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A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect disruptions to splicing

ABSTRACT: Mutations that cause exon skipping can have severe consequences on gene function and cause disease. Here we explore how human genetic variation affects exon recognition by developing a Multiplexed Functional Assay of Splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter, and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs). Importantly, we find that 83% of SDVs are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate extant, rare genetic variants, even outside the context of disease, can have large functional effects at appreciable rates, and that MFASS enables their empirical assessment for large-effect splicing defects at scale.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120695 | GEO | 2018/10/02

REPOSITORIES: GEO

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A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect disruptions to splicing

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