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How cyanobacteria pose new problems to old methods: challenges in microarray time series analysis.

ABSTRACT: BACKGROUND: The transcriptomes of several cyanobacterial strains have been shown to exhibit diurnal oscillation patterns, reflecting the diurnal phototrophic lifestyle of the organisms. The analysis of such genome-wide transcriptional oscillations is often facilitated by the use of clustering algorithms in conjunction with a number of pre-processing steps. Biological interpretation is usually focussed on the time and phase of expression of the resulting groups of genes. However, the use of microarray technology in such studies requires the normalization of pre-processing data, with unclear impact on the qualitative and quantitative features of the derived information on the number of oscillating transcripts and their respective phases. RESULTS: A microarray based evaluation of diurnal expression in the cyanobacterium Synechocystis sp. PCC 6803 is presented. As expected, the temporal expression patterns reveal strong oscillations in transcript abundance. We compare the Fourier transformation-based expression phase before and after the application of quantile normalization, median polishing, cyclical LOESS, and least oscillating set (LOS) normalization. Whereas LOS normalization mostly preserves the phases of the raw data, the remaining methods introduce systematic biases. In particular, quantile-normalization is found to introduce a phase-shift of 180°, effectively changing night-expressed genes into day-expressed ones. Comparison of a large number of clustering results of differently normalized data shows that the normalization method determines the result. Subsequent steps, such as the choice of data transformation, similarity measure, and clustering algorithm, only play minor roles. We find that the standardization and the DTF transformation are favorable for the clustering of time series in contrast to the 12 m transformation. We use the cluster-wise functional enrichment of a clustering derived by LOS normalization, clustering using flowClust, and DFT transformation to derive the diurnal biological program of Synechocystis sp.. CONCLUSION: Application of quantile normalization, median polishing, and also cyclic LOESS normalization of the presented cyanobacterial dataset lead to increased numbers of oscillating genes and the systematic shift of the expression phase. The LOS normalization minimizes the observed detrimental effects. As previous analyses employed a variety of different normalization methods, a direct comparison of results must be treated with caution.

SUBMITTER: Lehmann R

PROVIDER: S-EPMC3679775 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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How cyanobacteria pose new problems to old methods: challenges in microarray time series analysis.

Lehmann Robert R Machné Rainer R Georg Jens J Benary Manuela M Axmann Ilka I Steuer Ralf R

BMC bioinformatics 20130421

<h4>Background</h4>The transcriptomes of several cyanobacterial strains have been shown to exhibit diurnal oscillation patterns, reflecting the diurnal phototrophic lifestyle of the organisms. The analysis of such genome-wide transcriptional oscillations is often facilitated by the use of clustering algorithms in conjunction with a number of pre-processing steps. Biological interpretation is usually focussed on the time and phase of expression of the resulting groups of genes. However, the use o ...[more]

PMID: 23601192

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Project description:While genome-wide gene expression data are generated at an increasing rate, the repertoire of approaches for pattern discovery in these data is still limited. Identifying subtle patterns of interest in large amounts of data (tens of thousands of profiles) associated with a certain level of noise remains a challenge. A microarray time series was recently generated to study the transcriptional program of the mouse segmentation clock, a biological oscillator associated with the periodic formation of the segments of the body axis. A method related to Fourier analysis, the Lomb-Scargle periodogram, was used to detect periodic profiles in the dataset, leading to the identification of a novel set of cyclic genes associated with the segmentation clock. Here, we applied to the same microarray time series dataset four distinct mathematical methods to identify significant patterns in gene expression profiles. These methods are called: Phase consistency, Address reduction, Cyclohedron test and Stable persistence, and are based on different conceptual frameworks that are either hypothesis- or data-driven. Some of the methods, unlike Fourier transforms, are not dependent on the assumption of periodicity of the pattern of interest. Remarkably, these methods identified blindly the expression profiles of known cyclic genes as the most significant patterns in the dataset. Many candidate genes predicted by more than one approach appeared to be true positive cyclic genes and will be of particular interest for future research. In addition, these methods predicted novel candidate cyclic genes that were consistent with previous biological knowledge and experimental validation in mouse embryos. Our results demonstrate the utility of these novel pattern detection strategies, notably for detection of periodic profiles, and suggest that combining several distinct mathematical approaches to analyze microarray datasets is a valuable strategy for identifying genes that exhibit novel, interesting transcriptional patterns.

Dataset Information

How cyanobacteria pose new problems to old methods: challenges in microarray time series analysis.

Publications

How cyanobacteria pose new problems to old methods: challenges in microarray time series analysis.

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