Using Functional Linkage Gene Networks to Study Human Diseases

Introduction And Background

With the development of sequencing technologies, whole genome sequencing has been achieved for diverse species (Flicek et al., 2008). For a fully sequenced organism, most protein-encoding genes can be readily identified by available bioinformatics approaches (Flicek et al., 2008). By contrast, it remains a challenging task to understand the specific biological functions of these genes, and how dysfunctions of these genes lead to diverse human disease phenotypes.

A particular cellular function usually requires the collaboration between a specific group of genes or proteins. Rather than acting alone, these genes interact and communicate with each other in diverse ways, but all for the common purpose of maintaining the normal status of a specific biological process (Kanehisa et al., 2004). On the other hand, when one or more genes involved in a particular biological process are dysfunctional, the normal status of the biological process might be perturbed, which might further cause the organism to show abnormal physiological phenotypes referred to as a disease (Goh et al., 2007). Correspondingly, therapeutic drugs aim to target the genes or proteins involved in these perturbed biological processes such that the normal status of the biological processes can be reestablished (Janga & Tzakos, 2009). Therefore, for gene function and human disease research, it is very important to consider individual genes as functional related components within a coherent biological system.

Recent network-based approaches have demonstrated great success in representing functional relationships among genes with applications to understand gene function and human disease (Ahmed & Xing, 2009; Franke et al., 2006; Huttenhower et al., 2009; Kohler et al., 2008; Lage et al., 2007; I. Lee et al., 2008b; Linghu et al., 2008; Linghu et al., 2009; McGary et al., 2007; Oti & Brunner, 2007; Oti et al., 2006; Schadt, 2009). In these networks, nodes represent genes, and edges represent functional associations between linked genes. These networks are referred to as functional linkage gene networks (FLN). In this chapter, we first review the molecular basis for genes working as a functional group, and demonstrate the existence of functional associations between genes implicated in a common disease. Next, we review ways to construct different types of FLNs, as well as two important FLN-based applications related to human diseases: prediction of new disease genes and therapeutic targets, and identification of disease-disease associations at the molecular level (Figure 1).