Human-chimpanzee DNA sequence variation in the four major genes of the renin angiotensin system
Human-chimpanzee DNA sequence variation in the four major genes of the renin angiotensin system
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DOI：
10.1006/geno.2000.6313
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发表时间：
2000-10-01
期刊：
影响因子：
4.4
通讯作者：
Jeunemaitre, X
中科院分区：
文献类型：
--
作者：
Dufour, C;Casane, D;Jeunemaitre, X
肾素血管紧张素系统（RAS）参与血压控制和水/钠代谢。编码该系统蛋白的基因是原发性高血压的候选基因。RAS涉及四种主要分子：血管紧张素原、肾素、血管紧张素I转换酶和血管紧张素II 1型受体（分别由基因AGT、REN、DCP 1和AGTR 1编码）。我们对这些基因的编码区和5'和3'非翻译区的17，037 bp进行了分子筛选，这些基因来自3到6只普通黑猩猩。我们在黑猩猩样本中发现了44个单核苷酸多态性（SNP），包括18个编码区SNP，其中5个导致氨基酸替换。我们观察到不同地点的共同和不同特征（1）非编码位点的核苷酸多样性相似：（2）非同义位点的核苷酸多样性较低，可能反映了纯化选择，AGT基因除外;（3）除AGTR 1基因外，其它基因的同义位点核苷酸多样性较高，其差异主要取决于密码子第3位的G+C含量。将黑猩猩的SNPs与先前报道的人类的SNPs进行比较，发现了119个具有固定差异的位点（包括62个编码位点，其中17个导致物种之间的氨基酸差异）。分析物种内的多态性和物种间的分歧揭示了这些基因的进化限制。特别是，在人类和黑猩猩之间的多态性和固定位点的突变模式的比较表明，高G+C含量的DCP 1基因保持积极的选择在其沉默的网站。最后，我们提出了人类RAS基因的68个祖先等位基因，并讨论了它们在未来高血压易感性相关研究中使用的意义。(C)北京大学出版社.
The renin angiotensin system (RAS) is involved in blood pressure control and water/sodium metabolism. The genes encoding the proteins of this system are candidate genes for essential hypertension. The RAS involves four main molecules: angiotensinogen, renin, angiotensin I-converting enzyme, and the angiotensin II type 1 receptor (encoded by the genes AGT, REN, DCP1, and AGTR1, respectively). We performed a molecular screening over 17,037 bp of the coding and 5' and 3' untranslated regions of these genes, from three to six common chimpanzees. We identified 44 single-nucleotide polymorphisms (SNPs) in chimpanzee samples, including 18 coding-region SNPs, 5 of which led to an amino acid replacement. We observed common and different features at various sites (synonymous, nonsynonymous, and noncoding) within and between the four chimpanzee genes: (1) the nucleotide diversity at noncoding sites was similar; (2) the nucleotide diversity at nonsynonymous sites was low, probably reflecting purifying selection, except for the AGT gene; (3) the nucleotide diversity at synonymous sites, which was dependent on the G+C content at the third position of the codon, was high, except for the AGTR1 gene. Comparison of the chimpanzee SNPs with those previously reported for humans identified 119 sites with fixed differences (including 62 coding sites, 17 of which resulted in amino acid differences between the species). Analysis of polymorphism within species and divergence between species shed light on the evolutionary constraints on these genes. In particular, comparison of the pattern of mutation at polymorphic and fixed sites between humans and chimpanzees suggested that the high G+C content of the DCP1 gene was maintained by positive selection at its silent sites. Finally, we propose 68 ancestral alleles for the human RAS genes and discuss the implications for their use in future hypertension-susceptibility association studies. (C) 2000 Academic Press.