Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs

Abstract

Although considerable progress has been made in understanding the genetic basis of morphologic traits (for example, body size and coat color) in dogs and wolves, the genetic basis of their behavioral divergence is poorly understood. An integrative approach using both behavioral and genetic data is required to understand the molecular underpinnings of the various behavioral characteristics associated with domestication. We analyze a 5-Mb genomic region on chromosome 6 previously found to be under positive selection in domestic dog breeds. Deletion of this region in humans is linked to Williams-Beuren syndrome (WBS), a multisystem congenital disorder characterized by hypersocial behavior. We associate quantitative data on behavioral phenotypes symptomatic of WBS in humans with structural changes in the WBS locus in dogs. We find that hypersociability, a central feature of WBS, is also a core element of domestication that distinguishes dogs from wolves. We provide evidence that structural variants in GTF2I and GTF2IRD1, genes previously implicated in the behavioral phenotype of patients with WBS and contained within the WBS locus, contribute to extreme sociability in dogs. This finding suggests that there are commonalities in the genetic architecture of WBS and canine tameness and that directional selection may have targeted a unique set of linked behavioral genes of large phenotypic effect, allowing for rapid behavioral divergence of dogs and wolves, facilitating coexistence with humans.

Fig. 1. Association of structural variants with indices of human-directed social behavior.

Association with ABS (A), HYP (B), and SIS (C). Manhattan plots show statistical significance of each variant as a function of position in target region. Blue line denotes statistical significance to Bonferroni-corrected level (P = 2.38 × 10⁻³). Genic and intergenic variants are shown as green and red boxes, respectively.

Fig. 2. Association of structural variants with human-directed social behavior in multivariate regressions.

Association in behavioral index model (A) and PC model (B). Manhattan plots show statistical significance of each variant as a function of position in the target region. Blue line denotes significance to Bonferroni-corrected level (P = 2.38 × 10⁻³); dashed purple line denotes suggestive significance (P = 0.01). Genic and intergenic variants are shown as green and red boxes, respectively.