Reconstructing gene-regulatory networks from time series, knock-out data, and prior knowledge.
BACKGROUND
Cellular processes are controlled by gene-regulatory networks. Several computational methods are currently used to learn the structure of gene-regulatory networks from data. This study focusses on time series gene expression and gene knock-out data in order to identify the underlying network structure. We compare the performance of different network reconstruction methods using synthetic data generated from an ensemble of reference networks. Data requirements as well as optimal experiments for the reconstruction of gene-regulatory networks are investigated. Additionally, the impact of prior knowledge on network reconstruction as well as the effect of unobserved cellular processes is studied.


RESULTS
We identify linear Gaussian dynamic Bayesian networks and variable selection based on F-statistics as suitable methods for the reconstruction of gene-regulatory networks from time series data. Commonly used discrete dynamic Bayesian networks perform inferior and this result can be attributed to the inevitable information loss by discretization of expression data. It is shown that short time series generated under transcription factor knock-out are optimal experiments in order to reveal the structure of gene regulatory networks. Relative to the level of observational noise, we give estimates for the required amount of gene expression data in order to accurately reconstruct gene-regulatory networks. The benefit of using of prior knowledge within a Bayesian learning framework is found to be limited to conditions of small gene expression data size. Unobserved processes, like protein-protein interactions, induce dependencies between gene expression levels similar to direct transcriptional regulation. We show that these dependencies cannot be distinguished from transcription factor mediated gene regulation on the basis of gene expression data alone.


CONCLUSIONS
Currently available data size and data quality make the reconstruction of gene networks from gene expression data a challenge. In this study, we identify an optimal type of experiment, requirements on the gene expression data quality and size as well as appropriate reconstruction methods in order to reverse engineer gene regulatory networks from time series data.
Geier
Florian
F
Institute of Physics, University of Freiburg, Hermann-Herder Str, 3, 79104 Freiburg, Germany. florian.geier@fdm.uni-freiburg.de
Timmer
Jens
J
Fleck
Christian
C
D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D008954:Models, Biological; D016011:Normal Distribution; D013997:Time Factors