DNA methylation and its relationship to gene expression and physiologic traits

DNA甲基化及其与基因表达和生理特征的关系

• 批准号: 8449676
• 负责人: Matteo Pellegrini
• 金额: $ 43.61万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449676
• 关键词: Bioinformatics; Candidate Disease Gene; Cells; Cytosine; DNA; DNA Methylation; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Employee Strikes; Epigenetic Process; Etiology; Exhibits; Female; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Global Change; Heart Diseases; Human; Human Genome; Hybrids; Inbred Strain; Inbred Strains Mice; Individual; Laboratories; Liver; Malignant Neoplasms; Maps; Measures; Metabolic; Methodology; Methylation; Mono-S; Mouse Strains; Mus; Obesity; Parents; Pattern; Phenotype; Physiological; Population; Proteomics; Quantitative Trait Loci; RNA; Resolution; Site; System; Technology; Testing; Thymine; Time; Transgenic Organisms; Variant; base; bisulfite; clinical phenotype; disease phenotype; genetic resource; genome analysis; genome wide association study; genome-wide; high throughput technology; imprint; interest; male; metabolomics; methylome; molecular phenotype; novel; protein metabolite; sex; trait; transcriptomics

DESCRIPTION (provided by applicant): Common diseases, such as heart disease, diabetes, and cancer, exhibit multifactorial etiologies with clear genetic and environmental contributions. Tremendous progress in understanding the genetic basis of common disease has been made during the past decade through the sequencing of the human and other genomes, analysis of common variation in human populations, and the development of high throughput technologies for genotyping and gene expression analyses. Over the past several years, Human Genome Wide Association Studies (GWAS) have robustly revealed hundreds of novel loci for common diseases, although in most cases these explain a small fraction of the estimated genetic component. Efforts to extend association approaches, by searching for less common or rare variants using array technologies and high throughput sequencing, are underway. It has also become clear that epigenetics, of which DNA methylation is one of the more stable and heritable manifestations, is an important, although largely uncharacterized, contributor to common diseases. We now propose to extend GWAS in a novel direction by examining, on a global level, the relationship between the methylation state of the genome, DNA variation, gene expression, and physiologic traits associated with common disease. The proposal evolved from the complementary ongoing studies in the laboratories of Drs. Lusis, Pellegrini, and Jacobsen, which coincide with the development of highly efficient sequencing technologies that have made large scale bisulfite sequencing studies feasible. Specifically, the laboratory of Dr. Lusis has developed a "systems genetics" resource consisting of 100 inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP), that has sufficient power to achieve high resolution mapping (1-2 Mb) for loci contributing to transcriptomic, proteomic, metabolomic, and physiologic traits. The laboratories of Drs. Pellegrini and Jacobsen have the capacity to contribute the latest generation sequencing technology and expertise for the purpose of establishing the genome-wide DNA methylation status for 100 mouse strains in the HMDP at single base resolution. This study will represent the first systematic effort to associate epigenetic patterns with metabolic and common disease phenotypes on a genome-wide scale. If funded, we believe this project will significantly alter the paradigm of GWAS studies, by demonstrating the impact of epigenetics on heritable phenotypic traits.

描述（由申请人提供）：常见疾病，例如心脏病，糖尿病和癌症，表现出具有清晰遗传和环境贡献的多因素病因。在过去的十年中，通过人类和其他基因组的测序，人群中常见变异的分析以及用于基因分型和基因表达分析的高通量技术的发展，在过去的十年中，已经取得了巨大的进步。在过去的几年中，人类基因组广泛的关联研究（GWAS）强劲地揭示了数百种新型基因座常见疾病，尽管在大多数情况下，它们解释了一小部分估计的遗传成分。正在进行努力，通过搜索阵列技术和高吞吐量测序的较少常见或稀有变体来扩展关联方法。同样清楚的是，表观遗传学，其中DNA甲基化是最稳定和可遗传的表现之一，这是重要的，尽管很大程度上没有表现为常见疾病。现在，我们建议通过在全球水平上研究基因组的甲基化状态，DNA变异，基因表达和与共同疾病相关的生理性状之间的关系，以朝着新的方向扩展GWA。该提案是从DRS实验室进行的互补研究中演变而来的。 Lusis，Pellegrini和Jacobsen与高效的测序技术的发展相吻合，这些技术使大规模的Bisulfite测序研究可行。具体而言，Lusis博士的实验室已经开发了一种“系统遗传学”资源，该资源由100个近交菌株组成，称为Hybrid Mouse多样性面板（HMDP），该面板具有足够的能力，可以实现高分辨率映射（1-2 MB），以促进转录，蛋白质组分，蛋白质组，分泌组分和物理学和物理学和物理学和物理学细节。博士的实验室。 Pellegrini和Jacobsen具有最新一代测序技术和专业知识的能力，目的是在单个碱基分辨率下建立HMDP中100个小鼠菌株的全基因组DNA甲基化状态。这项研究将代表将表观遗传模式与全基因组量表相关的代谢和常见疾病表型的首次系统努力。如果资助，我们认为该项目将通过证明表观遗传学对可遗传表型特征的影响，从而显着改变GWAS研究的范式。