Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

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http://hdl.handle.net/10138/298270

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Zhang , S , Samocha , K E , Rivas , M A , Karczewski , K J , Daly , E , Schmandt , B , Neale , B M , MacArthur , D G & Daly , M J 2018 , ' Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides ' , Genome Research , vol. 28 , no. 7 , pp. 968-974 . https://doi.org/10.1101/gr.231902.117

Title: Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides
Author: Zhang, Sidi; Samocha, Kaitlin E.; Rivas, Manuel A.; Karczewski, Konrad J.; Daly, Emma; Schmandt, Ben; Neale, Benjamin M.; MacArthur, Daniel G.; Daly, Mark J.
Contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
Date: 2018-07
Language: eng
Number of pages: 7
Belongs to series: Genome Research
ISSN: 1088-9051
URI: http://hdl.handle.net/10138/298270
Abstract: Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.
Subject: PROTEIN-TRUNCATING VARIANTS
REGULATORY ELEMENTS
GENETIC-VARIATION
DISEASE
BRAIN
SCHIZOPHRENIA
TRANSCRIPTOME
EXPRESSION
PATHOLOGY
HUMANS
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
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