Heritability of gene expression variants in isogenic mice

等基因小鼠基因表达变异的遗传力

• 批准号: 8588711
• 负责人: DARIO BOFFELLI
• 金额: $ 16.02万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588711
• 关键词: Accounting; Address; Affect; Animals; Appearance; Biological; Breeding; Brothers; Color; Complex; Cues; Cytosine; DNA Methylation; DNA Resequencing; Diet; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Fatty acid glycerol esters; Female; Frequencies; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genome; Goals; Heritability; Inherited; Label; Methylation; Modeling; Molecular; Mouse Strains; Mus; Parents; Pattern; Plants; Regulator Genes; Residual state; Risk; Sister; Source; System; Variant; Work; base; cell type; cohort; disorder risk; epigenetic marker; epigenetic variation; epigenome; genetic pedigree; genome sequencing; genome wide association study; genome-wide; human disease; interest; kindred; male; monocyte; offspring; research study; trait; transcriptome sequencing; transmission process

DESCRIPTION (provided by applicant): The "missing heritability" problem, highlighted by genomewide association studies of human disease, is the inability of common genetic variation to fully account for the heritability of complex traits. This proposal deals with one possible explanation for missing heritability: transgenerational inheritance of epigenetic variants independently of genome sequence. Work by one of the PIs and others in plant and animal species has shown that inheritance of epigenetic variants is very different from Mendelian inheritance. However the number of epigenetic variants that can be transmitted from parents to offspring, and the persistence of transmission through multiple generations, have never been systematically studied in animals. The overall goal of this project is to quantify transmissibilityof epigenetic variation through multiple generations. Isogenic mouse strains allow this study to be carried out in conditions that minimize genetic and environmental factors. We are interested in epigenetic variants that have functional consequences: for this reason we will use gene expression variants, in a single homogeneous cell type, as the functional readout of epigenetic variation. Gene expression variants are common in isogenic mice. We hypothesize that gene expression variants can be transmitted through multiple generations, and that such transmission is affected by selection or environmental cues (such as diet). To accept or reject this hypothesis, we will use RNA-Seq to identify gene expression variants in a cohort of isogenic mice, and use these mice as founders of 5-generation pedigrees in which the appearance, disappearance, and transmission of variants will be quantified. In one set of pedigrees, specific expression variants will be selected for breeding; another set will be maintained on a high-fat diet. Finally, we will correlate gene expression variants with methylation variants, and resequence selected mice to assess the true degree of their isogenicity. This study will demonstrate how many epigenetic variants are transmitted from parents to offspring, how stable their transmissibility is through multiple generations, and how transmissibility is affected by selection and the environment.

描述（由申请人提供）：全基因组关联研究人类疾病的“缺失遗传力”问题是无法完全解释复杂性状的遗传力的常见遗传变异。该建议涉及缺少遗传力的一种可能解释：独立于基因组序列的表观遗传变体的跨代遗传。 PIS和其他人在动植物物种中的作品表明，表观遗传变异的遗传与门德尔的遗传大不相同。但是，从未在动物中系统地研究了可以从父母传播到后代的表观遗传变体的数量，以及通过多代传播的持久性。该项目的总体目标是通过多代量化表观遗传变异的可传播性。等生小鼠菌株允许在最小化遗传和环境因素的条件下进行这项研究。我们对具有功能后果的表观遗传变体感兴趣：因此，我们将在单个均质细胞类型中使用基因表达变体作为表观遗传变异的功能读数。基因表达变异在等基因小鼠中很常见。我们假设基因表达变异可以通过多代传播，并且这种传播受到选择或环境提示（例如饮食）的影响。接受或拒绝这一假设， 我们将使用RNA-seq鉴定同源小鼠队列中的基因表达变异，并将这些小鼠作为5代家谱的创始人，其中将量化变体的外观，消失和传播。在一组谱系中，将选择特定的表达变异来繁殖。另一组将保持高脂饮食。最后，我们将将基因表达变异与甲基化变异相关联，并选择了选择小鼠以评估其同源性的真实程度。这项研究将证明从父母传播了多少表观遗传变异，通过多代人的传播性如何稳定，以及如何受到选择和环境的影响。