The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus
The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus
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DOI：
10.1086/420854
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发表时间：
2004-05-01
影响因子：
9.8
通讯作者：
Moyzis, RK
中科院分区：
文献类型：
--
作者：
Wang, E;Ding, YC;Moyzis, RK
人类多巴胺受体D4（DRD 4）基因的7个重复（7 R）等位基因与寻求新奇和注意力缺陷/多动障碍的人格特质的关联已被报道。最近，基于DRD 4 7 R 48-bp串联重复序列（VNTR）的不寻常的DNA序列组织，我们提出7 R等位基因起源于一种罕见的突变事件，通过正选择增加到高频率。我们现在已经对103个VNTR的2 R、4 R或7 R变体纯合个体的整个DRD 4基因座进行了重新测序，这是一种直接估计单倍型多样性的方法。使用了来自非洲、欧洲、亚洲、北美和南美以及太平洋岛屿血统的个体的DNA。4 R/4 R纯合子表现出很少的连锁不平衡（LD）在该地区的研究，与更多的多态性观察到的DNA样本来自非洲的个人。相反，围绕7 R等位基因的强LD的证据是戏剧性的，所有7 R/7 R个体（包括来自非洲的那些）在大多数多态性位点表现出相同的等位基因。通过对该基因座上18个高杂合性位点的等位基因内比较，我们估计7 R等位基因出现于旧石器时代晚期之前（近似于40，000- 50，000年前）。此外，在这些多态性位点处的重组模式是作用于7 R VNTR本身而不是相邻位点处的选择所预期的模式。我们提出了一个模型，在DRD 4位点的选择与这些观察到的LD模式和已知的受体变体之间的生化和生理差异一致。
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 (similar to40,000-50,000 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.