학술논문
Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.
Document Type
Article
Author
Einson, Jonah; Glinos, Dafni; Boerwinkle, Eric; Castaldi, Peter; Darbar, Dawood; Andrade, Mariza de; 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 J. F.; Meyers, Deborah A.; Mitchell, Braxton D.
Source
Subject
*AUTISM risk factors
*GENETIC mutation
*SEQUENCE analysis
*GENETIC polymorphisms
*ALLELES
*BIOINFORMATICS
*MESSENGER RNA
*HAPLOTYPES
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Language
ISSN
0016-6731
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 spliceregulatory variants may play a role in reducing the damaging effects of rare exonic variants. [ABSTRACT FROM AUTHOR]