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Knowledge of the perturbation design is essential for accurate gene regulatory network inference
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0001-8284-356x
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0002-6362-0659
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Number of Authors: 62022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 16531Article in journal (Refereed) Published
Abstract [en]

The gene regulatory network (GRN) of a cell executes genetic programs in response to environmental and internal cues. Two distinct classes of methods are used to infer regulatory interactions from gene expression: those that only use observed changes in gene expression, and those that use both the observed changes and the perturbation design, i.e. the targets used to cause the changes in gene expression. Considering that the GRN by definition converts input cues to changes in gene expression, it may be conjectured that the latter methods would yield more accurate inferences but this has not previously been investigated. To address this question, we evaluated a number of popular GRN inference methods that either use the perturbation design or not. For the evaluation we used targeted perturbation knockdown gene expression datasets with varying noise levels generated by two different packages, GeneNetWeaver and GeneSpider. The accuracy was evaluated on each dataset using a variety of measures. The results show that on all datasets, methods using the perturbation design matrix consistently and significantly outperform methods not using it. This was also found to be the case on a smaller experimental dataset from E. coli. Targeted gene perturbations combined with inference methods that use the perturbation design are indispensable for accurate GRN inference.

Place, publisher, year, edition, pages
2022. Vol. 12, no 1, article id 16531
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-210751DOI: 10.1038/s41598-022-19005-xISI: 000865282300021PubMedID: 36192495Scopus ID: 2-s2.0-85139173448OAI: oai:DiVA.org:su-210751DiVA, id: diva2:1706460
Available from: 2022-10-26 Created: 2022-10-26 Last updated: 2023-09-14Bibliographically approved
In thesis
1. In silico modelling for refining gene regulatory network inference
Open this publication in new window or tab >>In silico modelling for refining gene regulatory network inference
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gene regulation is at the centre of all cellular functions, regulating the cell's healthy and pathological responses. The interconnected system of regulatory interactions is known as the gene regulatory network (GRN), where genes influence each other to maintain strict and robust control. Today a large number of methods exist for inferring GRNs, which necessitates benchmarking to determine which method is most suitable for a specific goal. Paper I presents such a benchmark focusing on the effect of using known perturbations to infer GRNs. 

A further challenge when studying GRNs is that experimental data contains high levels of noise and that artefacts may be introduced by the experiment itself. The LSCON method was developed in paper II to reduce the effect of one such artefact that can occur if the expression of a gene shows no or minimal change across most or all experiments. 

 With few fully determined biological GRNs available, it is problematic to use these to evaluate an inference method's correctness. Instead, the GRN field relies on simulated data, using a known GRN and generating the corresponding data. When simulating GRNs, capturing the topological properties of the biological GRN is vital. The FFLatt algorithm was developed in paper III to create scale-free, feed-forward loop motif-enriched GRNs, capturing two of the most prominent topological features in biological GRNs. 

 Once a high-quality GRN is obtained, the next step is to simulate gene expression data corresponding to the GRN. In paper IV, building on the FFLatt method, an open-source Python simulation tool called GeneSNAKE was developed to generate expression data for benchmarking purposes. GeneSNAKE allows the user to control a wide range of network and data properties and improves on previous tools by featuring a variety of perturbation schemes along with the ability to control noise and modify the perturbation strength.

Place, publisher, year, edition, pages
Stockohlm: Department of Biochemistry and Biophysics, Stockholm University, 2023. p. 49
Keywords
Gene regulatory networks, simulation, benchmarking, method development
National Category
Bioinformatics and Systems Biology
Research subject
Biochemistry towards Bioinformatics
Identifiers
urn:nbn:se:su:diva-221155 (URN)978-91-8014-504-6 (ISBN)978-91-8014-505-3 (ISBN)
Public defence
2023-10-27, Air and Fire, SciLifeLab, Tomtebodavägen 23A, Solna, 14:00 (English)
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Supervisors
Available from: 2023-10-04 Created: 2023-09-14 Last updated: 2023-09-29Bibliographically approved

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Seçilmiş, DenizHillerton, ThomasSonnhammer, Erik L. L.

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