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首页> 外文期刊>Genes, brain, and behavior >Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.
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Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.

机译：使用SERT突变小鼠作为人类多基因和上位性状和疾病模型的实验性基因相互作用研究。

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Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.
机译：当前的证据表明，实际上，与许多其他常见的医学疾病一样，所有神经精神疾病都具有遗传上的复杂性，并受到多种相互作用基因以及环境的综合影响。然而，事实证明，在人类研究中，累加或上位基因相互作用很难检测和评估。小鼠的表型，包括行为和药物反应，可以为人类疾病提供相关的模型。因此，对小鼠中基因-基因相互作用的研究可以帮助人们理解复杂的人类疾病的分子遗传基础。血清素转运蛋白（SERT，5-HTT，SLC6A4）为研究此类相互作用提供了相关模型，其原因如下：SERT中的人类变异与多种神经精神病和其他医学疾病以及定量特征有关; SERT阻滞剂是治疗许多神经精神疾病的有效方法;对杂合和纯合SERT敲除小鼠的表型特征有很好的初步了解;并且人们对SERT表达的变异与许多其他神经精神病学和神经药理学感兴趣的基因的表达之间的相互作用有了越来越广泛的了解。本文提供了SERT基因表达的定量变化与其他五个小鼠基因（DAT，NET，MAOA，5-HT（1B）和BDNF）表达变化之间通过实验获得的相互作用的示例。在人类中，所有这六个基因均具有多态性，在超过500篇报道中，这些多态性已作为神经精神病和其他疾病的候选者而被独立研究。在这里审查的小鼠的实验研究中，基因-基因相互作用导致协同，拮抗（包括“拯救”或“互补”）或更复杂的定量改变。通过比较野生型小鼠与具有单个等位基因或单个基因靶向破坏的小鼠和具有多个基因的部分或完全破坏的小鼠的行为，生理和神经化学表型进行比较。在中间的定量变化（例如脑5-羟色胺差异）的基础上，可以最好地理解几种描述性表型。我们讨论了这些相互作用为研究复杂的人类神经精神病和SERT可能导致的其他疾病（包括发育异常，肥胖，多物质滥用等）中的基因-基因相互作用提供模型的方式。

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