In Silico Pleiotropy Analysis in KEGG Signaling Networks Using a Boolean Network Model

Pleiotropy, which refers to the ability of different mutations on the same gene to cause different pathological effects in human genetic diseases, is important in understanding system-level biological diseases. Although some biological experiments have been proposed, still little is known about pleiotropy on gene–gene dynamics, since most previous studies have been based on correlation analysis. Therefore, a new perspective is needed to investigate pleiotropy in terms of gene–gene dynamical characteristics. To quantify pleiotropy in terms of network dynamics, we propose a measure called in silico Pleiotropic Scores (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>s</mi><mi>P</mi><mi>S</mi></mrow></semantics></math></inline-formula>), which represents how much a gene is affected against a pair of different types of mutations on a Boolean network model. We found that our model can identify more candidate pleiotropic genes that are not known to be pleiotropic than the experimental database. In addition, we found that many types of functionally important genes tend to have higher <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>s</mi><mi>P</mi><mi>S</mi></mrow></semantics></math></inline-formula> values than other genes; in other words, they are more pleiotropic. We investigated the relations of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>s</mi><mi>P</mi><mi>S</mi></mrow></semantics></math></inline-formula> with the structural properties in the signaling network and found that there are highly positive relations to degree, feedback loops, and centrality measures. This implies that the structural characteristics are principles to identify new pleiotropic genes. Finally, we found some biological evidence showing that <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>s</mi><mi>P</mi><mi>S</mi></mrow></semantics></math></inline-formula> analysis is relevant to the real pleiotropic data and can be considered a novel candidate for pleiotropic gene research. Taken together, our results can be used to understand the dynamics pleiotropic characteristics in complex biological systems in terms of gene–phenotype relations.