Splicing of designer exons informs a biophysical model for exon definition

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Pre-mRNA molecules in humans contain mostly short internal exons flanked by longer introns. To explain the removal of such introns, exon recognition instead of intron recognition has been proposed. We studied this exon definition using designer exons made up of prototype modules of our own design (including an exonic splicing enhancer, ESE, or silencer, ESS) in a three exon minigene. We found an optimal size range for inclusion that surprisingly shifted depending on the splice site sequences used. For the ESE, we found, unexpectedly, a position independent enhancement in inclusion. For the ESS we found a step-wise positional increase in its effects, being lowest at the 5’ end. To quantitatively apply these results, we developed a biophysical model for exon definition of internal exons undergoing co-transcriptional splicing. This model features commitment to inclusion before the downstream exon is synthesized and competition between skipping and inclusion fates afterwards.

M.A. Arias, A. Lubkin, and L.A. Chasin. 2015.  Splicing of designer exons informs a biophysical model for exon definition. RNA. 21: 213-229. doi:10.1261/rna.048009.114

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