Abstract

To understand regulatory systems, it is useful to systematically determine how individual genes contribute to the expression of all other genes. We have therefore monitored genome-wide mRNA expression for individual deletions of one-quarter of yeast genes. By including gene expression profiles of double deletions, we could also investigate genetic interactions, a phenomenon where combinations of mutations lead to unexpected effects. Understanding mechanisms of genetic interactions is important for deciphering pathway architecture as well as understanding the relationship between genetic variation and disease. To decipher potential mechanisms we have employed modelling approaches using Boolean networks and Petri Net modelling where genes are represented as nodes and relationships between genes as edges. This allowed over 9 million possible models to be enumerated and exposed that a quantitative edge difference is a strict requirement to explain inversion, a previously uncharacterized genetic interaction pattern. Genetic interactions between mutated genes likely play an important role in cancer onset and progression. Little is however known about the genetic interactions within pediatric cancer. To create an initial map of potential genetic interactions within cancer and further study their underlying mechanisms, we have analysed close to 2,600 childhood tumours for mutually exclusive or co-occurring interactions between the different cancer types. This map also provides a solid starting point to select candidates for experimental validation as well as extending the analyses to investigate the contribution of genetic interactions towards structural variants, genetic predisposition and cellular pathways.