title: Evidence of positive selection acting at the human dopamine receptor D4 gene locus.
abstract: Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold "younger" than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.
authors.affiliation: Department of Biological Chemistry, College of Medicine, University of California, Irvine, CA 92697, USA.
authors.forename: Yuan-Chun
authors.initials: YC
authors.lastname: Ding
authors.forename: Han-Chang
authors.initials: HC
authors.lastname: Chi
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Grady
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Morishima
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kidd
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.forename: Pamela
authors.initials: P
authors.lastname: Flodman
authors.forename: M Anne
authors.initials: MA
authors.lastname: Spence
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schuck
authors.forename: James M
authors.initials: JM
authors.lastname: Swanson
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Robert K
authors.initials: RK
authors.lastname: Moyzis
mesh_terms: D000483:Alleles; D001483:Base Sequence; D019143:Evolution, Molecular; D005091:Exons; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4; D011995:Recombination, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D013997:Time Factors
chemical_list: C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4