Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis.

Background: Epistasis, the phenomenon where the effect of one gene (or variant) is masked or modified by one or more other genes, can significantly contribute to the observed phenotypic variance of complex traits. To date, it has been generally assumed that genetic interactions can be detected using a Cartesian, or multiplicative, interaction model commonly utilized in standard regression approaches. However, a recent study investigating epistasis in obesity-related traits in rats and mice has identified potential limitations of the Cartesian model, revealing that it only detects some of the genetic interactions occurring in these systems. By applying an alternative approach, the exclusive-or (XOR) model, the researchers detected a greater number of epistatic interactions and identified more biologically relevant ontological terms associated with the interacting loci. This suggests that the XOR model may provide a more comprehensive understanding of epistasis in these species and phenotypes. To further explore these findings and determine if different interaction models also make up distinct epistatic networks, we leverage network science to provide a more comprehensive view into the genetic interactions underlying BMI in this system.

Results: Our comparative analysis of networks derived from Cartesian and XOR interaction models in rats () uncovers distinct topological characteristics for each model-derived network. Notably, we discover that networks based on the XOR model exhibit an enhanced sensitivity to epistatic interactions. This sensitivity enables the identification of network communities, revealing novel trait-related biological functions through enrichment analysis. Furthermore, we identify triangle network motifs in the XOR epistatic network, suggestive of higher-order epistasis, based on the topology of lower-order epistasis.

Conclusions: These findings highlight the XOR model's ability to uncover meaningful biological associations as well as higher-order epistasis from lower-order epistatic networks. Additionally, our results demonstrate that network approaches not only enhance epistasis detection capabilities but also provide more nuanced understandings of genetic architectures underlying complex traits. The identification of community structures and motifs within these distinct networks, especially in XOR, points to the potential for network science to aid in the discovery of novel genetic pathways and regulatory networks. Such insights are important for advancing our understanding of phenotype-genotype relationships.