Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.

Cambridge Suda Genomic Resource Center Jiangsu Key Laboratory of Neuropsychiatric Diseases Medical college of Soochow University Suzhou Jiangsu China

CELPHEDIA PHENOMIN Institut Clinique de la Souris Illkirch France

College of Veterinary Medicine Seoul National University and Korea Mouse Phenotyping Center Seoul Republic of Korea

Cyrus Tang Hematology Center Collaborative Innovation Center of Hematology Soochow University Suzhou China

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Physiology University of Texas Southwestern Medical Center Dallas Texas United States of America

European Molecular Biology Laboratory European Bioinformatics Institute Hinxton United Kingdom

German Center for Diabetes Research Neuherberg Germany

German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health Munich Germany

Medical Research Council Harwell Institute Harwell United Kingdom

National Laboratory Animal Center National Applied Research Laboratories Taipei Taiwan

RIKEN BioResource Center Tsukuba Japan

School of Medicine and Dentistry Queen Mary University of London London United Kingdom

School of Medicine and Mouse Biology Program University of California Davis California United States of America

SKL of Pharmaceutical Biotechnology and Model Animal Research Center Collaborative Innovation Center for Genetics and Development Nanjing Biomedical Research Institute Nanjing University Nanjing China

State Key Laboratory of Radiation Medicine and Prevention Medical college of Soochow University Suzhou China

The Centre for Phenogenomics Toronto Canada

The Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton United Kingdom

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