A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly
A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly
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DOI：
10.1007/s10519-008-9233-0
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发表时间：
2009-01-01
影响因子：
2.6
通讯作者：
Posthuma, Danielle
中科院分区：
文献类型：
--
作者：
Bochdanovits, Zoltan;Gosso, Florencia M.;Posthuma, Danielle
比较基因组学为揭示复杂性状的遗传基础提供了一种新的方法。我们进行了两个阶段的分析，其中确定在灵长类动物中增强蛋白质进化的基因随后在当前人类群体中在人类和黑猩猩之间不同的氨基酸位点处搜索非同义编码SNP的存在。灵长类动物中的正选择基因通常被认为决定了人类和黑猩猩之间的表型差异，例如我们物种的认知能力增强。预期在人类中在正选择的氨基酸位点处分离的氨基酸取代会影响人类之间的表型差异。因此，我们在两个基于家族的队列和一个基于人群的队列中进行了认知能力与五个具有一个以上此类多态性的基因中最可能的候选基因之间的关联研究。β-2肾上腺素能受体Arg 16 Gly多态性的衍生的人类特异性等位基因被发现在年轻的、以家庭为基础的队列中是表现智商的增加者等位基因，但在苏格兰的大型队列中，在两种不同的认知测量中是减少者等位基因。已知该多态性影响信号传导活性，并且β-2肾上腺素能信号传导的调节已被证明可以调节记忆巩固，这是一种与认知相关的特征。在不同队列中观察到的两个年龄组中多态性对认知的相反影响类似于ADRB 2对高血压的影响，这也被报道为年龄依赖性的。这一结果说明了比较基因组学在检测与人类行为有关的基因方面的相关性。
Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.