Serotonin transporter: evolution and impact of polymorphic transcriptional regulation.
The serotonin transporter (SERT) is the primary drug target in the current antidepressant therapy. A functional polymorphism in the 2nd intron of the 5HTT gene encoding the SERT has been identified and associated with susceptibility to affective disorders and treatment response to antidepressants. This study addresses the possible impact of the variable number of tandem repeats (VNTR) to behavior and disease by examining the evolutionary origin and mechanisms of differential transcriptional regulation of SERT. We trace the evolutionary origin of the VNTR and show that it is present and varies extensively across the great apes and monkeys as well as in rodents while it is absent in non-mammals. As in humans, the VNTR sequence may be polymorphic within species and thus it may underlie both inter- and intraspecies differences. Also, we find new putative binding sites for several transcription factors in the VNTRs of all mammalian SERT genes. The number of these putative binding sites varies proportionally to the length of the VNTR. We propose that the intronic VNTR have been selectively targeted through mammalian evolution to finetune transcriptional regulation of the serotonin expression.
Søeby
Karen
K
Research Institute of Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark. joel.gelernter@yale.edu
Larsen
Svend A
SA
Olsen
Line
L
Rasmussen
Henrik B
HB
Werge
Thomas
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D018598:Minisatellite Repeats / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D050486:Serotonin Plasma Membrane Transport Proteins; D014158:Transcription, Genetic / Q000235:genetics
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins