Genome-wide detection of human variants that disrupt intronic branchpoints
Zhang, Peng (The Rockefeller University)
Philippot, Quentin (Paris Cité University)
Ren, Weicheng (Karolinska Institutet (Estocolm, Suècia))
Lei, Wei-Te (The Rockefeller University)
Li, Juan (The Rockefeller University)
Stenson, Peter D. (Cardiff University)
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron)
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron)
Boisson, Bertrand (Paris Cité University)
Zhang, Shen-Ying (Paris Cité University)
Puel, Anne (Paris Cité University)
Pan-Hammarström, Qiang (Karolinska Institutet (Estocolm, Suècia))
Zhang, Qian (Paris Cité University)
Cooper, David N. (Cardiff University)
Abel, Laurent (Paris Cité University, Imagine Institute)
Casanova, Jean-Laurent (HHMI)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	The search for candidate variants underlying human disease in massive parallel sequencing data typically focuses on coding regions and essential splice sites, mostly ignoring noncoding variants. The RNA spliceosome recognizes intronic branchpoint (BP) motifs at the beginning of splicing and operates mostly within introns to define the exon-intron boundaries; however, BP variants have been paid little attention. We established a comprehensive genome-wide database and knowledgebase of BP and developed BPHunter for systematic and informative genome-wide detection of intronic variants that may disrupt BP and splicing, together with an effective strategy for prioritizing BP variant candidates. BPHunter not only constitutes an important resource for understanding BP, but should also drive discovery of BP variants in human genetic diseases and traits. Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found 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, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical 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 were validated experimentally. BPHunter is publicly available from and.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Branchpoint ; Splicing ; Intronic variant ; Disease genetics ; Software
Publicat a:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 119 (october 2022) , ISSN 1091-6490

DOI: 10.1073/pnas.2211194119
PMID: 36306325

12 p, 2.0 MB

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