Boolean modelling sheds light on regulatory circuits

16 Dec 2010

Pairs of almost similar genes have long been thought to act as back up for each other. But in their paper published in Cell on December 10, shared first authors Patrick Kemmeren and Sake van Wageningen and their colleagues from the group of Frank Holstege (NBIC /UMC Utrecht) show that such gene pairs actually form regulatory circuits that influence different combinations of cellular processes. This way, an organism can efficiently couple or decouple processes, for example when dealing with altered environmental conditions. The ability to use genetic information in such an efficient way may also explain the high level of conservation of some of these gene pairs during evolution.

The group analysed 150 deletion mutants of kinases and phosphatases in baker's yeast (Saccharomyces cerevisiae) using DNA microarrays to study relationships between phosphorylation-based signalling pathways. They particularly focused on genetic buffering relationships such as redundancy. To this end, they selected double mutants that exhibited a markedly different effect on growth compared to the effect of each single mutant. This resulted in the identification of three types of genetic buffering mechanisms: mixed epistasis, complete redundancy and quantitative redundancy.

Modelling the module
In mixed epistasis there is only partial overlap in function between the two genes and their coupling usually involved additional regulatory mechanisms such as repression of one by the other. This allows the gene pair to operate as a regulatory module that can control different processes under different circumstances. To unravel the mode of action of such a module, the researchers zoomed in on the FUS3-KSS1 kinase pair. "Our starting point was to define the regulatory module as a model consisting of four nodes: two regulators and two responses. We defined a number of boundary conditions, for example that each node was controlled by a maximum of two inputs and that there should always be at least one route to the responses, R1 and R2", Patrick Kemmeren explains. "This resulted in 794,176 possible models. Using Boolean modelling, Philip Lijnzaad reduced these to 106 models that would actually lead to the minimal mixed epistatic effect. Further pruning left us with 28 root models that all exhibit the experimentally observed mixed epistasis." Although the modelling concentrated on one particular gene pair, the approach revealed important information on how gene pairs with only partial overlap in function can operate as an effective regulatory module that has the ability to act as a multi-process control unit. In turn, this would explain their evolutionary conservation.

Sake van Wageningen, Patrick Kemmeren, et al., Functional Overlap and Regulatory Links Shape Genetic Interactions between Signaling Pathways, Cell, 143, 991-1004, December 10, 2010 http://www.cell.com/abstract/S0092-8674(10)01301-2

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