The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus.
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.
Wang
E
E
Department of Biological Chemistry, University of California at Irvine, Irvine, CA 92697, USA.
Ding
Y-C
YC
Flodman
P
P
Kidd
J R
JR
Kidd
K K
KK
Grady
D L
DL
Ryder
O A
OA
Spence
M A
MA
Swanson
J M
JM
Moyzis
R K
RK
D000483:Alleles; D019143:Evolution, Molecular; D005091:Exons; D018740:Genetic Heterogeneity; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D018598:Minisatellite Repeats / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4; D011995:Recombination, Genetic; D012641:Selection, Genetic
C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4