Existence of Causation without Correlation in Transcriptional Networks

It is commonly assumed that lack of correlation is evidence for lack of causal relationship. Here, however we show that in transcriptional networks, causal linkages can exist in the absence of correlation. We find that a substantial proportion of transcribed genes in yeast and in mouse, show evidence of state-dependent (nonlinear) and temporally coordinated dynamics in their expression patterns (65-77%). Using a test that accommodates this fact, we uncover strong causal relationships that are invisible to correlation-based analyses for both yeast and mouse models. Specifically, for yeast we detect uncorrelated causal relationships for the transcriptional regulators <i>WHI5</i> and <i>YHP1,</i> and can verify these relationships experimentally. These genes reside at important checkpoints in the cell cycle where multiple signals are integrated at single nodes, giving rise to causal relationships, that despite being uncorrelated, can be accurately detected (71-78%) using a nonlinear causality test.