Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets

A. Vinayagama, T.E. Gibsonb, H.-J. Lee, B. Yilmazeld, C. Roeseld, Y. Kwona, A. Sharma, Y.-Y. Liu, N. Perrimona, A.-L. Barabasi.
PNAS
10.1073, 1-6 (2016).
April 18, 2016

Abstract

The  protein–protein interaction (PPI) network is crucial for cellular  information processing and decision-making. With suitable inputs, PPI  networks drive the cells to diverse functional outcomes such as cell  proliferation or cell death. Here, we characterize the structural  controllability of a large directed human PPI network comprising 6,339  proteins and 34,813 interactions. This network allows us to classify proteins  as “indispensable,” “neutral,” or “dispensable,” which correlates  to increasing, no effect, or decreasing the number of driver nodes in the  network upon removal of that protein. We find that 21% of the proteins in the  PPI network are indispensable. Interestingly, these indispensable proteins  are the primary targets of disease-causing mutations, human viruses, and  drugs, suggesting that altering a network’s control property is critical  for the transition between healthy and disease states. Furthermore, analyzing  copy number alterations data from 1,547 cancer patients reveals that 56 genes  that are frequently amplified or deleted in nine different cancers are  indispensable. Among the 56 genes, 46 of them have not been previously  associated with cancer. This suggests that controllability analysis is very  useful in identifying novel disease genes and potential drug targets.