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WIREs Syst Biol Med
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Comparative systems biology: from bacteria to man

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Abstract Comparative analyses, as carried out by comparative genomics and bioinformatics, have proven extremely powerful to obtain insight into the identity of specific genes that underlie differences and similarities across species. The central concept developed in this chapter is that important aspects of the functional differences between organisms derive not only from the differences in genetic components (which underlies comparative genomics) but also from dynamic, molecular (physical) interactions. Approaches that aim at identifying such network‐based rather than component‐based homologies between species we shall call Comparative Systems Biology. It will be illustrated by a number of examples from metabolic networks from prokaryotes, via yeast, to man. The potential for species comparisons, at the genome‐scale using classical approaches and at the more detailed level of dynamic molecular networks will be illustrated. In our opinion, comparative systems biology, as a marriage between bioinformatics and systems biology, will offer new insights into the nature of organisms for the benefit of medicine, biotechnology, and drug design. As dynamic modeling is becoming more mainstream in cell biology, the potential of comparative systems biology will become more evident. Copyright © 2010 John Wiley & Sons, Inc. This article is categorized under: Analytical and Computational Methods > Computational Methods

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Schematic representation of the metabolic reconstruction process. The sequenced genome, experimental data on medium requirements, product formation, and substrate utilization as well as biochemical pathway knowledge are used to reconstruct the metabolic map of the organism.

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Drug selectivity illustrated by the effect of inhibition of an enzyme on the phenotype in both the host and the parasite to be inhibited. Phenotype could be the flux of ATP production.

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Comparison of different feedback mechanisms on the upper part of glycolysis in different species and human cell types. See text for details.

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(a) Simplified stoichiometry of glycolysis in Saccharomyces cerevisiae, which is identical or similar to most other organisms. Two steps invest ATP (HK and PFK), whereas at lower glycolysis 4 ATP are gained. (b) In trypanosomes, part of glycolysis is compartmentalized in the so‐called glycosome. Within the glycosome, no net ATP is produced, and hence, there is no ‘turbo’ design.

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Possible functional relationships between genes associates to reactions at distance one in a metabolic network, and the subsequent expectation of gene organization and/or regulation. Genes B and C are fully coupled, and they will be often found to be co‐localized in operons, or be co‐regulated (illustrated by sharing a transcription factor upstream the coding region). Genes A and B are directionally coupled, with the presence of A coupled to that of B. Consequently, the chance is low to find gene A without the presence of gene B in any genome. Genes C and D are not coupled at all, and therefore no specific predictions can be made.

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Gene–protein‐reaction associations on top a the genome‐scale metabolic network. The relationships can be many‐to‐many, here illustrated by the example of pyruvate‐formate lyase in the genome of L. plantarum WCFS1. Two proteins are both required (in an AND relationship) for an active PFL protein. Moreover, there are two copies of the complex on the genome (which constitutes an OR relationship). Note that the two complexes have been defined on the basis of the genome localization.

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