DNA methylation and its relationship to gene expression and physiologic traits

描述(由申请人提供)：常见疾病，如心脏病、糖尿病和癌症，表现出多因素病因，具有明显的遗传和环境因素。在过去的十年里，通过对人类和其他基因组的测序，对人类群体中常见变异的分析，以及用于基因分型和基因表达分析的高通量技术的发展，在理解常见疾病的遗传基础方面取得了巨大的进展。在过去的几年里，人类基因组广泛关联研究(GWAS)有力地揭示了数百个常见疾病的新基因座，尽管在大多数情况下，这些基因座解释了估计的遗传成分的一小部分。通过使用阵列技术和高通量测序寻找不太常见或罕见的变异，扩展关联方法的努力正在进行中。表观遗传学也变得很明显，DNA甲基化是比较稳定和可遗传的表现之一，是常见疾病的一个重要因素，尽管很大程度上没有特征。我们现在建议通过在全球水平上检查基因组甲基化状态、DNA变异、基因表达和与常见疾病相关的生理特征之间的关系，将GWAS扩展到一个新的方向。该建议源于Lusis、Pellegrini和Jacobsen博士的实验室正在进行的互补研究，这些研究与高效测序技术的发展相吻合，这些技术使大规模亚硫酸氢盐测序研究成为可能。特别是，Lusis博士的实验室开发了一个由100个近交系小鼠组成的“系统遗传学”资源，称为杂交小鼠多样性小组(HMDP)，该小组有足够的能力实现高分辨率图谱(1-2Mb)，对影响转录、蛋白质组、代谢组和生理性状的基因座进行定位。Pellegrini博士和Jacobsen博士的实验室有能力贡献最新一代的测序技术和专业知识，以确定HMDP中100个小鼠品系在单碱基分辨率下的全基因组DNA甲基化状态。这项研究将是首次在全基因组范围内将表观遗传模式与代谢和常见疾病表型联系起来的系统性努力。如果得到资助，我们相信这个项目将通过展示表观遗传学对可遗传表型特征的影响，显著改变GWAs研究的范式。

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.