High-throughput discovery of genetic determinants of circadian misalignment.
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 regula...
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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008577&type=printable |
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| author | Tao Zhang Pancheng Xie Yingying Dong Zhiwei Liu Fei Zhou Dejing Pan Zhengyun Huang Qiaocheng Zhai Yue Gu Qingyu Wu Nobuhiko Tanaka Yuichi Obata Allan Bradley Christopher J Lelliott Sanger Institute Mouse Genetics Project Lauryl M J Nutter Colin McKerlie Ann M Flenniken Marie-France Champy Tania Sorg Yann Herault Martin Hrabe De Angelis Valerie Gailus Durner Ann-Marie Mallon Steve D M Brown Terry Meehan Helen E Parkinson Damian Smedley K C Kent Lloyd Jun Yan Xiang Gao Je Kyung Seong Chi-Kuang Leo Wang Radislav Sedlacek Yi Liu Jan Rozman Ling Yang Ying Xu |
| author_facet | Tao Zhang Pancheng Xie Yingying Dong Zhiwei Liu Fei Zhou Dejing Pan Zhengyun Huang Qiaocheng Zhai Yue Gu Qingyu Wu Nobuhiko Tanaka Yuichi Obata Allan Bradley Christopher J Lelliott Sanger Institute Mouse Genetics Project Lauryl M J Nutter Colin McKerlie Ann M Flenniken Marie-France Champy Tania Sorg Yann Herault Martin Hrabe De Angelis Valerie Gailus Durner Ann-Marie Mallon Steve D M Brown Terry Meehan Helen E Parkinson Damian Smedley K C Kent Lloyd Jun Yan Xiang Gao Je Kyung Seong Chi-Kuang Leo Wang Radislav Sedlacek Yi Liu Jan Rozman Ling Yang Ying Xu |
| author_sort | Tao Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c12d6bf50c5146379916d239a99b9e3e |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-c12d6bf50c5146379916d239a99b9e3e2025-08-20T02:11:01ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-01-01161e100857710.1371/journal.pgen.1008577High-throughput discovery of genetic determinants of circadian misalignment.Tao ZhangPancheng XieYingying DongZhiwei LiuFei ZhouDejing PanZhengyun HuangQiaocheng ZhaiYue GuQingyu WuNobuhiko TanakaYuichi ObataAllan BradleyChristopher J LelliottSanger Institute Mouse Genetics ProjectLauryl M J NutterColin McKerlieAnn M FlennikenMarie-France ChampyTania SorgYann HeraultMartin Hrabe De AngelisValerie Gailus DurnerAnn-Marie MallonSteve D M BrownTerry MeehanHelen E ParkinsonDamian SmedleyK C Kent LloydJun YanXiang GaoJe Kyung SeongChi-Kuang Leo WangRadislav SedlacekYi LiuJan RozmanLing YangYing XuCircadian 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008577&type=printable |
| spellingShingle | Tao Zhang Pancheng Xie Yingying Dong Zhiwei Liu Fei Zhou Dejing Pan Zhengyun Huang Qiaocheng Zhai Yue Gu Qingyu Wu Nobuhiko Tanaka Yuichi Obata Allan Bradley Christopher J Lelliott Sanger Institute Mouse Genetics Project Lauryl M J Nutter Colin McKerlie Ann M Flenniken Marie-France Champy Tania Sorg Yann Herault Martin Hrabe De Angelis Valerie Gailus Durner Ann-Marie Mallon Steve D M Brown Terry Meehan Helen E Parkinson Damian Smedley K C Kent Lloyd Jun Yan Xiang Gao Je Kyung Seong Chi-Kuang Leo Wang Radislav Sedlacek Yi Liu Jan Rozman Ling Yang Ying Xu High-throughput discovery of genetic determinants of circadian misalignment. PLoS Genetics |
| title | High-throughput discovery of genetic determinants of circadian misalignment. |
| title_full | High-throughput discovery of genetic determinants of circadian misalignment. |
| title_fullStr | High-throughput discovery of genetic determinants of circadian misalignment. |
| title_full_unstemmed | High-throughput discovery of genetic determinants of circadian misalignment. |
| title_short | High-throughput discovery of genetic determinants of circadian misalignment. |
| title_sort | high throughput discovery of genetic determinants of circadian misalignment |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008577&type=printable |
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