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. 2002 Jan 22;99(2):862-7.
doi: 10.1073/pnas.022614799.

Evidence for positive selection and population structure at the human MAO-A gene

Yoav Gilad  1 , Shai Rosenberg, Molly Przeworski, Doron Lancet, Karl Skorecki
Affiliations

Evidence for positive selection and population structure at the human MAO-A gene

Yoav Gilad et al. Proc Natl Acad Sci U S A. .

Abstract

We report the analysis of human nucleotide diversity at a genetic locus known to be involved in a behavioral phenotype, the monoamine oxidase A gene. Sequencing of five regions totaling 18.8 kb and spanning 90 kb of the monoamine oxidase A gene was carried out in 56 male individuals from seven different ethnogeographic groups. We uncovered 41 segregating sites, which formed 46 distinct haplotypes. A permutation test detected substantial population structure in these samples. Consistent with differentiation between populations, linkage disequilibrium is higher than expected under panmixia, with no evidence of a decay with distance. The extent of linkage disequilibrium is not typical of nuclear loci and suggests that the underlying population structure may have been accentuated by a selective sweep that fixed different haplotypes in different populations, or by local adaptation. In support of this suggestion, we find both a reduction in levels of diversity (as measured by a Hudson-Kreitman-Aguade test with the DMD44 locus) and an excess of high frequency-derived variants, as expected after a recent episode of positive selection.

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Figures

Figure 1
Figure 1
Overall genomic structure and sequencing strategy for the MAO-A gene. The arrangement of exons is shown relative to the scale provided at the top. We indicate the position of each of the five resequenced regions. The sequencing strategy is illustrated for region 2, where the PCR products are shown as overlapping segments.
Figure 2
Figure 2
Recombination and the pattern of LD at the MAO-A gene. (A) Number of pairs with four gametes. Singletons were excluded from this analysis, because they cannot have four gametes by definition. The variable number tandem repeat (VNTR) was also excluded from the analysis because it is not binary. A dark square indicates that four gametes were observed at a pair of sites. An open square indicates that fewer then four gametes were observed at a pair of sites. (B) Pairs in significant LD. Singletons were excluded from this analysis because they cannot be significant on mathematical grounds. The VNTR was also excluded because it is not binary and hence not suitable for LD analysis. Dark squares indicate pairs in significant LD at the 5% level, assessed by a Fisher's Exact Test. Dots indicate complete or absolute LD, which is not significant. (C) Scatterplot of the decay of LD with physical distance. Each point is the absolute D′ value for a pair of sites separated by a given physical distance. Singletons were excluded from this analysis.
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