The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus

Abstract

Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (approximately 40000-50000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between receptor variants.

Figure  1

Polymorphism distribution at the DRD4 locus. Using VG (Nickerson et al. 1998), 70 DRD4 polymorphisms are displayed, with variants aligned along the horizontal axis. Approximate locations of the variants along the DRD4 locus (GenBank AC021663) are indicated by blue lines reaching to the diagrammatic representation of the gene. In this representation, exon positions are represented by blocks (yellow = noncoding; orange = coding; +1 = translation start), and the positions of Alu repetitive sequences are represented by pointed blue blocks. The positions of a 120-bp upstream duplication and the 48-bp VNTR in exon 3 are indicated by green triangles. A 288-bp site (designated −809 G/A to −521 C/T) at the promoter region that contains an anomalously high number of SNPs is indicated. These SNPs exhibit little difference in 4R vs. 7R frequency. Individuals (on the vertical axis) are grouped by VNTR length (4R/4R, 7R/7R, and 2R/2R) and by geographic origin (African, European, etc.) as indicated. Homozygotes for the allele with the highest relative frequency (common allele) are indicated by blue squares, homozygotes for alternative (rare) alleles by yellow squares, and heterozygotes by red squares. The 7R/7R and 2R/2R individuals were greatly oversampled in comparison to their population frequency; hence, common and rare alleles were defined by the frequencies in a randomly sampled population. SNP and genotype information is available at dbSNP and the authors' Web site.

Figure  2

Frequencies of DRD4 7R recombinant chromosomes. The graph shows the observed percentage of recombinant chromosomes at the 18 SNPs (table 1) versus the distance from the 7R VNTR. The curve is an empirically determined least-squares fit to the data. The diagrammatic representation of the DRD4 locus is as described in fig. 1.

Figure  3

A diagrammatic model for DRD4 variant selection. DRD4 2R, 4R, and 7R protein variants are shown diagrammatically, aligned on a scale of relative efficiency for cAMP reduction. These values were calculated from the data of Asghari et al. (1995), normalized to 4R=1.0. Haplotype nomenclature (i.e., 1-2-3-4) appears as proposed elsewhere (Ding et al. 2002). The unusual derivation of the 7R allele from the ancestral 4R allele (∼40,000–50,000 years ago) and its increase in prevalence are indicated by red to turquoise arrows. The subsequent derivation of the 2R allele from a 7R/4R recombination is indicated by turquoise to blue arrows.