Comprehensive identification of parent of origin effects in human and mouse

全面鉴定人类和小鼠的亲本效应

• 批准号: 8898866
• 负责人: Andrew James Sharp
• 金额: $ 44.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898866
• 关键词: Adult; Alleles; Animal Model; Child; Chromosomes; DNA; DNA Methylation; Data; Data Set; Detection; Development; Diabetes Mellitus; Disease; Epigenetic Process; Experimental Designs; Fathers; Fetal Tissues; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genome; Genomic Imprinting; Genotype; Goals; Growth and Development function; Heterozygote; Histocompatibility Testing; Human; Human Development; Human Genome; Hybrids; Individual; Inherited; Malignant Neoplasms; Mammals; Maps; Metabolic syndrome; Methods; Methylation; Mothers; Mus; Parents; Paternal uniparental disomy; Patients; Phenotype; Play; Population; RNA; RNA Sequences; Regulatory Element; Research; Risk; Role; SNP genotyping; Single Parent; Site; Syndrome; System; Text; Tissue-Specific Gene Expression; Uniparental Disomy; Variant; base; bisulfite sequencing; cohort; comparative; disease phenotype; disorder risk; gene function; genome wide association study; genome-wide; human disease; imprint; in vivo Model; insight; mammalian genome; novel; offspring; parental role; transcriptome sequencing

Genomic imprinting is an epigenetic mechanism that modifies gene expression in a manner that is dependent on parental origin. Some estimates suggest that as many as 3% of genes show evidence of imprinting. however the true extent of imprinting in mammals remains unknown. Many imprinted genes play important roles in development, and there is now good evidence that imprinting also contributes towards the common diseases such as cancer, diabetes and metabolic syndrome. The identification of imprinting is therefore important for the proper understanding of genome function in relation to disease. I propose a research plan that utilizes a variety of complementary strategies to identify parent of origin effects at both the DNA and RNA level using studies of human and mouse. Our three specific aims are: i) Perform comparative DNA methylation profiling in a cohort of 113 patients with uniparental disomy (UPD). Patients with UPD provide a unique system that allows the isolated study of DNA derived from a single parent, representing a powerful system for the detection of differentially methylated regions. These data will provide a genome-wide map of loci that show parent-of origin specific methylation in human. ii) Utilize a novel genome-wide association study approach that utilizes SNP genotype and gene expression data in trios to identify imprinted regulatory elements. We will perform RNAseq studies of 150 offspring from HapMap trios for which genome-wide SNP data are available. These studies will allow genome- wide detection of regulatory elements that show parent of origin biases on gene expression. iii) Perform deep RNA sequencing and whole-genome bisulfite sequencing in three different adult and fetal tissues types isolated from F1 hybrid mice produced by reciprocal C57/Bl6 and Mus castaneus matings. These F1 hybrids represent an in vivo model in which there is a high heterozygosity rate across the genome, with each variant of defined parental origin, therefore representing a powerful system for detecting imprinting. These data will enable the comprehensive assessment of both imprinted gene expression and differential methylation marks in multiple tissue types. These studies will produce a comprehensive map of parent of origin effects in the mammalian genome, providing a strong basis for future studies of the effects of imprinting in many human diseases.

基因组印记是一种表观遗传机制，以依赖性方式修饰基因表达 关于父母的起源。一些估计表明，多达3％的基因表现出印迹的证据。然而 在哺乳动物中印刷的真实程度仍然未知。许多印迹基因在 发展，现在有充分的证据表明印迹也有助于常见疾病 例如癌症，糖尿病和代谢综合征。因此，识别印迹对于 与疾病有关的基因组功能的正确理解。我提出了一个利用一个的研究计划 使用DNA和RNA级别识别起源效应父母的各种互补策略 人类和小鼠的研究。我们的三个具体目标是： i）在113例单元疾病患者的队列中进行比较DNA甲基化分析 （UPD）。具有UPD的患者提供了一个独特的系统，该系统允许孤立研究从单个的DNA 父母，代表一个强大的系统，用于检测差异甲基化区域。这些数据将 提供全基因组基因座图，该图显示了人类中父母特有的甲基化。 ii）利用一种利用SNP基因型和基因的新型基因组关联研究方法 三重奏中的表达数据以识别印迹的调节元素。我们将进行150项RNASEQ研究 可以提供全基因组SNP数据的HAPMAP三重奏的后代。这些研究将允许基因组 - 广泛检测了显示基因表达的原始偏见父母的调节元素。 iii）在三个不同的成年和 从相互C57/BL6和mus castaneus递减产生的F1杂种小鼠中分离出的胎儿组织类型。 这些F1杂种代表了一个体内模型，其中基因组跨基因组具有较高的杂合速率， 因此，定义的父母来源的每个变体都代表了一个强大的系统来检测印迹。 这些数据将对印迹基因表达和差异进行全面评估 多种组织类型中的甲基化标记。 这些研究将为哺乳动物基因组中起源效应的父母综合图，即 为未来对许多人类疾病的印迹的影响的研究提供了强有力的基础。