Systems and methods for determining effects of therapies and genetic variation on polyadenylation site selection

A computer system comprising a digital processing device comprising at least one processor, an operating system configured to perform executable instructions, a memory, and a computer program including instructions executable by the digital processing device to create an application for determining an effect of an antisense oligonucleotide on a plurality of candidate polyadenylation sites, the application comprising:

• a sequence module programmed to provide a plurality of genomic sequences, wherein the plurality of genomic sequences comprises (1) a reference sequence and (2) a variant sequence obtained by computer processing the reference sequence based on the antisense oligonucleotide, wherein the antisense oligonucleotide is complementary to at least a portion of the reference sequence;
• an identification module programmed to, for each of the plurality of genomic sequences, identify a plurality of candidate polyadenylation sites in the genomic sequence;
• a feature extraction module programmed to, for each of the plurality of genomic sequences, extract a polyadenylation feature vector for each of the plurality of candidate polyadenylation sites, wherein each of the polyadenylation feature vectors comprises one or more features determined at least based on one or more nucleotides in the genomic sequence;
• a preference computation module programmed to, for each of the plurality of genomic sequences, apply a trained algorithm to the plurality of polyadenylation feature vectors to calculate a set of preferences p1, p2, . . . , pn, corresponding to the plurality of candidate polyadenylation sites;
• and a processing module programmed to process the plurality of sets of preferences for each of the plurality of genomic sequences with each other to determine the effect of the antisense oligonucleotide.

A non-transitory computer-readable medium comprising machine-executable code that, upon execution by one or more computer processors, implements a method for determining an effect of an antisense oligonucleotide on a plurality of candidate polyadenylation sites, the method comprising:

• (a) providing a plurality of genomic sequences, wherein the plurality of genomic sequences comprises (1) a reference sequence and (2) a variant sequence obtained by computer processing the reference sequence based on the antisense oligonucleotide, wherein the antisense oligonucleotide is complementary to at least a portion of the reference sequence;
• and
• (b) for each of the plurality of genomic sequences:
• i. identifying a plurality of candidate polyadenylation sites in the genomic sequence;
• ii. extracting a polyadenylation feature vector for each of the plurality of candidate polyadenylation sites, wherein each of the polyadenylation feature vectors comprises one or more features determined at least based on one or more nucleotides in the genomic sequence;
• and
• iii. applying a trained algorithm to the plurality of polyadenylation feature vectors to calculate a set of preferences p1, p2, . . . , pn corresponding to the plurality of candidate polyadenylation sites;
• and
• (c) processing the plurality of sets of preferences for each of the plurality of genomic sequences with each other to determine the effect of the antisense oligonucleotide.