Mapping and Microarray Gene Expression Analysis in a Model of Excessive Drinking

描述（申请人提供）：乙醇饮用是一种复杂的性状，因此受到多种遗传和环境因素的影响。一次检查一个基因的影响忽略了可能的相互作用的重要性（例如，上位性，等位基因内超显性;参见菲利普斯和贝尔纳普，2002）。我们建议利用杂交的方法，导致过量饮酒的基因集的映射。已经发现C57 BL/6 J（B6）x FVB/NJ（FVB）F1小鼠消耗的乙醇甚至比高乙醇偏好的B6品系更多（Blednov等人，2005年）。我们将利用这一发现，解决过量饮酒的遗传模式相结合的数量性状位点（QTL）定位与微阵列基因表达分析，以确定共定位的行为（bQTL）和表达QTL（eQTL）。在具体目标1中，将使用B6 FVBF 2绘制过量自愿乙醇消费的bQTL。F2将用于确定单独和成对组合中每个QTL的遗传模式（加性、完全显性、超显性、上位性）。在特定目标2中，F3-F4个体将用于脑区域特异性基因表达分析。将选择通过其基因型预测为高或低饮酒个体的个体进行微阵列分析。这些数据将进行eQTL分析。这将使我们能够鉴定定位到共同染色体区域的bQTL和eQTL，从而提供影响饮酒性状的特定基因的证据。将从INIA神经回路组确定的靶组织中选择待研究的脑区域。在具体目标3中，将测量可能的遗传相关反应，以探索极端饮酒性状与其他性状（如乙醇戒断、条件性味觉厌恶、戒断诱导饮酒、黑暗中饮酒、乙醇接受和乙醇条件性位置偏好）之间的推定遗传关系。当我们获得影响高饮酒性状的基因的特定位置的证据时，将根据先前的QTL定位数据选择其他性状进行检查，这些QTL定位数据已经确定了这些性状与我们确定的位置的关联。未来的工作也将集中在最重要的候选基因牵连我们的组合bQTL：eQTL分析。

DESCRIPTION (provided by applicant): Ethanol drinking is a complex trait, and thus influenced by multiple genetic and environmental factors. Examining the influence of one gene at a time ignores the importance of possible interactions (e.g., epistasis, intra-allelic overdominance; see Phillips & Belknap, 2002). We propose to utilize a filial cross approach for the mapping of gene sets that result in excessive alcohol intake. C57BL/6J (B6) x FVB/NJ (FVB) F1 mice have been found to consume more ethanol than even the high ethanol preference B6 strain (Blednov et al., 2005). We will take advantage of this finding to resolve mode of inheritance for excessive drinking by combining quantitative trait locus (QTL) mapping with microarray gene expression analysis to identify colocalization of behavioral (bQTL) and expression QTL (eQTL). In Specific Aim 1, bQTL for excessive voluntary ethanol consumption will be mapped using the B6FVBF2. The F2 will be used to determine the mode of inheritance (additive, fully dominant, overdominant, epistatic) for each QTL taken singly and also in pairwise combinations. In Specific Aim 2, F3-F4 individuals will be used for brain region specific gene expression analyses. Individuals predicted by their genotype to be high or low drinking individuals will be selected for microarray profiling. These data will be subjected to eQTL analyses. This will allow us to identify bQTL and eQTL that are mapped to common chromosomal regions providing evidence of the specific gene(s) influencing the drinking trait. Brain regions to be studied will be selected from target tissues identified by the INIA Neurocircuitry group. In Specific Aim 3, possible genetically correlated responses will be measured to explore putative genetic relationships between the extreme drinking trait and others such as ethanol withdrawal, conditioned taste aversion, withdrawal induced drinking, drinking in the dark, ethanol acceptance, and ethanol conditioned place preference. As we obtain evidence for the specific locations of genes that influence the high drinking trait, other traits will be chosen for examination based on previous QTL mapping data that have identified associations of those traits with the locations we identify. Future work will also be focused on the most significant candidate genes implicated by our combined bQTL:eQTL analyses.