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.
Highlights
Recent studies have highlighted the utility of the BXD murine genetic reference population in the study of metabolism [1]
The BXD population consists of,100 related strains descended from C57BL/6J (B6) and DBA/2J (D2) [2], and has wide phenotypic variance in key traits such as blood pressure [3], body weight, and glucose response [1] caused by,5 million sequence variants segregating across the population
QTL analysis indicated that,40% of this variance is due to the aryl hydrocarbon receptor (Ahr)
Summary
Recent studies have highlighted the utility of the BXD murine genetic reference population in the study of metabolism [1]. Many specific variants have been established as causal of overt phenotypic changes, including SNPs in the aryl hydrocarbon receptor (Ahr) mediating TCDD response [4], missense SNPs in alkaline phosphatase causing impaired vitamin B6 metabolism and bone weakness [1], and a CNV of glyoxalase 1 causing increased anxiety [5]. Ahr is a basic helix-loop-helix (bHLH) transcription factor that has been established over the past decades as a key regulator of a variety of processes, including embryonic development [6], xenobiotic metabolism [7], immune response and inflammation [8], and tumorigenesis [9]. AHR dissociates from its chaperones, dimerizes with the aryl hydrocarbon nuclear translocator (ARNT)
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