High-throughput discovery of genetic determinants of circadian misalignment
High-throughput discovery of genetic determinants of circadian misalignment
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高通量发现昼夜节律失调的遗传决定因素
DOI：
10.1371/journal.pgen.1008577
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发表时间：
2020-01
期刊：
影响因子：
4.5
通讯作者：
e Ky
中科院分区：
文献类型：
--
作者：
Tao Zhang;Pancheng Xie;Yingying Dong;Zhiwei Liu;Fei Zhou;Dejing Pan;Zhengyun Huang;Qiaocheng Zhai;Yue Gu;Qingyu Wu;Nobuhiko Tanaka;uichi Obata;Allan Bradley;Christopher J;Marie-France Champy;teve D. M. Brown;Terry Meehan;Helen E. Parkinson;Kent Lloyd;e Ky
昼夜节律系统通过允许生物体适应环境线索的日常变化（如光/暗周期），为生物体提供了适应性优势。生物钟背后的分子机制已经被很好地描述了。然而，内部生物钟是如何与规律的每日光/暗周期相结合的，目前尚不清楚。通过收集和分析来自国际小鼠表型联盟（IMPC）的2000多只野生型小鼠的间接量热（IC）数据，我们表明活动的开始时间和峰值阶段以及食物摄入节律是筛选昼夜节律失调缺陷的可靠参数。我们开发了一种机器学习算法，用现有的数据集来量化我们的错位筛选（SyncScreener）中的这两个参数，并使用它来筛选来自五个IMPC表型中心的750个突变小鼠系。五个基因（Slc7a11, Rhbdl1, Spop， Ctc1和Oxtr）的突变被发现与活动模式或食物摄入的改变有关。通过对Slc7a11tm1a/tm1a小鼠的进一步研究，我们证实了Slc7a11tm1a/tm1a小鼠在模拟时差和骨骼光周期刺激下的高级活动期表型。Slc7a11的破坏影响了视交叉上核的细胞间通讯，提示时钟神经元的同步缺陷。我们的研究建立了一种系统的表型分析方法，可用于揭示小鼠昼夜节律夹带的机制。
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.
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影响因子：
3.4
作者：
Karatsoreos, IN;Romeo, RD;Silver, R
通讯作者：
Silver, R
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Bradley A
影响因子：
16.2
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通讯作者：
Herzog ED
影响因子：
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作者：
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通讯作者：
Hastings, Michael H.