Genetic and molecular analysis of wild-derived arrhythmic mice.
A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (tau), quantitative trait locus (QTL) analysis was performed using F(2) mice obtained from an F(1) cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For tau, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.
Watanabe
Tsuyoshi
T
Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
Suzuki
Tohru
T
Ishikawa
Akira
A
Yokota
Yuki
Y
Ueda
Hiroki R
HR
Yamada
Rikuhiro G
RG
Tei
Hajime
H
Imai
Saki
S
Tomida
Shigeru
S
Kobayashi
Junya
J
Naito
Emiko
E
Yasuo
Shinobu
S
Nakao
Nobuhiro
N
Namikawa
Takao
T
Yoshimura
Takashi
T
Ebihara
Shizufumi
S
D019943:Amino Acid Substitution; D000818:Animals; D000835:Animals, Wild / Q000235:genetics* / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D003433:Crosses, Genetic; D003624:Darkness; D004843:Epistasis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D008126:Lod Score; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D040641:Quantitative Trait Loci / Q000235:genetics; D017422:Sequence Analysis, DNA; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse