Delbrück S J, Wendel B, Grunewald I, Sander T, Morris-Rosendahl D, Crocq M A, Berrettini W H, Hoehe M R
Genome Research, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Cytogenet Cell Genet. 1997;79(3-4):214-20. doi: 10.1159/000134726.
Allelic variation of the human serotonin transporter gene (SLC6A4) has recently been shown to modulate anxiety-related traits. A tandemly repeated sequence in close proximity to the promoter was found to be represented by a long (L) and short (S) variant, differentially modulating gene expression in vitro. Specifically, allele S, generated by a deletion of 44 bp involving repeats VI to VIII, reduced transcriptional efficiency, gene expression, and 5-hydroxytryptamine uptake and was associated with increased neuroticism scores. We have now identified a novel allelic variant of this promoter-linked polymorphism that is significantly larger than the L allele and which we have designated allele XL (for "extra large"). Sequence analysis revealed that XL arose through duplication of an internal segment composed of repeat elements VI to IX, comprising 85 bp in total, and, most notably, including the segments deleted in the S allele. Additional allelic variants larger than human allele L were observed predominantly in various nonhuman primates. Preliminary data indicated that these variable allelic extensions similarly originate from this specific repeat region. These allelic variants may serve as a valuable model system to further elucidate the relationship between repeat structure, regulatory properties, and behavioral correlates. Finally, allelic variants were found to vary significantly among different human populations, with allele XL being uniquely present in individuals of African origin, allele L most frequent in Africans and Caucasians of Western European descent, and allele S most abundant in East Asians.
人类血清素转运体基因（SLC6A4）的等位基因变异最近被证明可调节与焦虑相关的性状。人们发现，启动子附近的一个串联重复序列存在长（L）和短（S）两种变体，它们在体外对基因表达的调节作用不同。具体而言，由涉及重复序列VI至VIII的44 bp缺失产生的S等位基因降低了转录效率、基因表达和5-羟色胺摄取，并与神经质得分增加有关。我们现在鉴定出了这种启动子相关多态性的一种新的等位基因变体，它比L等位基因大得多，我们将其命名为XL等位基因（“超大”之意）。序列分析显示，XL等位基因是由一个内部片段重复产生的，该内部片段由重复元件VI至IX组成，总共85 bp，最值得注意的是，包括S等位基因中缺失的片段。在各种非人类灵长类动物中主要观察到了比人类L等位基因更大的其他等位基因变体。初步数据表明，这些可变的等位基因延伸同样起源于这个特定的重复区域。这些等位基因变体可能是一个有价值的模型系统，有助于进一步阐明重复结构、调控特性和行为相关性之间的关系。最后，人们发现等位基因变体在不同人类群体中存在显著差异，XL等位基因仅存在于非洲裔个体中，L等位基因在非洲人和西欧血统的高加索人中最常见，而S等位基因在东亚人中最为丰富。
