title: Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world.
abstract: 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 (14400 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.
authors.affiliation: Division of Genetic Diagnosis, The University of Tokyo, Tokyo 108-8639, Japan. tnakajim@ims.u-tokyo.ac.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Stephen
authors.initials: S
authors.lastname: Wooding
authors.forename: Takuro
authors.initials: T
authors.lastname: Sakagami
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Gen
authors.initials: G
authors.lastname: Tamiya
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishigami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.forename: Batmunkh
authors.initials: B
authors.lastname: Munkhbat
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Jia
authors.initials: J
authors.lastname: Guan-Jun
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hayasaka
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ishida
authors.forename: Naruya
authors.initials: N
authors.lastname: Saitou
authors.forename: Karel
authors.initials: K
authors.lastname: Pavelka
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lalouel
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D000349:Africa; D000808:Angiotensinogen / Q000235:genetics*; D001208:Asia; D002877:Chromosomes, Human / Q000235:genetics*; D005060:Europe; D014644:Genetic Variation; D005828:Genetics, Population; D005843:Geography; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012641:Selection, Genetic
chemical_list: D000808:Angiotensinogen