Gunnar Boldhaus

The complex interactions involved in regulation of a cell's function are captured by its interaction graph. More often than not, detailed knowledge about enhancing or suppressive regulatory influences and cooperative effects is lacking and merely the presence or absence of directed interactions is known. Here we investigate to which extent such reduced information allows to forecast the effect of a knock-out or a combination of knock-outs. Specifically we ask in how far the lethality of eliminating nodes may be predicted by their network centrality, such as degree and betweenness, without knowing the function of the system. The function is taken as the ability to reproduce a fixed point under a discrete Boolean dynamics. We investigate two types of stochastically generated networks: fully random networks and structures grown with a mechanism of node duplication and subsequent divergence of interactions. On all networks we find that the out-degree is a good predictor of the lethality of a single node knock-out. For knock-outs of node pairs, the fraction of successors shared between the two knocked-out nodes (out-overlap) is a good predictor of synthetic lethality. Out-degree and out-overlap are locally defined and computationally simple centrality measures that provide a predictive power close to the optimal predictor.

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The response to a knockout of a node is a characteristic feature of a networked dynamical system. Knockout resilience in the dynamics of the remaining nodes is a sign of robustness. Here we study the effect of knockouts for binary state sequences and their implementations in terms of Boolean threshold networks. Besides random sequences with biologically plausible constraints, we analyze the cell cycle sequence of the species Saccharomyces cerevisiae and the Boolean networks implementing it. Comparing with an appropriate null model we do not find evidence that the yeast wildtype network is optimized for high knockout resilience. Our notion of knockout resilience weakly correlates with the size of the basin of attraction, which has also been considered a measure of robustness.

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The functioning of a living cell is largely determined by the structure of its regulatory network, comprising non-linear interactions between regulatory genes. An important factor for the stability and evolvability of such regulatory systems is neutrality – typically a large number of alternative network structures give rise to the necessary dynamics. Here we study the discretized regulatory dynamics of the yeast cell cycle [Li et al., PNAS, 2004] and the set of networks capable of reproducing it, which we call functional. Among these, the empirical yeast wildtype network is close to optimal with respect to sparse wiring. Under point mutations, which establish or delete single interactions, the neutral space of functional networks is fragmented into ≈ 4.7 × 10⁸ components. One of the smaller ones contains the wildtype network. On average, functional networks reachable from the wildtype by mutations are sparser, have higher noise resilience and fewer fixed point attractors as compared with networks outside of this wildtype component.

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Beziehungstipps aus der Mikrobiologie
FameLab Germany 2013

"Knockouts, Robustness and Cell Cycles"
ECCS10 Track E: From Molecules to Living Systems

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May 3, 2011
Leipzig (Germany)

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June 24, 2010
Université Paris-Sud - Orsay (France)

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June 23, 2010
Évry (France)

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December 12, 2009
Zurich (Switzerland)

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September 17, 2009
Singapore (Singapore)

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September 17, 2009
Singapore (Singapore)

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November 1, 2008
Palma de Mallorca (Spain)

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November 25, 2010
Leizig (Germany)

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September 17, 2010
Lisbon (Portugal)

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June 4, 2010
Rüdesheim am Rhein (Germany)

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September 29, 2009
Berlin (Germany)

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September 25, 2009
Warwick (UK)

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March 26, 2009
Dresden (Germany)

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February 17, 2009
Bled (Slovenia)

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July 28, 2008
Leipzig (Germany)

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November 23 - November 27, 2009
Palma de Mallorca (Spain)

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October 10 - October 12, 2008
Barcelona (Spain)

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September 13 - September 17, 2010
Lisbon (Portugal)

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September 21 - September 25, 2009
Warwick (UK)

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March 22 - March 27, 2009
Dresden (Germany)

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November 25 - November 26, 2010
Leipzig (Germany)

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November 25 - November 27, 2010
Leipzig (Germany)

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June 24, 2010
Leipzig (Germany)

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April 27, 2010
Dresden (Germany)

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November 23 - November 27, 2009
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September 28 - September 30, 2009
Berlin (Germany)

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July 30 - August 1, 2008
Leipzig (Germany)

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June 3 - June 5, 2010
Rüdesheim am Rhein (Germany)

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Leipzig (Germany)

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Jacobs University Bremen - Bremen (Germany)

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