Alternative splicing is a key step in eukaryotic gene expression that allows the production of multiple protein isoforms from the same gene. Even though splicing is perturbed in many diseases, we currently lack insights into regulatory mechanisms promoting its precision and efficiency. Using mechanistic mathematical modeling, we show that alternative splicing control is facilitated if spliceosomes recognize exons as functional units (exon definition). We find that exon definition is crucial to

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... revent the accumulation of partially spliced retention products during alternative splicing regulation. Furthermore, it modularizes splicing control, as multiple regulatory inputs are integrated into a common net input, irrespective of the location and nature of the corresponding cis-regulatory elements in the pre-mRNA. These predictions of our model are qualitatively and quantitatively supported by high-throughput mutagenesis data obtained for an alternatively spliced exon in the proto-oncogene RON (MST1R). Our analysis suggests that exon definition has evolved as the dominant splice-regulatory mechanism in higher organisms to promote robust and reliable splicing outcomes.