Abstract：
:Mutations that lead to splicing defects 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 can have large functional effects on splicing at appreciable rates, even outside the context of disease, and MFASS enables their empirical assessment at scale.
journal_name
Mol Celljournal_title
Molecular cellauthors
Cheung R,Insigne KD,Yao D,Burghard CP,Wang J,Hsiao YE,Jones EM,Goodman DB,Xiao X,Kosuri Sdoi
10.1016/j.molcel.2018.10.037subject
Has Abstractpub_date
2019-01-03 00:00:00pages
183-194.e8issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(18)30897-9journal_volume
73pub_type
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