Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions
Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions
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DOI：
10.1152/physiolgenomics.00114.2014
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发表时间：
2015-08-01
影响因子：
4.6
通讯作者：
Lu, Lu
中科院分区：
文献类型：
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作者：
Cook, Melloni N.;Baker, Jessica A.;Lu, Lu
酗酒、压力和焦虑是强烈相互作用的可遗传的多基因特征。在以前的研究中，我们确定了一个数量性状基因座（QTL）的小鼠染色体（Chr）1之间的23.0和31.5 Mb，调节乙醇对焦虑相关表型的影响的遗传差异。本研究的目标是扩展该位点的分析，重点是使用新的可用数据和工具识别候选基因。在C57 BL/6 J、DBA 2 J和72 BXD菌株中注射盐水或乙醇（1.8 g/kg）后，使用高架零迷宫评价了类迷宫行为。我们检测到压力和治疗及其相互作用对焦虑相关行为的显著影响，尽管令人惊讶的是，性别不是一个重要因素。Chr 1 QTL对乙醇处理组具有特异性。使用现在标准的生物信息学标准评估该基因座中的候选基因。胶原蛋白19 a1（Col 19 a1）和家族序列135 a（Fam 135 a）符合大多数标准，但表达水平较低，缺乏生物学验证，因此被认为是不太可能的候选者。相比之下，另外两个基因，异戊二烯化蛋白酪氨酸磷酸家族成员Ptp 4a 1（蛋白酪氨酸磷酸4a 1）和锌指蛋白Phf 3（植物同源结构域指蛋白3）符合我们的生物信息学标准，因此是强有力的候选者。这些发现也具有翻译相关性，因为Ptp 4a 1和Phf 3都已在人类全基因组关联研究中被提名为酒精依赖的候选基因。我们的研究结果支持了这一假设，即这些基因中的一个或两个的变体调节乙醇对焦虑相关行为影响的遗传差异。
Alcoholism, stress, and anxiety are strongly interacting heritable, polygenetic traits. In a previous study, we identified a quantitative trait locus (QTL) on murine chromosome (Chr) 1 between 23.0 and 31.5 Mb that modulates genetic differences in the effects of ethanol on anxiety-related phenotypes. The goal of the present study was to extend the analysis of this locus with a focus on identifying candidate genes using newly available data and tools. Anxiety-like behavior was evaluated with an elevated zero maze following saline or ethanol injections (1.8 g/kg) in C57BL/6J, DBA2J, and 72 BXD strains. We detected significant effects of strain and treatment and their interaction on anxiety-related behaviors, although surprisingly, sex was not a significant factor. The Chr1 QTL is specific to the ethanol-treated cohort. Candidate genes in this locus were evaluated using now standard bioinformatic criteria. Collagen 19a1 (Col19a1) and family sequence 135a (Fam135a) met most criteria but have lower expression levels and lacked biological verification and, therefore, were considered less likely candidates. In contrast, two other genes, the prenylated protein tyrosine phosphate family member Ptp4a1 (protein tyrosine phosphate 4a1) and the zinc finger protein Phf3 (plant homeoDomain finger protein 3) met each of our bioinformatic criteria and are thus strong candidates. These findings are also of translational relevance because both Ptp4a1 and Phf3 have been nominated as candidates genes for alcohol dependence in a human genome-wide association study. Our findings support the hypothesis that variants in one or both of these genes modulate heritable differences in the effects of ethanol on anxiety-related behaviors.