Evidence of positive selection acting at the human dopamine receptor D4 gene locus
Evidence of positive selection acting at the human dopamine receptor D4 gene locus
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DOI：
10.1073/pnas.012464099
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发表时间：
2002-01-08
影响因子：
11.1
通讯作者：
Moyzis, RK
中科院分区：
文献类型：
--
作者：
Ding, YC;Chi, HC;Moyzis, RK
据报道，人类多巴胺受体 D4 (DRD4) 基因的七次重复 (7R) 等位基因与注意力缺陷/多动障碍和寻求新奇的人格特质有关。这种多态性发生在 DRD4 编码区的 48 bp 串联重复中，最常见的等位基因包含 4 个重复 (4R)，较罕见的变体包含 2-11 个重复。在这里，我们通过代表全球人口样本的 600 个 DRD4 等位基因的 DNA 重测序/单倍型分析表明，2R-6R 等位基因的起源可以通过简单的一步重组/突变事件来解释。相比之下，7R 等位基因并不简单地与其他常见等位基因相关，其差异超过六次重组/突变。在 7R 等位基因和周围的 DRD4 多态性之间发现了强连锁不平衡，表明该等位基因比常见的 4R 等位基因至少“年轻”5-10 倍。基于观察到的非同义氨基酸变化的偏差、不寻常的 DNA 序列组织以及 DRD4 7R 等位基因周围的强连锁不平衡，我们提出该等位基因起源于罕见的突变事件，但通过正选择在人类群体中增加到高频率。
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.