Identifying Early Warning Signals for the Sudden Transition from Mild to Severe Tobacco Etch Disease by Dynamical Network Biomarkers.

Complex systems exhibit critical thresholds at which they transition among alternative phases. Complex systems theory has been applied to analyze disease progression, distinguishing three stages along progression: (i) a normal noninfected state; (ii) a predisease state, in which the host is infected and responds and therapeutic interventions could still be effective; and (iii) an irreversible state, where the system is seriously threatened. The dynamical network biomarker (DNB) theory sought for early warnings of the transition from health to disease. Such DNBs might range from individual genes to complex structures in transcriptional regulatory or protein-protein interaction networks. Here, we revisit transcriptomic data obtained during infection of tobacco plants with tobacco etch potyvirus to identify DNBs signaling the transition from mild/reversible to severe/irreversible disease. We identified genes showing a sudden transition in expression along disease categories. Some of these genes cluster in modules that show the properties of DNBs. These modules contain both genes known to be involved in response to pathogens (e.g.,