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High-throughput discovery of genetic determinants of circadian misalignment

机译：昼夜对准遗传决定因素的高通量发现

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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 Slc7a11 ~( tm1a/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.
机译：昼夜节日系统通过允许它们适应环境线索的日常变化，例如光/黑暗循环，为生物提供健康优势。昼夜钟表的分子机制已经很好地表征。然而，内部昼夜节奏时钟如何夹带常规日常光/暗循环仍不清楚。通过从国际小鼠表型联盟（IMPC）中获得的2000多种野生型小鼠的间接量热法（IC）数据收集和分析，我们表明活动和食品摄入节奏的起始时间和峰值是筛查缺陷的可靠参数昼夜失值。我们开发了一种机器学习算法，可以使用现有数据集来量化这些两个参数（Syncscreener），并用它来筛选来自五个IMPC表型中心的750个突变鼠标线。发现五个基因的突变体（SLC7a11，rhBd11，旋转液，CTC1和oxtr）与活性或食物摄入的改变模式相关。通过进一步研究SLC7A11〜（TM1A / TM1A）小鼠，我们证实了其先进的活性相表型响应于模拟的曲线和骨架光周期刺激。 SLC7A11的破坏影响了在核心核中的细胞间通信，表明时钟神经元同步的缺陷。我们的研究已经建立了一种系统的表型分析方法，可用于揭示小鼠核夹带机制。

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