Identification and Characterization of Tandem Repeats in Exon III of Dopamine Receptor D4 (DRD4) Genes from Different Mammalian Species

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.

Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity

“…Studies of molecular dynamics involving rare variants are needed to better understand the phenomenon, mainly because the VNTR is an intrinsically disordered region. 46 Although a recent study with 48 ancestry informative markers did not show significant population structure in southern Brazilians, 33 no genomic control was performed, therefore our findings could have been biased by hidden genetic heterogeneity present in our specific sample of the southern Brazilian population.…”

“…Other important finding is that the DRD4 VNTR region appears to be in a disordered protein region. 46 These regions are characterized as sequences in protein that lack regular secondary structure combined with a high degree of flexibility in the polypeptide strand and appear to have an important role in molecular recognition and signaling. 47 In the predicted polypeptide alignments, it was possible to verify that many of the observed changes are quite dramatic.…”

Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior

“…Tandem repeats in the third exon of DRD4 have already been identified in some NHPs such as vervet monkeys, macaques, and chimpanzees (see Livak et al 1995; Larsen et al 2005). Studies reporting the frequency of occurrence of different DRD4 alleles, however, have typically been conducted with relatively small captive populations.…”

Studying longitudinal trajectories in animal models of psychiatric illness and their translation to the human condition

“…Tandem repeats in the third exon of the dopamine receptor D4 gene ( DRD4 ) exist across a variety of species, including humans, vervets, dogs, dolphins, bears, raccoons, horses, and chimpanzees (see Larsen et al, 2005). Some species, including rhesus, pigtail, and Tonkean macaques, exhibit variation in the number of repeats present, with various alleles differing in frequencies across species (Livak et al, 1995; Wendland et al, 2006).…”