Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.
AG-gain
branchpoint
human genetics
intronic variant
splicing
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 Nov 2023
14 Nov 2023
Historique:
medline:
8
11
2023
pubmed:
6
11
2023
entrez:
6
11
2023
Statut:
ppublish
Résumé
Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene
Identifiants
pubmed: 37931111
doi: 10.1073/pnas.2314225120
pmc: PMC10655562
doi:
Substances chimiques
RNA Splice Sites
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2314225120Subventions
Organisme : NCI NIH HHS
ID : F99 CA274708
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI162568
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI163029
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI095983
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Organisme : NIH HHS
ID : S10 OD018521
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142737
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
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