Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Einson, Jonah, Glinos, Dafni, Boerwinkle, Eric, Castaldi, Peter, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick, Fornage, Myriam, Gabriel, Stacey, Germer, Soren, Gibbs, Richard, Hersh, Craig P, Johnsen, Jill, Kaplan, Robert, Konkle, Barbara A, Kooperberg, Charles, Nassir, Rami, Loos, Ruth JF, Meyers, Deborah A, Mitchell, Braxton D, Psaty, Bruce, Vasan, Ramachandran S, Rich, Stephen S, Rienstra, Michael, Rotter, Jerome I, Saferali, Aabida, Shoemaker, Moore Benjamin, Silverman, Edwin, Smith, Albert Vernon, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Mohammadi, Pejman, Castel, Stephane E, Iossifov, Ivan, Lappalainen, Tuuli (August 2023) Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. Genetics: a periodical record of investigations bearing on heredity and variation, 224 (4). iyad115. ISSN 0016-6731

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Abstract

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > splice site
CSHL Authors:	Iossifov, Ivan
Communities:	CSHL labs > Iossifov lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 August 2023
Date Deposited:	21 Sep 2023 13:34
Last Modified:	08 Jan 2024 19:24
PMCID:	PMC10411602
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40932

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