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.
Highlights
The human dopamine receptor D4 (DRD4; MIM 126452) gene, located on chromosome 11p15.5, contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor
To investigate whether the observed distribution of allele frequencies at the DRD4 VNTR is deviated from the expectation under neutrality, we performed the Ewens-Watterson homozygosity test [23], where the sum of squared allele frequencies (F) was calculated for the observed data, and the observed F value was compared with the expected ones generated by simulating samples under neutrality
No significant extended linkage disequilibrium (LD) from the DRD4 7R allele to single nucleotide polymorphisms (SNPs) outside the DRD4 locus was detected in the present study
Summary
The human dopamine receptor D4 (DRD4; MIM 126452) gene, located on chromosome 11p15.5, contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. Ten VNTR alleles with two (2R) to eleven (11R) repeats have been identified so far. The receptor encoded by the DRD4 7R allele has functional properties different from those by the DRD4 2R and 4R alleles. The DRD4 7R protein, compared with DRD4 2R and DRD4 4R, has different binding affinity to clozapine and spiperone [1], and shows a blunted intracellular response to dopamine [3]. The repeat sequence of the DRD4 7R allele suppresses the expression level of DRD4 compared to the DRD4 2R and 4R alleles [4]. The DRD4 7R allele has been reported to be associated with behavioral and psychiatric phenotypes such as novelty seeking [5,6] and attentiondeficit hyperactivity disorder [7,8], even though there are conflicting results [9,10,11,12,13]
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