Direct Testing for Allele-Specific Expression Differences Between Conditions

Allelic imbalance (AI) indicates the presence of functional variation in cis regulatory regions. Detecting cis regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here, we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (G×E) interactions, and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and, as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a Drosophila melanogaster population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies, and we show that AI × genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1s was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of G×E and G×G, and reaffirms a previous finding that cis regulation is robust between environments.