Improving the accuracy of gene regulatory network inference from noisy data

Gene regulatory networks (GRNs) control physiological and pathological processes in a living organism, and their accurate inference from measured gene expression can identify therapeutic mechanisms for complex diseases such as cancers. The biggest obstacle in achieving the accurate reconstruction of GRNs is called ‘noise’, which considerably alters the measured gene expression because the noise generally dominates the biological signal. This situation needs to be addressed carefully so that GRN inference methods do not estimate a fit to the noise instead of the underlying biological signal. Potential noise compensation approaches are a must if the goal is to reconstruct the true system. To this end, within the scope of this doctoral thesis, I developed two methods that, in different ways, overcome the obstacles introduced by noise in gene expression data. Method 1 allows the collection of more informative subsets of genes whose expression is not as highly affected as those which cause the system to be overall uninformative. Method 2 infers a perturbation design that is better suited to the gene expression data than the originally intended design, and therefore produces more accurate GRNs at high noise levels. Furthermore, a benchmark study was carried out which compares the methodological backgrounds of GRN inference methods in terms of whether they utilize knowledge of the perturbation design or not, which clearly shows that utilization of the perturbation design is essential for accurate inference of GRNs. Finally a method is presented to improve GRN inference accuracy by selecting the GRN with the optimal sparsity based on information theoretical criteria. The three new methods (PAPERS I, II and IV) can also be used together, which is shown in this thesis to improve the GRN inference accuracy considerably more than the methods separately. As inference of accurate GRNs is a major challenge in gene regulation, the methods presented in this thesis represent an important contribution to move the field forward