scMAPA: Identification of cell-type–specific alternative polyadenylation in complex tissues

Abstract

Background Alternative polyadenylation (APA) causes shortening or lengthening of the 3ʹ-untranslated region (3ʹ-UTR) of genes (APA genes) in diverse cellular processes such as cell proliferation and differentiation. To identify cell-type–specific APA genes in scRNA-Seq data, current bioinformatic methods have several limitations. First, they assume certain read coverage shapes in the scRNA-Seq data, which can be violated in multiple APA genes. Second, their identification is limited between 2 cell types and not directly applicable to the data of multiple cell types. Third, they do not control undesired source of variance, which potentially introduces noise to the cell-type–specific identification of APA genes. Findings We developed a combination of a computational change-point algorithm and a statistical model, single-cell Multi-group identification of APA (scMAPA). To avoid the assumptions on the read coverage shape, scMAPA formulates a change-point problem after transforming the 3ʹ biased scRNA-Seq data to represent the full-length 3ʹ-UTR signal. To identify cell-type–specific APA genes while adjusting for undesired source of variation, scMAPA models APA isoforms in consideration of the cell types and the undesired source. In our novel simulation data and data from human peripheral blood mononuclear cells, scMAPA outperforms existing methods in sensitivity, robustness, and stability. In mouse brain data consisting of multiple cell types sampled from multiple regions, scMAPA identifies cell-type–specific APA genes, elucidating novel roles of APA for dividing immune cells and differentiated neuron cells and in multiple brain disorders. Conclusions scMAPA elucidates the cell-type–specific function of APA events and sheds novel insights into the functional roles of APA events in complex tissues.

A Survey on Methods for Predicting Polyadenylation Sites from DNA Sequences, Bulk RNA-seq, and Single-cell RNA-seq

“…and roar [118], directly discover APA site switching by detecting sudden change of read density at terminal exons without identifying APA sites. Recently, several tools were developed for scRNA-seq, such as SCUREL [119], scMAPA [120], and scDAPA [121].…”

“…Some approaches for RNA-seq, such as PHMM [115], ChangePoint [116], MISO [117], and roar [118], directly discover APA site switching by detecting sudden change of read density at terminal exons without identifying APA sites. Recently, several tools were developed for scRNA-seq, such as SCUREL [119], scMAPA [120], and scDAPA [121]. For example, our group developed scDAPA [121] for characterizing differential usages of APA in different cell types using 10x Chromium data, and found APA plays important role in acute myeloid leukemia [114].…”