National Institute of Advanced Industrial Science and Technology, Computational Biology Research Center, Koto, Tokyo, Japan.
IET Syst Biol. 2009 Nov;3(6):487-95. doi: 10.1049/iet-syb.2008.0179.
Many genes related to the circadian rhythm, especially those involved in phase shifts induced by different environmental stimuli, still remain enigmatic. In this study, the authors monitored the expression of rat genes measured with multiple phase-resetting stimuli, and developed a technique to extract the candidate genes for the changes in circadian rhythm by the stimuli, from microarray data. First, the spectra for the time series of gene expression were estimated by fast Fourier transform, and then two fitting methods, the random period fitting method and the conditional curve fitting method, using the estimated periods as the initial values, were applied to the control and the stimulated expression data to estimate the periods and the phases. Finally, by comparing the two sets of periods and phases, the period change and the phase shift by stimuli were estimated to extract the candidate genes related to the master clock, by mapping the period change and the phase shift on a two-dimensional space, a period-phase map (PPM). As an indirect validation of the genes selected by our method, the significant enrichment of extracted gene clusters on the PPM was further evaluated, in terms of biological function. As a result, the gene clusters related to photoreceptors and neural regulation emerged on the PPM, thus implying the relationships in the stimulus response of the master clock that resides in the brain at the intersection of the optic nerves. Thus, the present approach is a feasible means to explore the oscillatory genes related to stimulus responses.
许多与生物钟相关的基因，尤其是那些涉及不同环境刺激引起的相位变化的基因，仍然是个谜。在这项研究中，作者监测了大鼠基因在多种相位重置刺激下的表达，并开发了一种从微阵列数据中提取受刺激影响的生物钟节律变化候选基因的技术。首先，通过快速傅里叶变换估计基因表达时间序列的频谱，然后使用估计的周期作为初始值，应用随机周期拟合方法和条件曲线拟合方法对对照和刺激表达数据进行拟合，以估计周期和相位。最后，通过比较两组周期和相位，通过将周期变化和刺激引起的相位变化映射到二维空间上，即周期-相位图（PPM），来提取与主钟相关的候选基因。作为我们方法选择的基因的间接验证，进一步评估了 PPM 上提取的基因簇在生物学功能方面的显著富集。结果表明，与光感受器和神经调节相关的基因簇出现在 PPM 上，这暗示了位于视神经交叉处的大脑中的主钟在刺激反应中的关系。因此，本研究提出了一种探索与刺激反应相关的振荡基因的可行方法。
