Back to industrial propertyPre-mRNA splicing is the process by which introns are removed form transcripts and exons are joined together to form mature mRNAs that are then exported to the cytoplasm and translated. Altered splicing is an important mechanism by which genetic variants cause disease. Multiplex assays of variant effects (MAVEs) have revealed that random nucleotide substitutions in exons frequently affect splicing, with 60-70% of substitutions in over 90% of positions in alternatively-spliced exons and 5% of substitutions in constitutively-spliced exons altering exon inclusion. Comprehensive testing has also shown that ~10% of disease-causing missense variants, as well as 3% of common exonic substitutions, affect splicing. For example, in humans, FAS exon 6 ecocdes a transmembrane leix of the FAS/CD95 receptor. Inclusion of this exon generates a proapoptotic receptor whereas exon skipping produces an anti-apoptotic soluble inhibitor. A variant in exon 6 that causes exon 6 skipping causes autoimmune lymphoproliferative syndrome (ALPS).This invention relates to generation of oligonucleotides having desirable properties, and to methods of generatign oligonucleotides. In particular, the invention relates to a mehtod and system for generating antisense oligonucleotides that modulates splicing.
