De-novo learning of genome-scale regulatory networks in S. cerevisiae

De-novo reverse-engineering of genome-scale regulatory networks is a fundamental problem of biological and translational research. One of the major obstacles in developing and evaluating approaches for de-novo gene network reconstruction is the absence of high-quality genome-scale gold-standard networks of direct regulatory interactions. To establish a foundation for assessing the accuracy of de-novo gene network reverse-engineering, we constructed high-quality genomescale gold-standard networks of direct regulatory interactions in Saccharomyces cerevisiae that incorporate binding and gene knockout data. Then we used 7 performance metrics to assess accuracy of 18 statistical association-based approaches for de-novo network reverse-engineering in 13 different datasets spanning over 4 data types. We found that most reconstructed networks had statistically significant accuracies. We also determined which statistical approaches and datasets/data types lead to networks with better reconstruction accuracies. While we found that de-novo reverseengineering of the entire network is a challenging problem, it is possible to reconstruct sub-networks around some transcription factors with good accuracy. The latter transcription factors can be identified by assessing their connectivity in the inferred networks. Overall, this study provides the gene network reverse-engineering community with a rigorous assessment of the accuracy of S. cerevisiae gene network reconstruction and variability in performance of various approaches for learning both the entire network and sub-networks around transcription factors.