Human-chimpanzee DNA sequence variation in the four major genes of the renin angiotensin system

The renin angiotensin system (RAS) is involved in blood pressure control an d water/sodium metabolism. The genes encoding the proteins of this system a re candidate genes for essential hypertension. The RAS involves four main m olecules: angiotensinogen, renin, angiotensin I-converting enzyme, and the angiotensin II type 1 receptor (encoded by the genes AGT, REN, DCP1, and AG TR1, respectively). We performed a molecular screening over 17,037 bp of th e coding and 5' and 3' untranslated regions of these genes, from three to s ix common chimpanzees. We identified 44 single-nucleotide polymorphisms (SN Ps) 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 n ucleotide diversity at synonymous sites, which was dependent on the G+C con tent at the third position of the codon, was high, except for the AGTR1 gen e. Comparison of the chimpanzee SNPs with those previously reported for hum ans identified 119 sites with fixed differences (including 62 coding sites, 17 of which resulted in amino acid differences between the species). Analy sis of polymorphism within species and divergence between species shed ligh t on the evolutionary constraints on these genes. In particular, comparison of the pattern of mutation at polymorphic and fixed sites between humans a nd chimpanzees suggested that the high G+C content of the DCP1 gene was mai ntained by positive selection at its silent sites. Finally, we propose 68 a ncestral alleles for the human RAS genes and discuss the implications for t heir use in future hypertension-susceptibility association studies. (C) 200 0 Academic Press.