Mapping Tameness in the Williams-Beuren Syndrome Critical Region: Implication of TFII-I Transcription Factors in the Behavioral Phenotype of Domestic Dogs

Abstract

Tameness is among the most outstanding phenotypic differences between dogs (Canis lupus familiaris) and wolves (Canis lupus) and is believed to have been directly selected for during the domestication process. While studies have identified the genetic basis of many of the morphological differences between wild and tame animals, the genetic basis of this profound behavioral transformation remains to be elucidated. A recent study identified the canine analog of the Williams-Beuren syndrome critical region (WBSCR) as a candidate for being under positive selection during domestication. Deletion of this region in humans causes Williams- Beuren syndrome (WBS), a multi-system congenital disorder characterized by hypersocial behavior. The remarkable similarity between the behavioral presentation of WBS and the overt friendliness of domesticated dogs suggests that there may be similarities in the genetic architecture of the two phenotypes. To investigate this hypothesis I develop a novel structural variant (SV) discovery pipeline and use it to characterize structural variation in the canine WBSCR in 16 dogs and 8 human-socialized wolves. Using linear mixed models, I detect associations between SVs in several genes deleted in WBS and tame behavior in canids. My results implicate the TFII-I family of basal transcription factors, genes previously implicated in the behavioral phenotype of patients with WBS, suggesting that there are commonalities in the genetic architecture of WBS and canine tameness. These findings suggest that the TFII-I transcription factors should be a priority for future study of the genetic basis of tame behavior, and that traditional approaches to genotype-phenotype association, which rely almost exclusively on single nucleotide variation, provide an incomplete understanding of the genetic architecture of at least one complex phenotype.