TY - JOUR
T1 - Natural Selection and Population History in the Human Angiotensinogen Gene (AGT)
T2 - 736 Complete AGT Sequences in Chromosomes from Around the World
AU - Nakajima, Toshiaki
AU - Wooding, Stephen
AU - Sakagami, Takuro
AU - Emi, Mitsuru
AU - Tokunaga, Katsushi
AU - Tamiya, Gen
AU - Ishigami, Tomoaki
AU - Umemura, Satoshi
AU - Munkhbat, Batmunkh
AU - Jin, Feng
AU - Guan-Jun, Jia
AU - Hayasaka, Ikuo
AU - Ishida, Takafumi
AU - Saitou, Naruya
AU - Pavelka, Karel
AU - Lalouel, Jean Marc
AU - Jorde, Lynn B.
AU - Inoue, Ituro
N1 - Funding Information:
We are grateful for comments from Dr. Andreas Rohrwasser. This work was supported by the Future Program Grant of The Japan Society for the Promotion of Science (I.I. and M.E.); by the Ministry of Public Health and Welfare Research on Human Genome and Grant-in-Aid for Scientific Research on Medical Genome Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by National Institutes of Health grant HL070048.
PY - 2004/5
Y1 - 2004/5
N2 - Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A(-6) variant leads to the intriguing hypothesis that the G(-6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14,400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A(-6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A(-6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A(-6)G polymorphism. Further, haplotypes carrying the G(-6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G(-6) variant over the A(-6) variant in non-African populations. However, important localized effects may also be present.
AB - Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A(-6) variant leads to the intriguing hypothesis that the G(-6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14,400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A(-6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A(-6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A(-6)G polymorphism. Further, haplotypes carrying the G(-6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G(-6) variant over the A(-6) variant in non-African populations. However, important localized effects may also be present.
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U2 - 10.1086/420793
DO - 10.1086/420793
M3 - Article
C2 - 15077204
AN - SCOPUS:2342459066
SN - 0002-9297
VL - 74
SP - 898
EP - 916
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -