An Evolutionarily Conserved Role for the Aryl Hydrocarbon Receptor in the Regulation of Movement

Abstract

The BXD genetic reference population is a recombinant inbred panel descended from crosses between the C57BL/6 (B6) and DBA/2 (D2) strains of mice, which segregate for about 5 million sequence variants. Recently, some of these variants have been established with effects on general metabolic phenotypes such as glucose response and bone strength. Here we phenotype 43 BXD strains and observe they have large variation (∼5-fold) in their spontaneous activity during waking hours. QTL analyses indicate that ∼40% of this variance is attributable to a narrow locus containing the aryl hydrocarbon receptor (Ahr), a basic helix-loop-helix transcription factor with well-established roles in development and xenobiotic metabolism. Strains with the D2 allele of Ahr have reduced gene expression compared to those with the B6 allele, and have significantly higher spontaneous activity. This effect was also observed in B6 mice with a congenic D2 Ahr interval, and in B6 mice with a humanized AHR allele which, like the D2 allele, is expressed much less and has less enzymatic activity than the B6 allele. Ahr is highly conserved in invertebrates, and strikingly inhibition of its orthologs in D. melanogaster and C. elegans (spineless and ahr-1) leads to marked increases in basal activity. In mammals, Ahr has numerous ligands, but most are either non-selective (e.g. resveratrol) or highly toxic (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)). Thus, we chose to examine a major environmental influence—long term feeding with high fat diet (HFD)—to see if the effects of Ahr are dependent on major metabolic differences. Interestingly, while HFD robustly halved movement across all strains, the QTL position and effects of Ahr remained unchanged, indicating that the effects are independent. The highly consistent effects of Ahr on movement indicate that changes in its constitutive activity have a role on spontaneous movement and may influence human behavior.

QTLand systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field

“…The Ahr gene in the Chr 12 interval has been reported as modulating both horizontal and vertical movement (Williams et al . ). However, the effect found in that study was a main effect of the QTL whereas the effect that we report here is only significant in interaction with the Chr 14 locus and specific for rearing.…”

“…When molecular-genetic techniques became available that made it possible to determine the approximate locus of some of these polygenes (now termed quantitative trait loci -QTLs), open-field behavior again was among the first behavioral phenotypes to be so investigated (Flint et al 1995;Gershenfeld et al 1997;Mathis et al 1995;Mott & Flint 2002;Talbot et al 1999). Several loci have been mapped, although few genes have actually been identified (Logan et al 2013;Williams et al 2014;Yalcin et al 2004). Most of these studies were carried out using different heterogeneous populations, necessitating the genotyping at many marker loci of every individual mouse studied, whereas the other studies could use only the relatively moderate numbers of recombinant inbred (RI) strains that were then available.…”

The Movement Tracker: A Flexible System for Automated Movement Analysis in Invertebrate Model Organisms

“…8.37.2A-C). These three setups have worked for our experiments Mouchiroud et al, 2013;Williams et al, 2014), but we provide them as a guideline for how to create a simple setup adapted to a particular experiment, rather than as a definitive guide on how to quantify movement.…”

Functional Analysis of Genomic Variation and Impact on Molecular and Higher Order Phenotypes

“…Classic PheWAS linked this variant to the frequency with which cleft palates is induced by 2,3,7,8-tetrachlorodibenzofuran injection (GN ID 10714; q = 3.2×10 -3 ) (Figure 4-6d). Ahr variants have also been definitively linked to differences in locomotor activity [262]. Consistent with the results of the BXD PheWAS, a matched PheWAS in humans using BioVU links rs2066853 in AHR with cleft palate (p = 0.012; Figure 4-6e).…”

“…Nevertheless, many of the large ASE effects caused by strong cis-acting variants will often be well conserved across environments, cell types, and genetic backgrounds. For example, ASE effects due to copy number variants [199] [88], and nonsense mutations [262] will often produce strong and consistent ASE effects across many tissues and treatments.…”