Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene ( Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5′ flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5′ flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5′ flanking region of the gene.
DNA sequence variation underlies many differences both within and between species. In this paper, we investigate a specific DNA sequence that is thought to influence expression of a gene that modulates behavior, the vasopressin V1a receptor gene ( Avpr1a). Specifically, differences in the expression of V1a receptor in the brain have been causally tied to social behavior differences, but the genetic basis of these differences is not understood. Using transgenic mice, we investigate the role of DNA sequences upstream of this gene in generating species-specific and individual variation in Avpr1a expression. We find that, contrary to our expectation, this region has only a modest influence on differences in expression patterns across rodent species. This indicates that DNA elements outside of this region play a larger role in species-level differences in expression. We confirm that variation in Avpr1a expression mediated by this upstream region translates to differences in behavior. We also find that variable DNA sequences associated with repetitive motifs within this region subtly influence gene expression. Together these findings highlight the complexity of genetic mechanisms that influence diversity in brain receptor patterns and support the idea that variable repetitive elements can influence both species and individual differences in gene expression patterns.