PAcluster: Clustering polyadenylation site data using canonical correlation analysis.

Alternative polyadenylation (APA) is a pervasive mechanism that contributes to gene regulation. Increasing sequenced poly(A) sites are placing new demands for the development of computational methods to investigate APA regulation. Cluster analysis is important to identify groups of co-expressed genes. However, clustering of poly(A) sites has not been extensively studied in APA, where most APA studies failed to consider the distribution, abundance, and variation of APA sites in each gene. Here we constructed a two-layer model based on canonical correlation analysis (CCA) to explore the underlying biological mechanisms in APA regulation. The first layer quantifies the general correlation of APA sites across various conditions between each gene and the second layer identifies genes with statistically significant correlation on their APA patterns to infer APA-specific gene clusters. Using hierarchical clustering, we comprehensively compared our method with four other widely used distance measures based on three performance indexes. Results showed that our method significantly enhanced the clustering performance for both synthetic and real poly(A) site data and could generate clusters with more biological meaning. We have implemented the CCA-based method as a publically available R package called PAcluster, which provides an efficient solution to the clustering of large APA-specific biological dataset.