Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast

Abstract 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 o...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Deya Alzoubi, Abdelmoneim Amer Desouki, Martin J. Lercher
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c0f1bab04c3e40feba14e3a4d52be1dc
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c0f1bab04c3e40feba14e3a4d52be1dc
record_format	dspace
spelling	oai:doaj.org-article:c0f1bab04c3e40feba14e3a4d52be1dc2021-12-02T16:08:05ZFlux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast10.1038/s41598-019-47935-62045-2322https://doaj.org/article/c0f1bab04c3e40feba14e3a4d52be1dc2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47935-6https://doaj.org/toc/2045-2322Abstract 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.Deya AlzoubiAbdelmoneim Amer DesoukiMartin J. LercherNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-9 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Deya Alzoubi Abdelmoneim Amer Desouki Martin J. Lercher Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast
description	Abstract 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	article
author	Deya Alzoubi Abdelmoneim Amer Desouki Martin J. Lercher
author_facet	Deya Alzoubi Abdelmoneim Amer Desouki Martin J. Lercher
author_sort	Deya Alzoubi
title	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_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_sort	flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/c0f1bab04c3e40feba14e3a4d52be1dc
work_keys_str_mv	AT deyaalzoubi fluxbalanceanalysiswithorwithoutmolecularcrowdingfailstopredicttwothirdsofexperimentallyobservedepistasisinyeast AT abdelmoneimamerdesouki fluxbalanceanalysiswithorwithoutmolecularcrowdingfailstopredicttwothirdsofexperimentallyobservedepistasisinyeast AT martinjlercher fluxbalanceanalysiswithorwithoutmolecularcrowdingfailstopredicttwothirdsofexperimentallyobservedepistasisinyeast
_version_	1718384619173183488

Flux balance analysis with or without molecular crowding fails to predict two thirds of experimentally observed epistasis in yeast

Ejemplares similares