Dufour C, Casane D, Denton D, Wickings J, Corvol P, Jeunemaitre X
Pathologie Vasculaire et Endocrinologie Rénale, Collège de France, Chaire de Médecine Expérimentale et d'Endocrinologie Rénale, Institut National de la Santé et de la Recherche Médicale U36, Paris, 75005, France.
Genomics. 2000 Oct 1;69(1):14-26. doi: 10.1006/geno.2000.6313.
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.
肾素血管紧张素系统（RAS）参与血压调控以及水/钠代谢。该系统蛋白质的编码基因是原发性高血压的候选基因。RAS包含四个主要分子：血管紧张素原、肾素、血管紧张素I转换酶以及血管紧张素II 1型受体（分别由基因AGT、REN、DCP1和AGTR1编码）。我们对三只到六只普通黑猩猩的这些基因的编码区以及5'和3'非翻译区超过17,037 bp的区域进行了分子筛选。我们在黑猩猩样本中鉴定出44个单核苷酸多态性（SNP），其中包括18个编码区SNP，其中5个导致氨基酸替换。我们在四只黑猩猩基因内部和之间的各个位点（同义、非同义及非编码）观察到了共同和不同的特征：（1）非编码位点的核苷酸多样性相似；（2）除AGT基因外，非同义位点的核苷酸多样性较低，这可能反映了纯化选择；（3）同义位点的核苷酸多样性较高，其取决于密码子第三位的G+C含量，AGTR1基因除外。将黑猩猩的SNP与先前报道的人类SNP进行比较，确定了119个固定差异位点（包括62个编码位点，其中17个导致物种间氨基酸差异）。对物种内多态性和物种间差异的分析揭示了这些基因的进化限制。特别是，人类和黑猩猩之间多态性和固定位点的突变模式比较表明，DCP1基因的高G+C含量是通过其沉默位点的正选择得以维持的。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关联研究中的应用意义。
