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Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world - PubMed

Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world

Toshiaki Nakajima et al. Am J Hum Genet. 2004 May.

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.

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Figures

Figure 1
Figure 1

Distribution of sequence variations on three continents: Africa, Eurasia, and East Asia

Figure 2
Figure 2

A, Summary of sequence variation in AGT. Variable sites are color coded. Homozygotes for the derived allele are red, heterozygotes are purple, and homozygotes for the ancestral allele are blue. The ancestral allele at each locus was estimated on the basis of primate (Pan troglodytes verus, Gorilla gorilla, and Pongo pygmaeus) sequences. B, Sequence variation in AGT genotypes homozygous for G(−6), heterozygous, and homozygous for A(−6). SNPs in tight LD with A(−6)G (

r2>0.5

) are indicated by arrows and arrow heads.

Figure 3
Figure 3

Neighbor-joining tree based on Nei’s distance among seven populations. The shaded portion of each circle indicates the frequency of the A(−6)/T235 allele.

Figure 4
Figure 4

A, Structure of LD in three African populations (Pygmy, Nande, and Hema) and three non-African populations (Utah, Indian/Pakistani, and Korean). Each point represents a disequilibrium coefficient, |D′| and r2, calculated pairwise among 50 SNPs. Pairs in LD (

D′⩾0.75

,

r2⩾0.5

) are shaded. Arrowheads indicate SNPs that were not observed in each population sample. B, Pairwise r2 values in 15 population samples were plotted as a function of physical distance.

Figure 5
Figure 5

Sliding-window test of neutrality in AGT. Each window contains 20 SNPs, with a step size of 1 SNP. Arrows indicate SNPs in tight LD with T235M.

Figure 6
Figure 6

Sliding-window plots of θπ and θH in African samples (A) and Utah samples (B). Each window contains 20 SNPs, with a step size of 1 SNP. The sites of SNPs in tight LD with A(−6)G (

r2>0.5

) are indicated by arrows.

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References

Electronic-Database Information

    1. Arlequin, http://lgb.unige.ch/arlequin/ (for software for population genetic data analysis)
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for the sequence of AGT [accession number NM_000029 and X15323])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AGT and EHT) - PubMed

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