype; Goals; Health; Heritability; Human; Human Genetics; Human Genome; Human Microbiome; Human body; Individual; Individual Differences; Inflammation; Inflammatory; Knowledge; Laboratories; Libraries; Life Style; Linear Models; Link; Maps; Measures; Metabolic; Methods; Metric; Microbe; Modeling; Monozygotic Twinning; Monozygotic twins; Natural Immunity; Obesity; Pathway interactions; Phylogenetic Analysis; Population; Predisposition; Prevention; Process; Public Health; Quantitative Genetics; Quantitative Trait Loci; Reading; Registries; Relative (related person); Research; Research Personnel; Ribosomal RNA; Sampling; Single Nucleotide Polymorphism; Smoking; Taxon; Testing; Time; Twin Multiple Birth; United States National Institutes of Health; Validation; Variant; base; disorder prevention; genetic variant; genome wide association study; genome-wide; genome-wide analysis; gut microbiota; improved; indexing; interest; microbiome; microorganism interaction; non-genetic; rRNA Genes; therapeutic target; transmission process; volunteer

DESCRIPTION (provided by applicant): The microbes that inhabit the human body are now viewed as an integral component of our biology, and microbiome variability can result in differences in predisposition to disease. The growing interest in this new field of human-microbiome interactions is underscored by the inclusion of the Human Microbiome Project (HMP) in the NIH RoadMap priorities. Our proposed research will complement and extend the goals of the HMP by establishing heritable components of the human microbiome and elucidating the relationship between host genotype and gut microbiome variability. The proposed research will attempt to quantify the magnitude of heritable, inter-individual differences in microbiome composition. To achieve this objective, we will pursue three 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 characterize the microbiomes of 4,000 twin pairs through application of high-throughput Illumina sequencing of fecal samples to generate approximately 300,000 16S rRNA gene sequences for each individual. These rRNA sequence data will catalog and quantify inter-individual variability in microbiota and produce a phylogenetic representation of the microbiome species composition from which several diversity metrics will be distilled. A subset of twins will be sampled at 5 time points to assess temporal stability of microbiome composition. For Specific Aim 2, we will establish the heritability of the gut microbiota by identifying measures of diversity and specific taxon composition that are under host genetic control. The genome-wide SNP data will be used to estimate the proportion of the genome that is shared between each dizygotic (DZ) twin pair (which varies between about 35% and 65%). We will use the covariance of this Identity-by-Descent (IBD) sharing with the microbiome metrics to estimate genetic variance components and provide tests of the hypothesis that each microbiome attribute is heritable. For Specific Aim 3, we will apply IBD and association mapping to identify regions of the human genome responsible for the observed variation in gut microbiomes. At each point along the genome the local IBD sharing for each DZ twin-pair will be inferred, and quantitative genetic models will be fitted by maximum likelihood to estimate additive and dominance variance components for regions containing candidate genes (e.g., innate immunity genes/pathways) and for each local region of the genome. Likelihood ratio tests will determine whether each region has a significant QTL. In addition, we will cluster microbiomes by similarity and identify regions of the human genome with high levels of IBD sharing for twin pairs with similar microbiomes. 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.

描述（由申请人提供）：现在居住在人体的微生物被视为我们生物学的组成部分，微生物组的变异性可能导致疾病易感性的差异。由于将人类微生物组项目（HMP）纳入NIH路线图优先级，人们对这个新的人类微生物组相互作用的兴趣日益增长。我们提出的研究将通过建立人类微生物组的可遗传组成部分并阐明宿主基因型与肠道微生物组变异性之间的关系来补充和扩展HMP的目标。拟议的研究将尝试量化微生物组组成中可遗传的，个体间差异的大小。为了实现这一目标，我们将追求三个特定的目标，以分析Twinsuk项目已获得的全基因组SNP基因型数据，以鉴定微生物组组成的遗传决定因素。对于特定的目标1，我们将通过应用高通量光照射样品测序来表征4,000对双对的微生物组，从而为每个个体生成大约300,000 16S rRNA基因序列。这些rRNA序列数据将分类并量化微生物群的个体间变异性，并产生微生物组物种组成的系统发育表示，从中可以蒸馏出几种多样性指标。双胞胎的子集将在5个时间点进行采样，以评估微生物组组成的时间稳定性。对于特定的目标2，我们将通过确定在宿主遗传控制下的多样性和特定分类单元组成的措施来确定肠道菌群的遗传力。全基因组SNP数据将用于估计每个双胞胎（DZ）双对之间共享基因组的比例（大约在35％至65％之间）。我们将使用与微生物组指标共享这种身份（IBD）共享的协方差来估计遗传方差成分，并提供了每个微生物组属性都是可遗传的假设的测试。对于特定目标3，我们将应用IBD和关联映射来识别导致肠道微生物组变异的人类基因组的区域。在沿基因组的每个点上，将推断出每个DZ双对的局部IBD共享，并且最大似然的定量遗传模型将适合估计包含候选基因区域（例如，先天免疫基因/途径）的添加剂和优势方差成分以及基因局部的每个区域。似然比测试将确定每个区域是否具有显着的QTL。此外，我们将通过相似性聚集微生物组，并确定人类基因组的区域，具有相似微生物组的双胞胎对IBD共享。这项研究的结果将用于建立人类基因组区域与微生物组组成之间的联系。这项研究的结果有可能揭示人类宿主 - 微生物相互作用，可能适用于预防和治疗慢性炎症性疾病。