Genome-wide detection of human variants that disrupt intronic branchpoints
Genome-wide detection of human variants that disrupt intronic branchpoints
ABSTRACT Pre-mRNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Fifty-six rare variants in 44 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach has been available to efficiently detect such variants in next-generation sequencing (NGS) data. We established a comprehensive human genome-wide BP database by integrating existing BP data, and by generating new BP data from RNA-seq of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We in-depth characterize multiple features of BP in major and minor introns, and find that BP and BP-2 (two-nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, whilst being comparable to the exonic background. We develop BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition in NGS data. BPHunter retrospectively identifies 48 of the 56 known pathogenic BP mutations in which we summarize a strategy for prioritizing BP mutation candidates, and the remaining 8 all create AG dinucleotides between BP and acceptor site which is probably the reason for mis-splicing. We demonstrate the utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia, and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which we validate experimentally. BPHunter is publicly available from https://hgidsoft.rockefeller.edu/BPHunter and https://github.com/casanova-lab/BPHunter.
Casanova Jean-Laurent、Zhang Peng、Philippot Quentin、Stenson Peter D.、Puel Anne、Cooper David N.、Lei Wei-Te、Colobran Roger、Zhang Shen-Ying、Li Juan、Boisson Bertrand、Zhang Qian、Abel Laurent、Ren Weicheng、Pan-Hammarstr?m Qiang、Palac¨an Pere Soler
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University||Laboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine Institute||Howard Hughes Medical InstituteSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityLaboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine InstituteInstitute of Medical Genetics, School of Medicine, Cardiff UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University||Laboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine InstituteInstitute of Medical Genetics, School of Medicine, Cardiff UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversityJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies||Diagnostic Immunology Group, Vall d?ˉHebron Research Institute (VHIR), Vall d?ˉHebron University Hospital (HUVH), Vall d?ˉHebron Barcelona Hospital Campus||Immunology Division, Genetics Department, Vall d?ˉHebron University Hospital (HUVH), Vall d?ˉHebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University||Laboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine InstituteSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University||Laboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine InstituteSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller UniversitySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University||Laboratory of Human Genetics of Infectious Diseases, Necker Branch||University of Paris, Imagine InstituteDepartment of Biosciences and Nutrition, Karolinska InstitutetDepartment of Biosciences and Nutrition, Karolinska InstitutetInfection in Immunocompromised Pediatric Patients Research Group, Vall d?ˉHebron Research Institute (VHIR), Vall d?ˉHebron University Hospital (HUVH), Vall d?ˉHebron Barcelona Hospital Campus||Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d?ˉHebron University Hospital (HUVH), Vall d?ˉHebron Research Institute (VHIR), Vall d?ˉHebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB)||Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
基础医学分子生物学遗传学
BranchpointSplicingIntronic VariantHuman GenomeDisease GeneticsNext-Generation SequencingCOVID-19LymphomaSoftwareWebserver
Casanova Jean-Laurent,Zhang Peng,Philippot Quentin,Stenson Peter D.,Puel Anne,Cooper David N.,Lei Wei-Te,Colobran Roger,Zhang Shen-Ying,Li Juan,Boisson Bertrand,Zhang Qian,Abel Laurent,Ren Weicheng,Pan-Hammarstr?m Qiang,Palac¨an Pere Soler.Genome-wide detection of human variants that disrupt intronic branchpoints[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2022.04.18.488668.点此复制
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