人类 CYP3A 基因座的分子群体遗传学：正选择的特征及其对进化环境医学的影响。
Molecular population genetics of human CYP3A locus: signatures of positive selection and implications for evolutionary environmental medicine.
机构信息
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Chinese National Human Genome Center at Beijing, Beijing, China.
出版信息
Environ Health Perspect. 2009 Oct;117(10):1541-8. doi: 10.1289/ehp.0800528. Epub 2009 Jun 18.
BACKGROUND
The human CYP3A gene cluster codes for cytochrome P450 (CYP) subfamily enzymes that catalyze the metabolism of various exogenous and endogenous chemicals and is an obvious candidate for evolutionary and environmental genomic study. Functional variants in the CYP3A locus may have undergone a selective sweep in response to various environmental conditions.
OBJECTIVE
The goal of this study was to profile the allelic structure across the human CYP3A locus and investigate natural selection on that locus.
METHODS
From the CYP3A locus spanning 231 kb, we resequenced 54 genomic DNA fragments (a total of 43,675 bases) spanning four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2), and randomly selected intergenic regions at the CYP3A locus in Africans (24 individuals), Caucasians (24 individuals), and Chinese (29 individuals). We comprehensively investigated the nucleotide diversity and haplotype structure and examined the possible role of natural selection in shaping the sequence variation throughout the gene cluster.
RESULTS
Neutrality tests with Tajima's D, Fu and Li's D* and F*, and Fay and Wu's H indicated possible roles of positive selection on the entire CYP3A locus in non-Africans. Sliding-window analyses of nucleotide diversity and frequency spectrum, as well as haplotype diversity and phylogenetically inferred haplotype structure, revealed that CYP3A4 and CYP3A7 had recently undergone or were undergoing a selective sweep in all three populations, whereas CYP3A43 and CYP3A5 were undergoing a selective sweep in non-Africans and Caucasians, respectively.
CONCLUSION
The refined allelic architecture and selection spectrum for the human CYP3A locus highlight that evolutionary dynamics of molecular adaptation may underlie the phenotypic variation of the xenobiotic disposition system and varied predisposition to complex disorders in which xenobiotics play a role.
背景
人类 CYP3A 基因簇编码细胞色素 P450（CYP）亚家族酶，该酶催化各种外源性和内源性化学物质的代谢，是进化和环境基因组研究的明显候选者。CYP3A 基因座中的功能变体可能在外源化学物质的作用下经历了选择清除。
目的
本研究旨在分析人类 CYP3A 基因座的等位基因结构，并研究该基因座的自然选择。
方法
我们从 CYP3A 基因座（跨度 231kb）中重新测序了 54 个基因组 DNA 片段（共 43675 个碱基），跨越四个基因（CYP3A4、CYP3A5、CYP3A7 和 CYP3A43）和两个假基因（CYP3AP1 和 CYP3AP2），并随机选择了 CYP3A 基因座在非洲人（24 人）、白种人（24 人）和中国人（29 人）中的基因间区。我们全面研究了核苷酸多样性和单倍型结构，并检查了自然选择在塑造整个基因簇序列变异中的可能作用。
结果
Tajima 的 D、Fu 和 Li 的 D和 F、以及 Fay 和 Wu 的 H 的中性检验表明，非非洲人中整个 CYP3A 基因座可能存在正选择作用。核苷酸多样性和频谱的滑动窗口分析、单倍型多样性和系统发育推断的单倍型结构表明，CYP3A4 和 CYP3A7 在所有三个群体中最近或正在经历选择清除，而 CYP3A43 和 CYP3A5 分别在非非洲人和白种人中经历选择清除。
结论
人类 CYP3A 基因座的精细等位基因结构和选择谱强调了分子适应的进化动态可能是外源性物质处置系统表型变异和复杂疾病易感性的基础，而这些疾病中外源性物质发挥了作用。
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