Trends in Genetics
Genome AnalysisPredicting gene function by conserved co-expression
Section snippets
Co-expression provides a weak signal for pathway prediction
Two large-scale expression datasets were obtained, one from S. cerevisiae [2] and one from C. elegans [3]. Uncentered correlation [1] was calculated between the expression profiles of all S. cerevisiae genes and between the expression profiles of all C. elegans genes. The higher the correlation (R) between two genes, the more probable it is that they act in the same pathway (Fig. 1). However, at a significant correlation threshold of 0.6 (P<0.005, Table 1), the fraction of annotated proteins
Significant levels of evolutionary conservation of co-expression
To evaluate whether evolutionary conservation (Fig. 2) can improve upon these limits in the use of co-expression for function prediction, we first established whether there is significant conservation, potentially reflecting selection pressure on maintaining functional interactions. To determine conservation between S. cerevisiae and C. elegans, we first need to define which genes are orthologs of each other, which we do based on phylogenetic trees allowing for multi to multi orthology
Conserved co-expression improves accuracy of pathway prediction
Does the conservation of co-expression after gene duplication or speciation increase the likelihood of a functional relationship between co-expressed genes? Conservation after duplication in S. cerevisiae does indeed increase the accuracy levels for prediction of functional interactions, albeit at the expense of coverage of known interactions (Fig. 1). The results for C. elegans are similar, but there are not enough genes annotated in the PATHWAY database to establish the accuracy for conserved
New predictions from old data
Co-expression conserved between S. cerevisiae and C. elegans of the hypothetical gene CAT5 (YOR125C, ZC395.2) and COQ2 (YNR041C, F57B9.4) confirms earlier predictions based on knock-out experiments [11] and homology relations [12] that CAT5 is 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinone mono-oxygenase, which is involved in ubiquinone synthesis, as COQ2 encodes para-hydroxybenzoate: polyprenyl transferase, which is also involved in ubiquinone synthesis.
A prediction based on conservation of
Modularity in pathway evolution
Of particular evolutionary importance is our finding of a substantial number of cases where, although the expression pattern of A′ and B′ has changed relative to their ancestors A and B, the co-expression of A′ and B′ is conserved. This seemingly contradicts the finding by Wagner that after duplication events, mRNA expression patterns diverge very quickly relative to amino acid sequence [21]. Yet, both results complement each other as we show that the co-expression is often conserved even when
Outlook
Correlations between expression profiles do not necessarily imply co-regulation, and co-regulation does not always indicate functional interaction. Thus, it is important for function prediction to increase the reliability of co-expression data. Overlapping transcriptional clusters from different clustering methods have led to the prediction of functional categories for many genes [5]. Here we show that both intraspecies and interspecies conservation make expression data useful for the reliable
Acknowledgements
This work was supported in part by a grant from the Netherlands Organization for Scientific Research (NWO).
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