A NOVEL ALLELIC VARIANT OF THE HUMAN SEROTONIN TRANSPORTER GENE REGULATORY POLYMORPHISM

Allelic variation of the human serotonin transporter gene (SLC6A4) has recently been shown to modulate anxiety-related traits. A tandemly re peated sequence in close proximity to the promoter was found to be rep resented by a long (L) and short (S) variant, differentially modulatin g gene expression in vitro. Specifically, allele S, generated by a del etion of 44 bp involving repeats VI to VIII, reduced transcriptional e fficiency, gene expression, and 5-hydroxytryptamine uptake and was ass ociated with increased neuroticism scores. We have now identified a no vel allelic variant of this promoter-linked polymorphism that is signi ficantly larger than the L allele and which we have designated allele XL (for ''extra large''). Sequence analysis revealed that XL arose thr ough duplication of an internal segment composed of repeat elements VI to IX, comprising 85 bp in total, and, most notably, including the se gments deleted in the S allele. Additional allelic variants larger tha n human allele L were observed predominantly in various nonhuman prima tes. Preliminary data indicated that these variable allelic extensions similarly originate from this specific repeat region. These allelic v ariants may serve as a valuable model system to further elucidate the relationship between repeat structure, regulatory properties, and beha vioral correlates. Finally, allelic variants were found to vary signif icantly among different human populations, with allele XL being unique ly present in individuals of African origin, allele L most frequent in Africans and Caucasians of Western European descent, and allele S mos t abundant in East Asians.