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Genome-scale gene/reaction essentiality and synthetic lethality analysis.

Suthers PF, Zomorrodi A, Maranas CD - Mol. Syst. Biol. (2009)

Bottom Line: Graph representations of these synthetic lethals reveal a variety of motifs ranging from hub-like to highly connected subgraphs providing a birds-eye view of the avenues available for redirecting metabolism and uncovering complex patterns of gene utilization and interdependence.The procedure also enables the use of falsely predicted synthetic lethals for metabolic model curation.By analyzing the functional classifications of the genes involved in synthetic lethals, we reveal surprising connections within and across clusters of orthologous group functional classifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.

ABSTRACT
Synthetic lethals are to pairs of non-essential genes whose simultaneous deletion prohibits growth. One can extend the concept of synthetic lethality by considering gene groups of increasing size where only the simultaneous elimination of all genes is lethal, whereas individual gene deletions are not. We developed optimization-based procedures for the exhaustive and targeted enumeration of multi-gene (and by extension multi-reaction) lethals for genome-scale metabolic models. Specifically, these approaches are applied to iAF1260, the latest model of Escherichia coli, leading to the complete identification of all double and triple gene and reaction synthetic lethals as well as the targeted identification of quadruples and some higher-order ones. Graph representations of these synthetic lethals reveal a variety of motifs ranging from hub-like to highly connected subgraphs providing a birds-eye view of the avenues available for redirecting metabolism and uncovering complex patterns of gene utilization and interdependence. The procedure also enables the use of falsely predicted synthetic lethals for metabolic model curation. By analyzing the functional classifications of the genes involved in synthetic lethals, we reveal surprising connections within and across clusters of orthologous group functional classifications.

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Related in: MedlinePlus

Topological and functional classification of clusters of SL gene pairs. Three types of network motifs are present: disjoint pairs (left); stars, or 1-connected motifs (center); and highly connected subgraphs, or k-connected motifs (right). Genes are color-coded in accordance to the COG (Tatusov et al, 2003) functional categorization. Names of genes are set in italics and the names of non-gene associated reactions are set in roman. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
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f1: Topological and functional classification of clusters of SL gene pairs. Three types of network motifs are present: disjoint pairs (left); stars, or 1-connected motifs (center); and highly connected subgraphs, or k-connected motifs (right). Genes are color-coded in accordance to the COG (Tatusov et al, 2003) functional categorization. Names of genes are set in italics and the names of non-gene associated reactions are set in roman. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).

Mentions: By testing the impact of the removal of one gene at a time on the feasibility of biomass formation, we identified a total of 188 essential genes (15% of total metabolic genes) and five essential non-gene associated reactions (out of a total of 155 present in the model) for the E. coli iAF1260 model (Feist et al, 2007) when incorporating the list of reactions suppressed under aerobic glucose medium conditions. These results are in agreement with the list reported by Feist et al (2007). The relatively small fraction of genes that are essential alludes to the built-in robustness of E. coli metabolism to single-gene deletions, implying that a higher-order gene essentiality analysis is indeed needed to adequately assess metabolic network redundancy. By using the exhaustive enumeration procedure described in the Materials and methods section, we identified 83 genes and four non-gene associated reactions involved in 86 SL pairs (∼0.01% of total possible pairs) as shown in Figure 1. All these SL pairs are next analyzed in detail in terms of their phenotypic, topological and functional impact.


Genome-scale gene/reaction essentiality and synthetic lethality analysis.

Suthers PF, Zomorrodi A, Maranas CD - Mol. Syst. Biol. (2009)

Topological and functional classification of clusters of SL gene pairs. Three types of network motifs are present: disjoint pairs (left); stars, or 1-connected motifs (center); and highly connected subgraphs, or k-connected motifs (right). Genes are color-coded in accordance to the COG (Tatusov et al, 2003) functional categorization. Names of genes are set in italics and the names of non-gene associated reactions are set in roman. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2736653&req=5

f1: Topological and functional classification of clusters of SL gene pairs. Three types of network motifs are present: disjoint pairs (left); stars, or 1-connected motifs (center); and highly connected subgraphs, or k-connected motifs (right). Genes are color-coded in accordance to the COG (Tatusov et al, 2003) functional categorization. Names of genes are set in italics and the names of non-gene associated reactions are set in roman. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
Mentions: By testing the impact of the removal of one gene at a time on the feasibility of biomass formation, we identified a total of 188 essential genes (15% of total metabolic genes) and five essential non-gene associated reactions (out of a total of 155 present in the model) for the E. coli iAF1260 model (Feist et al, 2007) when incorporating the list of reactions suppressed under aerobic glucose medium conditions. These results are in agreement with the list reported by Feist et al (2007). The relatively small fraction of genes that are essential alludes to the built-in robustness of E. coli metabolism to single-gene deletions, implying that a higher-order gene essentiality analysis is indeed needed to adequately assess metabolic network redundancy. By using the exhaustive enumeration procedure described in the Materials and methods section, we identified 83 genes and four non-gene associated reactions involved in 86 SL pairs (∼0.01% of total possible pairs) as shown in Figure 1. All these SL pairs are next analyzed in detail in terms of their phenotypic, topological and functional impact.

Bottom Line: Graph representations of these synthetic lethals reveal a variety of motifs ranging from hub-like to highly connected subgraphs providing a birds-eye view of the avenues available for redirecting metabolism and uncovering complex patterns of gene utilization and interdependence.The procedure also enables the use of falsely predicted synthetic lethals for metabolic model curation.By analyzing the functional classifications of the genes involved in synthetic lethals, we reveal surprising connections within and across clusters of orthologous group functional classifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.

ABSTRACT
Synthetic lethals are to pairs of non-essential genes whose simultaneous deletion prohibits growth. One can extend the concept of synthetic lethality by considering gene groups of increasing size where only the simultaneous elimination of all genes is lethal, whereas individual gene deletions are not. We developed optimization-based procedures for the exhaustive and targeted enumeration of multi-gene (and by extension multi-reaction) lethals for genome-scale metabolic models. Specifically, these approaches are applied to iAF1260, the latest model of Escherichia coli, leading to the complete identification of all double and triple gene and reaction synthetic lethals as well as the targeted identification of quadruples and some higher-order ones. Graph representations of these synthetic lethals reveal a variety of motifs ranging from hub-like to highly connected subgraphs providing a birds-eye view of the avenues available for redirecting metabolism and uncovering complex patterns of gene utilization and interdependence. The procedure also enables the use of falsely predicted synthetic lethals for metabolic model curation. By analyzing the functional classifications of the genes involved in synthetic lethals, we reveal surprising connections within and across clusters of orthologous group functional classifications.

Show MeSH
Related in: MedlinePlus