Role of maternal diet and allelic imbalance in behavior.

描述(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，特别是在宫内和产后期间，会增加人类患精神疾病的风险，并改变人类精神疾病动物模型的行为结果。其中一些影响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。在动物模型中识别既对环境变化做出反应又影响行为的特定基因，不仅可以揭示与大脑发育和功能有关的遗传途径，还可以揭示这些途径如何对环境中的外部因素敏感。这样的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。这项提议的目标是确定哪些基因的行为受到母亲营养的调节，以及哪些基因会影响成年后代的行为。实验设计包含几个创新的组成部分，并利用了用于小鼠研究的强大的新遗传资源--合作杂交(CC)。CC是一个重组近交系小鼠品系的小组，每个基因组由来自八个不同的创始人品系的遗传物质的平衡但随机的马赛克组成。这项拟议的研究使用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列杂交，从而允许在全基因组范围内调查因起源父母和母亲饮食而异的遗传效应。具体地说，交配的CC雌性在怀孕期间和产后将暴露于营养缺乏。CC-Rix后代随后将接受行为测试，并通过微阵列分析基因表达。在该项目期间开发的新的统计方法将被应用，以识别和表征品系和饮食特定的影响，以及由于等位基因不平衡而产生的起源亲本的影响。候选基因将通过对基因敲除小鼠的直接行为检查和基因敲除互补测试来评估，以验证饮食和菌株的作用。这项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、宫内暴露、母亲的饮食和父母是如何结合在一起影响行为的。

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.