A complex selection signature at the human AVPR1B gene

Abstract

Background: The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses.

Results: Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg) in this region has been subjected to directional selection.

Conclusion: Although the underlying selective pressure(s) remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

Figure 1

Phylogenetic tree of AVPR1B coding region. The d_N/d_S ratio (ω) is reported for each branch. Branch lengths correspond to d_N.

Figure 2

Sliding window analysis of θ_W and π over human-chimpanzee divergence along the AVPR1B gene region. Plots were separately performed for YRI (upper panel) and EU (lower panel). The intron-exon gene structure is also shown. Both θ_W (hatched line) and π (full line) are normalized to the human-chimpanzee divergence; windows of 1000 bp with a step of 100 bp were used. The shaded box indicates a resequencing gaps; the boxed regions are those we resequenced and analyzed.

Figure 3

Schematic representation of the three-dimensional model of the V1b receptor. Two different orientations of the modeled protein are shown. The 191 and the 364 residues are highlighted (orange halos). The former is in close proximity to the Asp185 and Cys186 residues (green halos) that are known to be in close contact with AVP.

Figure 4

Genealogy of A VPR1B Ex1 (A) and Ex2 (B) haplotypes reconstructed through median-joining networks. Each node represents a different haplotype, with the size of the circle proportional to the haplotype frequency. Also, circles are color-coded according to population (yellow: AA, blue: EU, green: YRI, red: AS). Polymorphisms are shown in red, green, blue or black if they are nonsynonymous, synonymous, located in UTRs or introns, respectively.

Figure 5

Estimated tree for the AVPR1B Ex2 gene region. Mutations are represented as black dots and named for their physical position along Ex2 region. Mutation numbering does not correspond to the one shown in figure 4B since, as reported in the text, 2 SNPs were removed as they violated the infinite site model. The absolute frequency of each haplotype is also reported.