Center for Integrative Genomics, University of Lausanne, Switzerland.
Vital-IT Systems Biology Division, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
PLoS Biol. 2018 Aug 9;16(8):e2005750. doi: 10.1371/journal.pbio.2005750. eCollection 2018 Aug.
Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep "sleep-wake" phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%-78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.
睡眠对于大脑的最佳功能和健康至关重要，但睡眠发挥这些有益作用的生物学基础在很大程度上仍是未知的。我们在 BXD 遗传参考群体（GRP）小鼠中使用系统遗传学方法，并组装了一个全面的实验知识库，包括深度的“睡眠-觉醒”表型、中枢和外周转录组以及在未受干扰的基线条件下和睡眠剥夺（SD）后收集的血浆代谢组数据。我们提供了分析工具来交互查询数据库、可视化由睡眠不足改变的分子网络，并确定候选基因的优先级。我们发现，一次性短暂的睡眠中断已经通过改变 60%-78%的转录组和代谢组，广泛重塑了系统遗传学景观，许多遗传位点影响变化的幅度和方向。利用所有组织层次进行的系统遗传学综合分析表明，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体转运和脂肪酸周转是睡眠不足的负面影响的底物。我们的分析表明，遗传异质性以及睡眠不足本身对转录组和代谢组的影响比以前报道的要广泛得多。
