This study investigates the regulation of alternative splicing (AS) and alternative polyadenylation (APA) in human tissues using deep sequencing of cDNA fragments. The researchers analyzed 15 diverse human tissues and cell lines, generating a digital inventory of gene and mRNA isoform expression. They found that 92-94% of human genes undergo AS, with ~86% having a minor isoform frequency of 15% or more. AS and APA events vary significantly between tissues, while individual variation is less common. The study also identified that tissue-specific regulation of AS is associated with increased sequence conservation in regulatory regions and the generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation. The study also found that alternative mRNA isoform expression varies between individuals, with ~10-30% of alternative transcript events exhibiting individual-specific variation. The researchers identified a class of "switch-like" exons that exhibit dramatically different inclusion levels between tissues, indicating the flexibility of the splicing regulatory machinery. These exons are often involved in regulating highly tissue-specific functions. The study also explored the coordination between splicing and polyadenylation, finding that tissue-specific regulation of APA is associated with increased conservation of regulatory sequences. The researchers identified that splicing and polyadenylation may be coordinately regulated across human tissues, with evidence suggesting that splicing and polyadenylation factors may play roles in both processes. The study concludes that tissue-specific AS and APA events are regulated by tissue-specific RNA binding factors that play roles in both of these RNA processing steps. These factors may include both canonical tissue-specific splicing factors and canonical UTR-binding factors. The findings suggest that tightly coordinated regulation of polyadenylation and splicing is essential for the appropriate expression of tissue-specific protein isoforms.This study investigates the regulation of alternative splicing (AS) and alternative polyadenylation (APA) in human tissues using deep sequencing of cDNA fragments. The researchers analyzed 15 diverse human tissues and cell lines, generating a digital inventory of gene and mRNA isoform expression. They found that 92-94% of human genes undergo AS, with ~86% having a minor isoform frequency of 15% or more. AS and APA events vary significantly between tissues, while individual variation is less common. The study also identified that tissue-specific regulation of AS is associated with increased sequence conservation in regulatory regions and the generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation. The study also found that alternative mRNA isoform expression varies between individuals, with ~10-30% of alternative transcript events exhibiting individual-specific variation. The researchers identified a class of "switch-like" exons that exhibit dramatically different inclusion levels between tissues, indicating the flexibility of the splicing regulatory machinery. These exons are often involved in regulating highly tissue-specific functions. The study also explored the coordination between splicing and polyadenylation, finding that tissue-specific regulation of APA is associated with increased conservation of regulatory sequences. The researchers identified that splicing and polyadenylation may be coordinately regulated across human tissues, with evidence suggesting that splicing and polyadenylation factors may play roles in both processes. The study concludes that tissue-specific AS and APA events are regulated by tissue-specific RNA binding factors that play roles in both of these RNA processing steps. These factors may include both canonical tissue-specific splicing factors and canonical UTR-binding factors. The findings suggest that tightly coordinated regulation of polyadenylation and splicing is essential for the appropriate expression of tissue-specific protein isoforms.