Using gene essentiality and synthetic lethality information to correct yeast and CHO cell genome-scale models

Ratul Chowdhury, Anupam Chowdhury, Costas D. Maranas

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Essentiality (ES) and Synthetic Lethality (SL) information identify combination of genes whose deletion inhibits cell growth. This information is important for both identifying drug targets for tumor and pathogenic bacteria suppression and for flagging and avoiding gene deletions that are non-viable in biotechnology. In this study, we performed a comprehensive ES and SL analysis of two important eukaryotic models (S. cerevisiae and CHO cells) using a bilevel optimization approach introduced earlier. Information gleaned from this study is used to propose specific model changes to remedy inconsistent with data model predictions. Even for the highly curated Yeast 7.11 model we identified 50 changes (metabolic and GPR) leading to the correct prediction of an additional 28% of essential genes and 36% of synthetic lethals along with a 53% reduction in the erroneous identification of essential genes. Due to the paucity of mutant growth phenotype data only 12 changes were made for the CHO 1.2 model leading to an additional correctly predicted 11 essential and eight non-essential genes. Overall, we find that CHO 1.2 was 76% less accurate than the Yeast 7.11 metabolic model in predicting essential genes. Based on this analysis, 14 (single and double deletion) maximally informative experiments are suggested to improve the CHO cell model by using information from a mouse metabolic model. This analysis demonstrates the importance of single and multiple knockout phenotypes in assessing and improving model reconstructions. The advent of techniques such as CRISPR opens the door for the global assessment of eukaryotic models.

Original languageEnglish (US)
Article numberA01
Pages (from-to)536-570
Number of pages35
JournalMetabolites
Volume5
Issue number4
DOIs
StatePublished - Jan 1 2015

Fingerprint

CHO Cells
Essential Genes
Yeast
Genes
Yeasts
Gene Deletion
Genome
Clustered Regularly Interspaced Short Palindromic Repeats
Phenotype
Biotechnology
Growth
Saccharomyces cerevisiae
Bacteria
Pharmaceutical Preparations
Ground penetrating radar systems
Synthetic Lethal Mutations
Neoplasms
Cell growth
Data structures
Tumors

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

Cite this

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abstract = "Essentiality (ES) and Synthetic Lethality (SL) information identify combination of genes whose deletion inhibits cell growth. This information is important for both identifying drug targets for tumor and pathogenic bacteria suppression and for flagging and avoiding gene deletions that are non-viable in biotechnology. In this study, we performed a comprehensive ES and SL analysis of two important eukaryotic models (S. cerevisiae and CHO cells) using a bilevel optimization approach introduced earlier. Information gleaned from this study is used to propose specific model changes to remedy inconsistent with data model predictions. Even for the highly curated Yeast 7.11 model we identified 50 changes (metabolic and GPR) leading to the correct prediction of an additional 28{\%} of essential genes and 36{\%} of synthetic lethals along with a 53{\%} reduction in the erroneous identification of essential genes. Due to the paucity of mutant growth phenotype data only 12 changes were made for the CHO 1.2 model leading to an additional correctly predicted 11 essential and eight non-essential genes. Overall, we find that CHO 1.2 was 76{\%} less accurate than the Yeast 7.11 metabolic model in predicting essential genes. Based on this analysis, 14 (single and double deletion) maximally informative experiments are suggested to improve the CHO cell model by using information from a mouse metabolic model. This analysis demonstrates the importance of single and multiple knockout phenotypes in assessing and improving model reconstructions. The advent of techniques such as CRISPR opens the door for the global assessment of eukaryotic models.",
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Using gene essentiality and synthetic lethality information to correct yeast and CHO cell genome-scale models. / Chowdhury, Ratul; Chowdhury, Anupam; Maranas, Costas D.

In: Metabolites, Vol. 5, No. 4, A01, 01.01.2015, p. 536-570.

Research output: Contribution to journalArticle

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