Methods and computer software for detecting splice variants

• US 20110208500A1
• Filed: 05/04/2011
• Published: 08/25/2011
• Est. Priority Date: 09/30/2005
• Status: Active Grant

• Current Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Blume, John E., Wang, Hui, Cawley, Simon, Williams, Alan, Clark, Tyson
• Granted Patent: US 8,170,808 B2
• Time in Patent Office: Days
• US Class Current: 703/11
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression

Abstract

Methods and software products for analysis of alternative splicing are disclosed. In general the methods involve normalizing probe set or exon intensity to an expression level measurement of the gene. The methods may be used to identify tissue-specific alternative splicing events.

Claims

1-12. -12. (canceled)

13. A method for predicting if an exon in a gene is differentially spliced in a first and second sample sets, comprising:

obtaining a first exon level intensity measurement for said exon in said first sample set and a second exon level intensity measurement for said exon in said second sample set;

assume under the null hypothesis of no alternative splicing for said exon that all exons of said gene are expressed at levels that are proportional to each other in said first and second sample sets;

fit a model that predicts exon response under said null hypothesis;

construct a statistic that measures how deviant the observed data is from the model;

use the statistic to construct a p-value; and

analyze the p-value to predict if the exon is differentially spliced.

14. The method of claim 13 wherein the model is e_i,j,k=α

_i,kg_j,k where e_i,j,k is the signal of the i-th exon of the j-th sample of the k-th gene, g_j,k is the signal of the k-th gene in the j-th sample, and α

_i,k is the ration of exon i signal to its gene signal.

15. The method of claim 13 wherein the model is e_i,j,k=α

_i,kp_i,j,kg_j,k

Where e_i,j,k is the signal of the i-th exon of the j-th sample of the k-th gene, g_j,k, is the signal of the k-th gene in the j-th sample, α

_i,k is the ratio of exon i signal to its gene signal in the sample where it is maximally expressed, and 0≦

p_i,j,k≦

1 is a Splicing Index that estimates the proportionate expression of this exon of this gene in tissue j.