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QAPA: A new method for the systematic analysis of alternative polyadenylation from RNA-seq data

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Alternative polyadenylation (APA) affects most mammalian genes. The genome-wide investigation of APA has been hampered by an inability to reliably profile it using conventional RNA-seq. We describe ‘Quantification of APA’ (QAPA), a method that infers APA from conventional RNA-seq data. | Ha et al. Genome Biology 2018 19 45 https doi.org 10.1186 s13059-018-1414-4 METHOD Open Access QAPA a new method for the systematic analysis of alternative polyadenylation from RNA-seq data Kevin C. H. Ha1 2 Benjamin J. Blencowe1 2 and Quaid Morris1 2 3 4 Abstract Alternative polyadenylation APA affects most mammalian genes. The genome-wide investigation of APA has been hampered by an inability to reliably profile it using conventional RNA-seq. We describe Quantification of APA QAPA a method that infers APA from conventional RNA-seq data. QAPA is faster and more sensitive than other methods. Application of QAPA reveals discrete temporally coordinated APA programs during neurogenesis and that there is little overlap between genes regulated by alternative splicing and those by APA. Modeling of these data uncovers an APA sequence code. QAPA thus enables the discovery and characterization of programs of regulated APA using conventional RNA-seq. Keywords High-throughput RNA sequencing Alternative polyadenylation Machine learning Background The polyadenylation machinery responsible for recog- Alternative cleavage and polyadenylation APA of pre- nition of poly A sites involves interactions between sev- mRNA results in the formation of multiple mRNA tran- eral trans-acting factors and cis-elements. The core 3 script isoforms with distinct 3 untranslated regions processing factors include cleavage and polyadenylation UTRs . Approximately 70 of mammalian protein- specificity factor CPSF cleavage stimulation factor coding genes contain multiple polyadenylation poly A CstF and cleavage factors I and II CFI and CFII 10 sites 1 2 . Thus APA much like alternative pre-mRNA 12 . Transcription of the poly A site by RNA polymer- splicing AS 3 4 contributes extensively to eukaryotic ase II results in the recruitment of the above complexes transcriptome diversity and complexity. APA can occur via recognition of two surrounding sequence motifs in within introns or within 3 UTR .