High-throughput discovery of genetic determinants of circadian misalignment.

Tao Zhang,Ann M Flenniken,Zhiwei Liu,Pancheng Xie,Colin Mckerlie,Fei Zhou,Yingying Dong,Yi Liu,Qiaocheng Zhai,Je Kyung Seong,Nobuhiko Tanaka,Jun Yan,Allan Bradley,Damian Smedley,Christopher J Lelliott,Qingyu Wu,Lauryl M J Nutter,Valerie Gailus Durner,Ying Xu,Jan Rozman,Tania Sorg,Xiang Gao,Chi-Kuang Leo Wang,Yue Gu,Ling Yang,Yuichi Obata,Zhengyun Huang,Helen Parkinson ,Radislav Sedláček ,Dandan Pan ,Martin Hrabě De Angelis ,Marie‐France Champy ,Yann Hérault ,Steve Brown ,Terrence F Meehan ,Kevin C K Lloyd ,Ann‐Marie Mallon

doi:10.1371/journal.pgen.1008577

Abstract

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.

Highlights

The circadian clock is one of the best-characterized mechanisms that can mediate the influence of environmental cues on molecular, physiological and behavioural activities in almost all organisms
Loss of synchrony between the internal circadian clock and environment day and night changes is responsible for jet lag, but may promote sleep disorders, metabolic disorders and many diseases
By analyzing the indirect calorimetry parameters from more than 2000 C57BL/6N mice and mice from 750 mutant lines, we identified 5 genes involved in circadian misalignment of activity and feeding behaviour

Summary

Introduction

The circadian clock is one of the best-characterized mechanisms that can mediate the influence of environmental cues on molecular, physiological and behavioural activities in almost all organisms. The suprachiasmatic nucleus (SCN) is the central circadian pacemaker in mammals that receives photic information via the retina, integrates time-related information of tissues and organs, and transmits timing information to cells and tissues to regulate physiology and behaviour to entrainment of animals to the daily changes of environmental cues [1,2]. Dysfunction or misalignment of the circadian clock with environmental cues alters the timing of the sleep-wake cycle [10,11,12]. Mice with mutations orthologous to the human mutations (PER2S662G, CK1δT44A) recapitulate human phase-advanced behavioural rhythms and transgenic mice carrying PER1S714G mutation advances feeding behaviour [13,14,15,16], indicating that mice are a good model for human

Methods

Results

Discussion

Conclusion