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A Multiplexed Assay for Exon Recognition Reveals that an Unappreciated Fraction of Rare Genetic Variants Cause Large-Effect Splicing Disruptions
- Source :
- Molecular cell, vol 73, iss 1
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Mutations that lead to splicing defects can have severe consequences on gene function and cause disease. Here, we explore how human genetic variation affects exon recognition by developing a multiplexed functional assay of splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs). Importantly, we find that 83% of SDVs are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate extant, rare genetic variants can have large functional effects on splicing at appreciable rates, even outside the context of disease, and MFASS enables their empirical assessment at scale.
- Subjects :
- Cell Separation
medicine.disease_cause
Medical and Health Sciences
massively parallel reporter assay
Exon
0302 clinical medicine
2.1 Biological and endogenous factors
Aetiology
Exome
Oligonucleotide Array Sequence Analysis
Genetics
0303 health sciences
Mutation
High-Throughput Nucleotide Sequencing
Exons
Hep G2 Cells
Biological Sciences
Flow Cytometry
RNA splicing
Sequence Analysis
rare variation
RNA Splicing
population variation
Context (language use)
Biology
Article
splicing
03 medical and health sciences
exon recognition
medicine
Humans
variant classification
Molecular Biology
Gene
030304 developmental biology
Gene Expression Profiling
Human Genome
Intron
Computational Biology
Reproducibility of Results
DNA
Sequence Analysis, DNA
Cell Biology
Introns
HEK293 Cells
Hela Cells
K562 Cells
030217 neurology & neurosurgery
Developmental Biology
HeLa Cells
Minigene
Subjects
Details
- ISSN :
- 10972765
- Volume :
- 73
- Database :
- OpenAIRE
- Journal :
- Molecular Cell
- Accession number :
- edsair.doi.dedup.....81075eaefd5ff8b0395e8969b500067f