Genome-Wide Epistatic Interaction Analysis Reveals Complex Genetic Determinants of Circadian Behavior in Mice

Abstract

Genetic heterogeneity underlies many phenotypic variations observed in circadian rhythmicity. Continuous distributions in measures of circadian behavior observed among multiple inbred strains of mice suggest that the inherent contributions to variability are polygenic in nature. To identify genetic loci that underlie this complex behavior, we have carried out a genome-wide complex trait analysis in 196 (C57BL/6J X BALB/cJ)F 2 hybrid mice. We have characterized variation in this panel of F 2 mice among five circadian phenotypes: free-running circadian period, phase angle of entrainment, amplitude of the circadian rhythm, circadian activity level, and dissociation of rhythmicity. Our genetic analyses of these phenotypes have led to the identification of 14 loci having significant effects on this behavior, including significant main effect loci that contribute to three of these phenotypic measures: period, phase, and amplitude. We describe an additional locus detection method, genome-wide genetic interaction analysis, developed to identify locus pairs that may interact epistatically to significantly affect phenotype. Using this analysis, we identified two additional pairs of loci that have significant effects on dissociation and activity level; we also detected interaction effects in loci contributing to differences of period, phase, and amplitude. Although single gene mutations can affect circadian rhythms, the analysis of interstrain variants demonstrates that significant genetic complexity underlies this behavior. Importantly, most of the loci that we have detected by these methods map to locations that differ from the nine known clock genes, indicating the presence of additional clock-relevant genes in the mammalian circadian system. These data demonstrate the analytical value of both genome-wide complex trait and epistatic interaction analyses in further understanding complex phenotypes, and point to promising approaches for genetic analysis of such phenotypes in other mammals, including humans.

Identification of genetic loci controlling bacterial clearance in experimental Salmonella enteritidis infection: an unexpected role of Nramp1 (Slc11a1) in the persistence of infection in mice

“…A genome-wide epistatic interaction analysis of our segregating F2 population may be necessary to reveal alleles that had relatively little effect on the phenotype individually but produce a significant effect when combined. 42 All together, these results underscore the genetic complexity of host resistance to S. enteritidis.…”

“…Ses2 explained 6% of the genetic variance and Ses3, 4% (Table 2). In these cases also, the C57BL/6J allele is protective and contributes in a recess- 33,9,36,25 D7Mit76,83,62,31,323,38,237,44,189 D8Mit3,41,56 D9Mit218,25,306,37 D10Mit80,38,42,10,205 D11Mit77,20,5,4,124,61 D12Mit182,49,12,59,46,60,14,Nds2 D13Mit236,139,147,30,36,151 D14Mit11,52,30 D15Mit12,26,46,47,29,42,242,159,35 D16Mit81,4,47,…”

Perchance to dream: Solving the mystery of sleep through genetic analysis

“…QTL and mutagenesis should be viewed as complementary approaches (Belknap et al, 2001). A good example of this was again provided by Takahashi's group for the circadian behavior in mice (Shimomura et al, 2001). Although most of the circadian "clock" genes that constitute the molecular circadian clock have been discovered mainly by direct molecular techniques and mutagenesis, these genes do not explain the complexity of the observed circadian behavior, i.e., none of the known "clock" genes has been found to be involved in the difference in circadian period length between BALB/c and C57BL/6 inbred mouse strains.…”

“…Although most of the circadian "clock" genes that constitute the molecular circadian clock have been discovered mainly by direct molecular techniques and mutagenesis, these genes do not explain the complexity of the observed circadian behavior, i.e., none of the known "clock" genes has been found to be involved in the difference in circadian period length between BALB/c and C57BL/6 inbred mouse strains. Instead, QTL analysis in a BALB/c ϫ C57BL/6 intercross panel revealed several new loci with epistatic interaction (Shimomura et al, 2001).…”

The Collaborative Cross, a community resource for the genetic analysis of complex traits

“…Epistatic and environmental interactions also influence this estimate. Mounting evidence suggests that gene-gene interactions are crucial in many complex disease etiologies [8][9][10] . A set of 1,000 strains will readily support simultaneous mapping of many two-way and three-way epistatic interactions.…”