Transcript Isoform Differences Across Human Tissues Are Predominantly Driven By Alternative Start And Termination Sites Of Transcription

Most human genes have multiple transcription start and polyadenylation sites, as well as alternatively spliced exons. Although such transcript isoform diversity contributes to the differentiation between cell types, the importance of contributions from the different isoform generating processes is unclear. To address this question, we used 798 samples from the Genotype-Tissue Expression (GTEx) to investigate cell type dependent differences in exon usage of over 18,000 protein-coding genes in 23 cell types. We found tissue-dependent isoform usage in about half of expressed genes. Overall, tissue-dependent splicing accounted only for a minority of tissue-dependent exon usage, most of which was consistent with alternative transcription start and termination sites. We verified this result on a second, independent dataset, Cap Analysis of Gene Expression (CAGE) data from the FANTOM consortium, which confirmed widespread tissue-dependent usage of alternative transcription start sites. Our analysis identifies transcription start and termination sites as the principal drivers of isoform diversity across tissues. Moreover, our results indicate that most tissue-dependent splicing involves untranslated exons and therefore may not have consequences at the proteome level.