Polysome sequencing data: Genetic and functional analysis of unproductive splicing using LeafCutter2

These events reduce overall protein expression levels of affected genes, potentially contributing to gene regulation and disease mechanisms.Here, we present LeafCutter2, which enables identification and quantification of unproductive splicing from short-read RNA-seq data.

LeafCutter2 requires minimal gene annotations (start and stop codons) to annotate NMD-inducing splicing events, and identifies differential unproductive splicing between groups, providing insights into its contributions to differential gene expression. Moreover, LeafCutter2 enables mapping of unproductive splicing quantitative trait loci (u-sQTLs), which often colocalize with expression QTLs and GWAS loci. Applying LeafCutter2 to RNA-seq data across human and 6 non-human species, we uncovered a broad landscape of unproductive splicing, which varies widely across tissues.