A new view of transcriptome complexity and regulation through the lens of local splicing variations

ELife
Jorge Vaquero-GarciaYoseph Barash

Abstract

Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.

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Datasets Mentioned

BETA
GSE30611

Methods Mentioned

BETA
short
RNA-Seq
GTPase
Chip-Seq
PMA
reverse transcription-PCR

Software Mentioned

ENSEMBL RESTful
bam2ssj
VOILA
MAJIQ Builder
rMATS
Ensembl
RefSeq
CLTA
DiffSplice
STAR

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