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Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast
Computational predictions of double gene knockout effects by flux balance analysis (FBA) have been used to characterized genome-wide patterns of epistasis in microorganisms. However, it is unclear how in silico predictions are related to in vivo epistasis, as FBA predicted only a minority of experim...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694147/ https://www.ncbi.nlm.nih.gov/pubmed/31413270 http://dx.doi.org/10.1038/s41598-019-47935-6 |
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author | Alzoubi, Deya Desouki, Abdelmoneim Amer Lercher, Martin J. |
author_facet | Alzoubi, Deya Desouki, Abdelmoneim Amer Lercher, Martin J. |
author_sort | Alzoubi, Deya |
collection | PubMed |
description | Computational predictions of double gene knockout effects by flux balance analysis (FBA) have been used to characterized genome-wide patterns of epistasis in microorganisms. However, it is unclear how in silico predictions are related to in vivo epistasis, as FBA predicted only a minority of experimentally observed genetic interactions between non-essential metabolic genes in yeast. Here, we perform a detailed comparison of yeast experimental epistasis data to predictions generated with different constraint-based metabolic modeling algorithms. The tested methods comprise standard FBA; a variant of MOMA, which was specifically designed to predict fitness effects of non-essential gene knockouts; and two alternative implementations of FBA with macro-molecular crowding, which account approximately for enzyme kinetics. The number of interactions uniquely predicted by one method is typically larger than its overlap with any alternative method. Only 20% of negative and 10% of positive interactions jointly predicted by all methods are confirmed by the experimental data; almost all unique predictions appear to be false. More than two thirds of epistatic interactions are undetectable by any of the tested methods. The low prediction accuracies indicate that the physiology of yeast double metabolic gene knockouts is dominated by processes not captured by current constraint-based analysis methods. |
format | Online Article Text |
id | pubmed-6694147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66941472019-08-19 Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast Alzoubi, Deya Desouki, Abdelmoneim Amer Lercher, Martin J. Sci Rep Article Computational predictions of double gene knockout effects by flux balance analysis (FBA) have been used to characterized genome-wide patterns of epistasis in microorganisms. However, it is unclear how in silico predictions are related to in vivo epistasis, as FBA predicted only a minority of experimentally observed genetic interactions between non-essential metabolic genes in yeast. Here, we perform a detailed comparison of yeast experimental epistasis data to predictions generated with different constraint-based metabolic modeling algorithms. The tested methods comprise standard FBA; a variant of MOMA, which was specifically designed to predict fitness effects of non-essential gene knockouts; and two alternative implementations of FBA with macro-molecular crowding, which account approximately for enzyme kinetics. The number of interactions uniquely predicted by one method is typically larger than its overlap with any alternative method. Only 20% of negative and 10% of positive interactions jointly predicted by all methods are confirmed by the experimental data; almost all unique predictions appear to be false. More than two thirds of epistatic interactions are undetectable by any of the tested methods. The low prediction accuracies indicate that the physiology of yeast double metabolic gene knockouts is dominated by processes not captured by current constraint-based analysis methods. Nature Publishing Group UK 2019-08-14 /pmc/articles/PMC6694147/ /pubmed/31413270 http://dx.doi.org/10.1038/s41598-019-47935-6 Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Alzoubi, Deya Desouki, Abdelmoneim Amer Lercher, Martin J. Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title | Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title_full | Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title_fullStr | Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title_full_unstemmed | Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title_short | Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
title_sort | flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694147/ https://www.ncbi.nlm.nih.gov/pubmed/31413270 http://dx.doi.org/10.1038/s41598-019-47935-6 |
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