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）：人类疾病的全基因组关联研究所强调的“缺失遗传性”问题是常见遗传变异无法完全解释复杂性状的遗传性。这个提议涉及缺失遗传性的一个可能的解释：独立于基因组序列的表观遗传变异的跨代遗传。其中一位PI和其他人在植物和动物物种中的工作表明，表观遗传变异的遗传与孟德尔遗传非常不同。然而，可以从父母传给后代的表观遗传变异的数量，以及通过多代传播的持续性，从未在动物中进行过系统的研究。该项目的总体目标是量化表观遗传变异通过多代的可传递性。同基因小鼠品系允许在最小化遗传和环境因素的条件下进行本研究。我们感兴趣的表观遗传变异，有功能的后果：出于这个原因，我们将使用基因表达变异，在一个单一的同质细胞类型，作为表观遗传变异的功能读出。基因表达变体在同基因小鼠中很常见。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线索（如饮食）的影响。接受或拒绝这个假设， 我们将使用RNA-Seq来鉴定同基因小鼠群中的基因表达变体，并使用这些小鼠作为5代谱系的建立者，其中变体的出现、消失和传播将被量化。在一组谱系中，将选择特定的表达变体用于育种;另一组将维持高脂肪饮食。最后，我们将基因表达变异与甲基化变异相关联，并对选定的小鼠进行重新测序，以评估其同源性的真实程度。这项研究将证明有多少表观遗传变异从父母传给后代，它们的遗传性在多代中有多稳定，以及遗传性如何受到选择和环境的影响。