Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides
- Sidi Zhang1,2,3,
- Kaitlin E. Samocha1,2,3,4,
- Manuel A. Rivas2,
- Konrad J. Karczewski1,2,
- Emma Daly1,
- Ben Schmandt1,
- Benjamin M. Neale1,2,4,
- Daniel G. MacArthur1,2 and
- Mark J. Daly1,2,4,5
- 1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 5Institute for Molecular Medicine Finland (FIMM), 00290 Helsinki, Finland
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.231902.117.
- Received November 1, 2017.
- Accepted May 31, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
