Vallender E J, Priddy C M, Hakim S, Yang H, Chen G-L, Miller G M
Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Genes Brain Behav. 2008 Aug;7(6):690-7. doi: 10.1111/j.1601-183X.2008.00407.x. Epub 2008 Apr 28.
The serotonin system underlies a wide variety of behavioral traits and its dysregulation is the cause of numerous neuropsychiatric disorders. Among genes involved in the system, the serotonin transporter (SERT) is integral and has been repeatedly shown to be associated with disease as well as being a primary drug target. In addition to promoter region variation, we identify here variation in a regulatory region in the 3' untranslated region (UTR) of the SERT gene in both humans and rhesus macaques. We comprehensively survey the 3' UTR of SLC6A4 in Indian-origin rhesus macaques to identify three single nucleotide polymorphisms (SNPs) creating two haplotypes, both derived from an ancestral sequence, that represent the vast majority of the alleles in the population. Through the use of a luciferase reporter gene assay, we are able to show that not only do these alleles have differential effects on gene expression, modulated through changes in messenger RNA stability, but that different commonly occurring SNPs in the human 3' UTR also have similar effects. This finding not only offers additional insight into the regulation, and thus dysregulation, of SERT expression, but also suggests the role of natural selection in maintaining both high and low SERT expression levels broadly across populations of multiple primate species.
血清素系统是多种行为特征的基础，其失调是众多神经精神疾病的病因。在该系统涉及的基因中，血清素转运体（SERT）不可或缺，并且多次被证明与疾病相关，同时也是主要的药物靶点。除启动子区域变异外，我们在此鉴定出人类和恒河猴中SERT基因3'非翻译区（UTR）调控区域的变异。我们全面调查了印度裔恒河猴中SLC6A4的3'UTR，以鉴定出三个单核苷酸多态性（SNP），它们形成了两种单倍型，均源自一个祖先序列，代表了该群体中绝大多数等位基因。通过使用荧光素酶报告基因检测，我们能够表明这些等位基因不仅通过信使核糖核酸稳定性的变化对基因表达有不同影响，而且人类3'UTR中不同的常见SNP也有类似作用。这一发现不仅为SERT表达的调控及失调提供了更多见解，还表明了自然选择在多种灵长类物种群体中广泛维持高和低SERT表达水平方面的作用。
