GLiMMPS: robust statistical model for regulatory variation of alternative splicing using RNA-seq data.

Keyan Zhao,Juw Park,Qing Zhou,Zhi-Xiang Lu,Yi Xing

doi:10.1186/gb-2013-14-7-r74

Keyan Zhao, Juw Park + Show 3 more

Open Access

https://doi.org/10.1186/gb-2013-14-7-r74

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Abstract

To characterize the genetic variation of alternative splicing, we develop GLiMMPS, a robust statistical method for detecting splicing quantitative trait loci (sQTLs) from RNA-seq data. GLiMMPS takes into account the individual variation in sequencing coverage and the noise prevalent in RNA-seq data. Analyses of simulated and real RNA-seq datasets demonstrate that GLiMMPS outperforms competing statistical models. Quantitative RT-PCR tests of 26 randomly selected GLiMMPS sQTLs yielded a validation rate of 100%. As population-scale RNA-seq studies become increasingly affordable and popular, GLiMMPS provides a useful tool for elucidating the genetic variation of alternative splicing in humans and model organisms.

Highlights

Alternative splicing (AS) is the process by which exons from precursor mRNA transcripts are differentially included during splicing, resulting in different mature mRNA isoforms from a single gene locus [1]
Based on the AS patterns, we classified the AS events into four categories (Figure S1 in Additional file 1): skipped exon (SE), alternative 5’ splice site (A5SS), alternative 3’ splice site (A3SS), and mutually exclusive exons (MXE)
We investigated all significant splicing Quantitative Trait Loci (sQTL) single-nucleotide polymorphism (SNP) (GLiMMPS false discovery rate (FDR) ≤0.1) in high (r2 >0.8) linkage disequilibrium (LD) with GWAS signal SNPs listed in the Catalog of Published Genome-Wide Association Studies [37]

Summary

Introduction

Alternative splicing (AS) is the process by which exons from precursor mRNA transcripts are differentially included during splicing, resulting in different mature mRNA isoforms from a single gene locus [1]. AS is a major contributor to the control of gene expression and protein diversity. More than 90% of human genes are alternatively spliced [2]. Changes in the relative ratio of alternatively spliced isoforms of a single gene can have significant phenotypic consequences and cause various diseases [3,4]. Genetic polymorphisms that alter cis splicing regulatory elements can result in difference of alternative splicing among human individuals and subsequently affect gene expression or protein activity. Genetic variation of alternative splicing in the sodium channel gene

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