Role of maternal diet and allelic imbalance in behavior.

描述（由申请人提供）：行为受遗传，环境以及两者之间复杂的相互作用的影响。在发育过程中的关键时间点暴露于营养缺乏，特别是在子宫内和产后期间，增加了人类精神疾病的风险，并改变了人类精神疾病动物模型的行为结果。其中一些效应与甲基化和基因表达的变化有关，这意味着表观遗传因素可能有助于潜在的疾病过程。在动物模型中识别出既能对环境变化做出反应又能影响行为的特定基因，不仅可以揭示参与大脑发育和功能的遗传途径，还可以揭示这些途径对环境中的外部因素是如何敏感的。这些研究可以揭示人类精神疾病的病因，并为预防和治疗提供新的线索。这项计划的目标是确定其行为受母体营养调节并影响成年后代行为的基因。实验设计包含几个创新的组成部分，并利用了一个强大的新的遗传资源的小鼠研究，协作交叉（CC）。CC是一组重组近交系小鼠，其基因组中的每一个都包括来自八个不同创始品系的遗传物质的平衡但随机的镶嵌。拟议的研究使用CC品系的已知单倍型组成来产生CC品系（CC重组近交系小鼠，或CC-RIX）之间相互交配的稀疏双杂交，这允许对因亲本来源和母体饮食而异的遗传效应进行全基因组调查。具体而言，交配CC雌性动物将在妊娠期间和产后期间暴露于营养缺乏。然后，CC-RIX后代将接受行为测试，并通过微阵列检测基因表达。将应用项目期间开发的新统计方法，以确定和表征菌株和饮食特异性效应，以及由于等位基因不平衡引起的亲本来源效应。候选基因将通过基因敲除小鼠的直接行为检查以及基因敲除互补试验进行评估，以验证饮食和品系的作用。拟议的研究代表了一个强大的新遗传平台的新应用，以阐明遗传学，子宫内暴露，母体饮食和父母的起源联合收割机如何结合起来影响行为。

DESCRIPTION (provided by applicant): Behavior is affected by genetics, the environment, and a complex interplay between the two. Exposure to nutritional deficiencies at critical time points during development, particularly while in utero and during the postpartum period, increases the risk of psychiatric disease in humans, and alters behavioral outcomes in animal models of human psychiatric disease. Some of these effects have been linked to changes in methylation and gene expression, implying that epigenetic factors may contribute to the underlying disease process. Identifying specific genes that respond both to environmental variation and that influence behavior in animal models can reveal not only genetic pathways involved in brain development and function, but also how such pathways are sensitive to external factors in the environment. Such studies can thereby shed light on the etiology of human psychiatric disease, and provide new clues to prevention and treatment. The goal of this proposal is to identify genes whose actions are modulated by maternal nutrition and that influence behavior in adult offspring. The experimental design contains several innovative components, and makes use of a powerful new genetic resource for mouse studies, the Collaborative Cross (CC). The CC is a panel of recombinant inbred mouse lines, each of whose genomes comprises a balanced but randomized mosaic of genetic material from eight diverse founder strains. The proposed study uses the known haplotypic composition of the CC lines to generate sparse diallel cross of reciprocal matings between CC strains (CC recombinant inbred mice, or CC-RIX) that allows a genomewide survey of genetic effects that vary by parent of origin and maternal diet. Specifically, mating CC females will be exposed to nutritional deficiencies during gestation and in the postpartum period. CC-RIX offspring will then be subject to behavioral testing and assayed for gene expression by microarray. Novel statistical methodology developed during the project will be applied in order to identify and characterize strain- and diet-specific effects, as well as parent of origin effects due to allelic imbalance. Candidate genes will be assessed by direct behavioral examination of knockout mice and also by knockout complementation testing to validate the role of both diet and strain. The proposed research represents a novel application of a powerful new genetic platform in order to elucidate how genetics, in utero exposures, maternal diet and parent-of-origin combine to affect behavior.