DRUG-INDUCED mRNA SIGNATURES ARE ENRICHED FOR THE MINORITY OF GENES THAT ARE HIGHLY HERITABLE

摘要

The blood gene expression signatures are used as biomarkers for immunological and non-immunological diseases.1 Therefore, it is important to understand the variation in blood gene expression patterns and the factors (heritable/non-heritable) that underlie this variation. In this paper, we study the relationship between drug effects on the one hand, and heritable and non-heritable factors influencing gene expression on the other. Understanding of this relationship can help select appropriate targets for drugs aimed at reverting disease phenotypes to healthy states. In order to estimate heritable and non-heritable effects on gene expression, we use Twin-ACE model on a gene expression dataset MuTHER,2 measured in blood samples from monozygotic and dizygotic twins. In order to associate gene expression with drug effects, we use CMap3,4 database. We show that, even though the expressions of most genes are driven by non-heritable factors, drugs are more likely to influence expression of genes, driven by heritable rather than non-heritable factors. We further study this finding in the context of a gene regulatory network. We investigate the relationship between the drug effects on gene expression and propagation of heritable and non-heritable factors through regulatory networks. We find that the decisive factor in determining whether a gene will be influenced by a drug is the flow of heritable effects supplied to the gene through regulatory network.