Evidence of positive selection acting
at the human dopamine receptor D4 gene locus
by
Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR,
Kidd KK, Flodman P, Spence MA, Schuck S, Swanson JM, Zhang YP, Moyzis RK.
Department of Biological Chemistry,
College of Medicine, University of California,
Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A 2002 Jan 8;99(1):309-14

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.

D4
D3
D2
D1+D2
Reward
Serotonin 5-HT2c
Dopamine and sex
D4-knockout mice
Personality genetics
D3 and antidepressants
Dopamine neurodynamics
Reward deficiency syndrome
Dopamine and reward signalling
The genetics of affective disorders
Depression, dopamine and dextroamphetamine

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