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Scheller, I.F. ; Lutz, K.* ; Mertes, C.* ; Yépez, V.A.* ; Gagneur, J.

Improved detection of aberrant splicing with FRASER 2.0 and the intron Jaccard index.

Am. J. Hum. Genet. 110, 2056-2067 (2023)
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Detection of aberrantly spliced genes is an important step in RNA-seq-based rare-disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method that outperformed alternative methods of detecting aberrant splicing. However, because FRASER's three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron-excision metric, the intron Jaccard index, that combines the alternative donor, alternative acceptor, and intron-retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs by using candidate rare-splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm, FRASER 2.0, called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare-splice-disrupting variants by 10-fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. To lower the multiple-testing correction burden, we introduce an option to select the genes to be tested for each sample instead of a transcriptome-wide approach. This option can be particularly useful when prior information, such as candidate variants or genes, is available. Application on 303 rare-disease samples confirmed the relative reduction in the number of outlier calls for a slight loss of sensitivity; FRASER 2.0 recovered 22 out of 26 previously identified pathogenic splicing cases with default cutoffs and 24 when multiple-testing correction was limited to OMIM genes containing rare variants. Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by drastically reducing the amount of splicing outlier calls per sample at minimal loss of sensitivity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Aberrant Splicing ; Rna-seq ; Outlier Detection ; Rare Disease ; Rare Disease Diagnostics ; Rare Variant; Variants
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 12, Pages: 2056-2067 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Office of the NIH Director
National Institutes of Health Common Fund, through the Office of Strategic Coordinatio
Intramural Research Program of the National Human Genome Research Institute
National Institute of Neurological Disorders and Stroke
National Institute of Mental Health
National Institute on Drug Abuse
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Cancer Institute
Common Fund of the Office of the Director of the National Institutes of Health
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
German Bundesministerium fur Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM