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Increasing evidence shows that genetic interaction across the entire genome may explain a non-trivial fraction of genetic diseases. Digenic interaction is the simplest manifestation of genetic interaction among genes. However, systematic exploration of digenic interactive effects on the whole genome is often discouraged by the high dimension burden. Thus, numerous digenic interactions are yet to be identified for many diseases. Here, we propose a Digenic Interaction Effect Predictor (DIEP), an accurate machine-learning approach to identify the genome-wide pathogenic coding gene pairs with digenic interaction effects. This approach achieved high accuracy and sensitivity in independent testing datasets, outperforming another gene-level digenic predictor (DiGePred). DIEP was also able to discriminate digenic interaction effect from bi-locus effects dual molecular diagnosis (pseudo-digenic). Using DIEP, we provided a valuable resource of genome-wide digenic interactions and demonstrated the enrichment of the digenic interaction effect in Mendelian and Oligogenic diseases. Therefore, DIEP will play a useful role in facilitating the genomic mapping of interactive causal genes for human diseases.

The usage of expressed somatic mutations may have a unique advantage in identifying active cancer driver mutations. However, accurately calling mutations from RNA-seq data is difficult due to confounding factors such as RNA-editing, reverse transcription, and gap alignment. In the present study, we proposed a framework (named RNA-SSNV, https://github.com/pmglab/RNA-SSNV) to call somatic single nucleotide variants (SSNV) from tumor bulk RNA-seq data. Based on a comprehensive multi-filtering strategy and a machine-learning classification model trained with comprehensively curated features, RNA-SSNV achieved the best precision–recall rate (0.880–0.884) in a testing dataset and robustly retained 0.94 AUC for the precision–recall curve in three validation adult-based TCGA (The Cancer Genome Atlas) datasets. We further showed that the somatic mutations called by RNA-SSNV tended to have a higher functional impact and therapeutic power in known driver genes. Furthermore, VAF (variant allele fraction) analysis revealed that subclonal harboring expressed mutations had evolutional selection advantage and RNA had higher detection power to rescue DNA-omitted mutations. In sum, RNA-SSNV will be a useful approach to accurately call expressed somatic mutations for a more insightful analysis of cancer drive genes and carcinogenic mechanisms.