title: A novel allelic variant of the human serotonin transporter gene regulatory polymorphism.
abstract: 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.
authors.affiliation: Genome Research, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: S J
authors.initials: SJ
authors.lastname: Delbrück
authors.forename: B
authors.initials: B
authors.lastname: Wendel
authors.forename: I
authors.initials: I
authors.lastname: Grunewald
authors.forename: T
authors.initials: T
authors.lastname: Sander
authors.forename: D
authors.initials: D
authors.lastname: Morris-Rosendahl
authors.forename: M A
authors.initials: MA
authors.lastname: Crocq
authors.forename: W H
authors.initials: WH
authors.lastname: Berrettini
authors.forename: M R
authors.initials: MR
authors.lastname: Hoehe
mesh_terms: D000349:Africa / Q000208:ethnology; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D005060:Europe; D019143:Evolution, Molecular; D005202:Asia, Eastern; D005787:Gene Frequency; D006071:Gorilla gorilla; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009656:North America; D011110:Polymorphism, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid; D050486:Serotonin Plasma Membrane Transport Proteins
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins