Phase analysis of circadian-related genes in two tissues.

BackgroundRecent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4–8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues.ResultsWe propose a set of techniques from circular statistics to analyze phase angles of circadian-related genes in two tissues. We first estimate the phases of a cycling gene separately in each tissue, which are then used to estimate the paired angular difference of the phase angles of the gene in the two tissues. These differences are modeled as a mixture of two von Mises distributions which enables us to cluster genes into two groups; one group having synchronized transcripts with the same phase in the two tissues, the other containing transcripts with a discrepancy in phase between the two tissues. For each cluster of genes we assess the association of phases across the tissue types using circular-circular regression. We also develop a bootstrap methodology based on a circular-circular regression model to evaluate the improvement in fit provided by allowing two components versus a one-component von-Mises model.ConclusionWe applied our proposed methodologies to the circadian-related genes common to heart and liver tissues in Storch et al. [2], and found that an estimated 80% of circadian-related transcripts common to heart and liver tissues were synchronized in phase, and the other 20% of transcripts were lagged about 8 hours in liver relative to heart. The bootstrap p-value for being one cluster is 0.063, which suggests the possibility of two clusters. Our methodologies can be extended to analyze peak expression times of circadian-related genes across more than two tissues, for example, kidney, heart, liver, and the suprachiasmatic nuclei (SCN) of the hypothalamus.

[1]  K. Mardia,et al.  Protein Bioinformatics and Mixtures of Bivariate von Mises Distributions for Angular Data , 2007, Biometrics.

[2]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[3]  N. Fisher,et al.  Statistical Analysis of Circular Data , 1993 .

[4]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.

[5]  Michael Ruogu Zhang,et al.  Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. , 1998, Molecular biology of the cell.

[6]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[7]  Steven M Reppert,et al.  Three period Homologs in Mammals: Differential Light Responses in the Suprachiasmatic Circadian Clock and Oscillating Transcripts Outside of Brain , 1998, Neuron.

[8]  B. D. Spurr,et al.  A comparison of various methods for estimating the parameters in mixtures of von Mises distributions , 1991 .

[9]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.

[10]  C. Ball,et al.  Identification of genes periodically expressed in the human cell cycle and their expression in tumors. , 2002, Molecular biology of the cell.

[11]  Shyamal D. Peddada,et al.  A geometric approach to determine association and coherence of the activation times of cell-cycling genes under differing experimental conditions , 2004, Bioinform..

[12]  Shyamal D Peddada,et al.  A random-periods model for expression of cell-cycle genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. R. McClung,et al.  Enhanced Fitness Conferred by Naturally Occurring Variation in the Circadian Clock , 2003, Science.

[14]  Peng Huang,et al.  The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA Damage Response In Vivo , 2002, Cell.