A QTL on mouse chromosome 12 for the genetic variance in free-running circadian period between inbred strains of mice

BACKGROUND: Many genes control circadian period in mice. Prior studies suggested a quantitative trait locus (QTL) on proximal mouse chromosome 12 for interstrain differences in circadian period. Since the B6.D2NAhr(d)/J strain has DBA/2 alleles for a portion of proximal chromosome 12 introgressed onto its C57BL/6J background, we hypothesized that these mice would have a shorter circadian period than C57BL/6J mice. METHODS: We compared circadian phenotypes of B6.D2NAhr(d)/J and C57BL/6 mice: period of general locomotor activity in constant dark and rest/activity pattern in alternating light and dark. We genotyped the B6.D2NAhr(d)/J mice to characterize the size of the genomic insert. To aid in identifying candidate quantitative trait genes we queried databases about the resident SNPs, whole brain gene expression in C57BL/6J versus DBA/2J mice, and circadian patterns of gene expression. RESULTS: The B6.D2NAhr(d)/J inbred mice have a shorter circadian period of locomotor activity than the C57BL/6J strain. Furthermore, the genomic insert is associated with another phenotype: the mean phase of activity minimum in the dark part of a light-dark lighting cycle. It was one hour later than in the background strain. The B6.D2NAhr(d)/J mice have a DBA/2J genomic insert spanning 35.4 to 41.0 megabase pairs on Chromosome 12. The insert contains 15 genes and 12 predicted genes. In this region Ahr (arylhydrocarbon receptor) and Zfp277 (zinc finger protein 277) both contain non-synonymous SNPs. Zfp277 also showed differential expression in whole brain and was cis-regulated. Three genes and one predicted gene showed a circadian pattern of expression in liver, including Zfp277. CONCLUSION: We not only fine-mapped the QTL for circadian period on chromosome 12 but found a new QTL there as well: an association with the timing of the nocturnal activity-minimum. Candidate quantitative trait genes in this QTL are zinc finger protein 277 and arylhydrocarbon receptor. Arylhydrocarbon receptor is structurally related to Bmal1, a canonical clock gene.