PolyAMiner-Bulk: A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data

More than half of human genes exercise alternative polyadenylation (APA) and generate mRNA transcripts with varying 3 untranslated regions (UTR). However, current computational approaches for identifying cleavage and polyadenylation sites (C/PASs) and quantifying 3UTR length changes from bulk RNA-seq data fail to unravel tissue- and disease-specific APA dynamics. Here, we developed a next-generation bioinformatics algorithm and application, PolyAMiner-Bulk, that utilizes an attention-based machine learning architecture and an improved vector projection-based engine to infer differential APA dynamics accurately. When applied to earlier studies, PolyAMiner-Bulk accurately identified more than twice the number of APA changes in an RBM17 knockdown bulk RNA-seq dataset compared to current generation tools. Moreover, on a separate dataset, PolyAMiner-Bulk revealed novel APA dynamics and pathways in scleroderma pathology and identified differential APA in a gene that was identified as being involved in scleroderma pathogenesis in an independent study. Lastly, we used PolyAMiner-Bulk to analyze the RNA-seq data of post-mortem prefrontal cortexes from the ROSMAP data consortium and unraveled novel APA dynamics in Alzheimers Disease. Our method, PolyAMiner-Bulk, creates a paradigm for future alternative polyadenylation analysis from bulk RNA-seq data.