期刊
GENOME RESEARCH
卷 28, 期 7, 页码 968-974出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.231902.117
关键词
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资金
- National Institute of General Medical Sciences Fellowship (NIGMS, NIH) [F32GM115208]
- Simons Foundation [SFARI 342292]
- Leona M. and Harry B. Helmsley Charitable Trust [2015PG-IBD001]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK043351] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM115208] Funding Source: NIH RePORTER
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.
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