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LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes

BACKGROUND: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therap...

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Autores principales: Alasiri, Abdulrahman, Karczewski, Konrad J., Cole, Brian, Loza, Bao-Li, Moore, Jason H., van der Laan, Sander W., Asselbergs, Folkert W., Keating, Brendan J., van Setten, Jessica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9893534/
https://www.ncbi.nlm.nih.gov/pubmed/36732776
http://dx.doi.org/10.1186/s13040-023-00321-5
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author Alasiri, Abdulrahman
Karczewski, Konrad J.
Cole, Brian
Loza, Bao-Li
Moore, Jason H.
van der Laan, Sander W.
Asselbergs, Folkert W.
Keating, Brendan J.
van Setten, Jessica
author_facet Alasiri, Abdulrahman
Karczewski, Konrad J.
Cole, Brian
Loza, Bao-Li
Moore, Jason H.
van der Laan, Sander W.
Asselbergs, Folkert W.
Keating, Brendan J.
van Setten, Jessica
author_sort Alasiri, Abdulrahman
collection PubMed
description BACKGROUND: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. RESULTS: We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. CONCLUSIONS: LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13040-023-00321-5.
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spelling pubmed-98935342023-02-03 LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes Alasiri, Abdulrahman Karczewski, Konrad J. Cole, Brian Loza, Bao-Li Moore, Jason H. van der Laan, Sander W. Asselbergs, Folkert W. Keating, Brendan J. van Setten, Jessica BioData Min Software BACKGROUND: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. RESULTS: We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. CONCLUSIONS: LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13040-023-00321-5. BioMed Central 2023-02-02 /pmc/articles/PMC9893534/ /pubmed/36732776 http://dx.doi.org/10.1186/s13040-023-00321-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Software
Alasiri, Abdulrahman
Karczewski, Konrad J.
Cole, Brian
Loza, Bao-Li
Moore, Jason H.
van der Laan, Sander W.
Asselbergs, Folkert W.
Keating, Brendan J.
van Setten, Jessica
LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title_full LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title_fullStr LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title_full_unstemmed LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title_short LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes
title_sort loftk: a framework for fully automated calculation of predicted loss-of-function variants and genes
topic Software
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9893534/
https://www.ncbi.nlm.nih.gov/pubmed/36732776
http://dx.doi.org/10.1186/s13040-023-00321-5
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