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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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Topological classification of motifs in SL reaction triples. Similarly with SL gene triples in Figure 3, SL reaction triples occur as both disjoint triples (left) and k-connected triples (right). Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
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f4: Topological classification of motifs in SL reaction triples. Similarly with SL gene triples in Figure 3, SL reaction triples occur as both disjoint triples (left) and k-connected triples (right). Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).

Mentions: Reaction SL triples are also pictorially shown as triangles with the three reactions depicted as edge connected nodes (see Figure 4). This graphical representation reveals that only a small number of reactions (i.e. 34) form small clusters (see Figure 4) while most of them (i.e. 129) are joined together into the highly connected large cluster I (i.e. giant component). For example, all three reactions in cluster A shown in Figure 4 are responsible for magnesium transport under different mechanisms. Interestingly, by looking at GPR associations we find that this cluster maps exactly to cluster A of Figure 3 as the two reactions MG2uabcpp and MG2tpp are coded for by the genes mgtA (b4242) and corA (b3816), respectively. The giant component (cluster I) consists of 129 reactions forming 222 SL triples. We used the mixed-integer optimization formulation proposed by Burgard et al (2001) to identify nine alternative reaction sets, each with 23 reactions (i.e. k=23) that allow for all biomass components formation (see Supplementary information). These nine minimal reaction sets spanned 29 different reactions, with seventeen of them present in all nine alternative minimal sets (see Supplementary information).


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

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

Topological classification of motifs in SL reaction triples. Similarly with SL gene triples in Figure 3, SL reaction triples occur as both disjoint triples (left) and k-connected triples (right). 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

f4: Topological classification of motifs in SL reaction triples. Similarly with SL gene triples in Figure 3, SL reaction triples occur as both disjoint triples (left) and k-connected triples (right). Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
Mentions: Reaction SL triples are also pictorially shown as triangles with the three reactions depicted as edge connected nodes (see Figure 4). This graphical representation reveals that only a small number of reactions (i.e. 34) form small clusters (see Figure 4) while most of them (i.e. 129) are joined together into the highly connected large cluster I (i.e. giant component). For example, all three reactions in cluster A shown in Figure 4 are responsible for magnesium transport under different mechanisms. Interestingly, by looking at GPR associations we find that this cluster maps exactly to cluster A of Figure 3 as the two reactions MG2uabcpp and MG2tpp are coded for by the genes mgtA (b4242) and corA (b3816), respectively. The giant component (cluster I) consists of 129 reactions forming 222 SL triples. We used the mixed-integer optimization formulation proposed by Burgard et al (2001) to identify nine alternative reaction sets, each with 23 reactions (i.e. k=23) that allow for all biomass components formation (see Supplementary information). These nine minimal reaction sets spanned 29 different reactions, with seventeen of them present in all nine alternative minimal sets (see Supplementary information).

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