Heritability of gene expression variants in isogenic mice

描述(申请人提供)：人类疾病的全基因组关联研究所强调的“缺失遗传力”问题是，普通遗传变异不能完全解释复杂性状的遗传力。这一建议解决了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和其他人在动植物物种中的研究表明，表观遗传变异的遗传与孟德尔遗传有很大不同。然而，可以从父母传给后代的表观遗传变异的数量，以及多代传播的持久性，从来没有在动物身上进行过系统的研究。这个项目的总体目标是量化表观遗传变异在多代之间的传递性。同基因的小鼠品系使这项研究可以在最大限度地减少遗传和环境因素的条件下进行。我们对具有功能结果的表观遗传变异感兴趣：出于这个原因，我们将使用单一同质细胞类型中的基因表达变异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个世代传播，这种传播受到选择或环境线索(如饮食)的影响。接受或拒绝这一假设， 我们将使用RNA-Seq来识别一组等基因小鼠中的基因表达变异，并将这些小鼠作为5代家系的创始人，在这些家系中，变异的出现、消失和传播将被量化。在一组家系中，将选择特定的表达变体进行繁殖；另一组将保持高脂肪饮食。最后，我们将把基因表达变异与甲基化变异联系起来，并对选定的小鼠进行重新测序，以评估它们的同源性的真实程度。这项研究将展示有多少表观遗传变异是从父母传给后代的，它们在多个世代中的传递性有多稳定，以及选择和环境如何影响传递性。

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.