Genetic factors play a significant role in risk for mood and anxiety disorders. Polymorphisms in genes that regulate the brain monoamine systems, such as catabolic enzymes and transporters, are attractive candidates for being risk factors for emotional disorders given the weight of evidence implicating monoamines involvement in these conditions. Several common genetic variants have been identified in the human serotonin transporter (5-HTT) gene, including a repetitive sequence located in the promoter region of the locus called the serotonin transporter-linked polymorphic region (5-HTT-LPR). This polymorphism has been associated with a number of mental traits in both humans and primates, including depression, neuroticism, and harm avoidance. Some, but not all, studies found a link between the polymorphism and 5-HTT levels, leaving open the question of whether the polymorphism affects risk for mental traits via changes in 5-HTT expression. To investigate the impact of the polymorphism on gene expression, serotonin homeostasis, and behavioral traits, we set out to develop a mouse model of the human 5-HTT-LPR. Here we describe the creation and characterization of a set of mouse lines with single-copy human transgenes carrying the short and long 5-HTT-LPR variants. Although we were not able to detect differences in expression between the short and long variants, we encountered several technical issues concerning the design of our humanized mice that are likely to have influenced our findings. Our study serves as a cautionary note for future studies aimed at studying human transgene regulation in the context of the living mouse.

中文翻译：

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人血清素转运蛋白相关的多态性区域的小鼠模型。

遗传因素在情绪和焦虑症风险中起重要作用。鉴于有大量证据表明单胺参与这些疾病，调节大脑单胺系统的基因（例如分解代谢酶和转运蛋白）中的多态性是情绪障碍危险因素的诱人候选者。在人类5-羟色胺转运蛋白（5-HTT）基因中已鉴定出几种常见的遗传变异，包括位于基因座启动子区域的重复序列，称为5-羟色胺转运蛋白连接的多态性区域（5-HTT-LPR）。这种多态性与人类和灵长类动物的许多心理特征有关，包括抑郁，神经质和避免伤害。一些（但不是全部）研究发现，多态性与5-HTT水平之间存在关联，这个多态性是否会通过5-HTT表达的改变影响精神特征的风险仍然存在一个问题。为了研究基因多态性对基因表达，5-羟色胺稳态和行为特征的影响，我们着手开发人5-HTT-LPR的小鼠模型。在这里，我们描述了带有短和长5-HTT-LPR变体的单拷贝人类转基因小鼠系的创建和表征。尽管我们无法检测到短变体和长变体之间的表达差异，但我们遇到了一些有关人源化小鼠设计的技术问题，这些问题可能会影响我们的发现。我们的研究为将来的研究提供了警告，该研究旨在研究活体小鼠环境下的人类转基因调控。