No evidence for strong recent positive selection favoring the 7 repeat allele of VNTR in the DRD4 gene

Abstract

The human dopamine receptor D4 (DRD4) gene contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. The DRD4 7R allele, which seems to have a single origin, is commonly observed in various human populations and the nucleotide diversity of the DRD4 7R haplotype at the DRD4 locus is reduced compared to the most common DRD4 4R haplotype. Based on these observations, previous studies have hypothesized that positive selection has acted on the DRD4 7R allele. However, the degrees of linkage disequilibrium (LD) of the DRD4 7R allele with single nucleotide polymorphisms (SNPs) outside the DRD4 locus have not been evaluated. In this study, to re-examine the possibility of recent positive selection favoring the DRD4 7R allele, we genotyped HapMap subjects for DRD4 VNTR, and conducted several neutrality tests including long range haplotype test and iHS test based on the extended haplotype homozygosity. Our results indicated that LD of the DRD4 7R allele was not extended compared to SNP alleles with the similar frequency. Thus, we conclude that the DRD4 7R allele has not been subjected to strong recent positive selection.

Figure 1. The averaged heterozygosity around DRD4 in HapMap populations.

The X axis represents the genomic position of SNP on chromosome 11. The Y axis represents the averaged heterozygosity calculated for SNPs within 25 kb on either side of the focal SNP. The allele frequency data were obtained from the HapMap database, and only SNPs that were analyzed in three HapMap populations (i.e., YRI, CEU, and JPT+CHB) were selected for the calculation. The dashed line indicates the position of the DRD4 VNTR.

Figure 2. LD structure around DRD4 VNTR.

The |D'| values for all pairwise combinations of SNPs spanning 200 kb and DRD4 VNTR allele (7R or 4R) are visualized. The positions of DRD4 7R and 4R alleles are indicated by arrows. Red squares indicate statistically significant LD (LOD >2) between the pair of loci, and darker colors of red indicate higher values of |D'|. Blue squares indicate |D'| of 1 but without statistical significance. White squares indicate |D'| of <1 with no statistically significant evidence of LD. (A) YRI. (B) CEU.

Figure 3. EHH values of DRD4 7R and 4R alleles.

Red and blue lines indicate EHH of the 7R-bearing chromosomes and 4R-bearing chromosomes, respectively. The allele frequencies of DRD4 7R and 4R in each population are presented in parentheses. The horizontal axis represents the physical position of SNPs on the chromosome 11. The position of DRD4 VNTR is indicated by an arrow. (A) YRI. (B) CEU.

Figure 4. Empirical distribution of REHH of SNPs on the chromosome 11.

For each SNP with an allele whose population frequency was similar to the DRD4 7R allele, the average of REHH values on both sides (i.e., centromere-proximal and cetromere-distal) was calculated, and the empirical distributions for SNPs on the chromosome 11 were obtained. The data of SNPs with the average of REHH more than 15 are excluded from the histogram. REHH was calculated at a distance of 0.25 centimorgans (cM) from the core SNP. REHH value of DRD4 7R is indicated by dashed line. (A) YRI. (B) CEU.

Figure 5. Empirical distribution of unstandardized iHS values of SNPs on the chromosome 11.

For each SNP with an allele whose population frequency was similar to the DRD4 7R allele, the unstandardized iHS was calculated and the empirical distributions for SNPs on the chromosome 11 were obtained. The iHH value (i.e., area under the EHH curve) was calculated until EHH reaches 0.05. Unstandardized iHS value of DRD4 7R is indicated by dashed line. (A) YRI. (B) CEU.

Figure 6. Power of LRH and iHS tests.

White and shaded bars indicate the LRT and iHS tests, respectively. The final population frequencies of the selected allele are (A) 0.15 and (B) 0.3.