Identification and characterization of tandem repeats in exon III of dopamine receptor D4 (DRD4) genes from different mammalian species.

Research Institute of Biological Psychiatry, H:S Sct. Hans Hospital, Roskilde, Denmark.
DNA and Cell Biology (Impact Factor: 2.34). 01/2006; 24(12):795-804. DOI: 10.1089/dna.2005.24.795
Source: PubMed

ABSTRACT In this study we have identified and characterized dopamine receptor D4 (DRD4) exon III tandem repeats in 33 public available nucleotide sequences from different mammalian species. We found that the tandem repeat in canids could be described in a novel and simple way, namely, as a structure composed of 15- and 12- bp modules. Tandem repeats composed of 18-bp modules were found in sequences from the horse, zebra, onager, and donkey, Asiatic bear, polar bear, common raccoon, dolphin, harbor porpoise, and domestic cat. Several of these sequences have been analyzed previously without a tandem repeat being found. In the domestic cow and gray seal we identified tandem repeats composed of 36-bp modules, each consisting of two closely related 18-bp basic units. A tandem repeat consisting of 9-bp modules was identified in sequences from mink and ferret. In the European otter we detected an 18-bp tandem repeat, while a tandem repeat consisting of 27-bp modules was identified in a sequence from European badger. Both these tandem repeats were composed of 9-bp basic units, which were closely related with the 9-bp repeat modules identified in the mink and ferret. Tandem repeats could not be identified in sequences from rodents. All tandem repeats possessed a high GC content with a strong bias for C. On phylogenetic analysis of the tandem repeats evolutionary related species were clustered into the same groups. The degree of conservation of the tandem repeats varied significantly between species. The deduced amino acid sequences of most of the tandem repeats exhibited a high propensity for disorder. This was also the case with an amino acid sequence of the human DRD4 exon III tandem repeat, which was included in the study for comparative purposes. We identified proline-containing motifs for SH3 and WW domain binding proteins, potential phosphorylation sites, PDZ domain binding motifs, and FHA domain binding motifs in the amino acid sequences of the tandem repeats. The numbers of potential functional sites varied pronouncedly between species. Our observations provide a platform for future studies of the architecture and evolution of the DRD4 exon III tandem repeat, and they suggest that differences in the structure of this tandem repeat contribute to specialization and generation of diversity in receptor function.

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    ABSTRACT: A large number of mammalian species harbor a tandem repeat in exon III of the gene encoding dopamine receptor D4 (DRD4), a receptor associated with cognitive functions. In this study, a DRD4 gene exon III tandem repeat from the order Cetacea was identified and characterized. Included in our study were samples from 10 white-beaked dolphins (Lagenorhynchus albirostris), 10 harbor porpoises (Phocoena phocoena), eight sperm whales (Physeter macrocephalus), and five minke whales (Balaenoptera acutorostrata). Using enzymatic amplification followed by sequencing of amplified fragments, a tandem repeat composed of 18-bp basic units was detected in all of these species. The tandem repeats in white-beaked dolphin and harbor porpoise were both monomorphic and consisted of 11 and 12 basic units, respectively. In contrast, the sperm whale harbored a polymorphic tandem repeat with size variants composed of three, four, and five basic units. Also the tandem repeat in minke whale was polymorphic; size variants composed of 6 or 11 basic units were found in this species. The consensus sequences of the basic units were identical in the closely related white-beaked dolphin and harbor porpoise, and these sequences differed by a maximum of two changes when compared to the remaining species. There was a high degree of similarity between the cetacean basic unit consensus sequences and those from members of the horse family and domestic cow, which also harbor a tandem repeat composed of 18-bp basic units in exon III of their DRD4 gene. Consequently, the 18-bp tandem repeat appears to have originated prior to the differentiation of hoofed mammals into odd-toed and even-toed ungulates. The composition of the tandem repeat in cetaceans differed markedly from that in primates, which is composed of 48-bp repeat basic units.
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    ABSTRACT: Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P=0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P=0.008 for total substitutions and P=0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.
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