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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 classification of motifs in SL gene triples. Both disjoint triples (left) and k-connected triples (right) are seen. Names of genes are set in italics and the names of non-gene associated reactions are set in roman type. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
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f3: Topological classification of motifs in SL gene triples. Both disjoint triples (left) and k-connected triples (right) are seen. Names of genes are set in italics and the names of non-gene associated reactions are set in roman type. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).

Mentions: Similarly to SL gene pairs, a variety of different topological motifs emerge when all SL gene triples are depicted. Note that we pictorially represented them using a triangle with the three members forming the SL triple depicted as edge connected nodes (see Figure 3). Figure 3 shows a number of disjoint triples and k-connected clusters of different size. An example of a disjoint triple is cluster A where two genes mgtA (b4242) and corA (b3816) form a SL triple with a non-gene associated reaction (i.e. Mg2t3_2pp (magnesium (Mg+2) transport in/out through proton antiport (periplasm)). All the components of this cluster are responsible for magnesium transport under different mechanisms. Cluster H is an example of a 1-connected cluster, where the presence of at least one gene (i.e. pitA or pitB) can prevent lethality. As seen in Figure 3, unlike SL gene pairs, only a small number of SL gene triples participate in disjoint triples. Instead the majority of them form complex k-connected clusters (e.g. clusters K, L and M). We used the mixed-integer optimization formulation proposed by Burgard et al (2001) to identify the minimum required set of genes (and non-gene associated reactions) in each of these clusters to prevent lethality. Surprisingly, for clusters K and L we found that the minimal sets contained only a single member (i.e. k=1). For example, by maintaining only the activity of purT (b1849) in cluster K or the activity of either purU (b1232) or purN (b2500) in cluster L, we can prevent lethality. Unlike clusters K and L, cluster M has fourteen alternative minimal sets each containing nine members (i.e. k=9) that need to be active to prevent lethality (see Supplementary information for complete listing).


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 gene triples. Both disjoint triples (left) and k-connected triples (right) are seen. Names of genes are set in italics and the names of non-gene associated reactions are set in roman type. 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

f3: Topological classification of motifs in SL gene triples. Both disjoint triples (left) and k-connected triples (right) are seen. Names of genes are set in italics and the names of non-gene associated reactions are set in roman type. Note that all the reaction abbreviations follow those in iAF1260 (Feist et al, 2007).
Mentions: Similarly to SL gene pairs, a variety of different topological motifs emerge when all SL gene triples are depicted. Note that we pictorially represented them using a triangle with the three members forming the SL triple depicted as edge connected nodes (see Figure 3). Figure 3 shows a number of disjoint triples and k-connected clusters of different size. An example of a disjoint triple is cluster A where two genes mgtA (b4242) and corA (b3816) form a SL triple with a non-gene associated reaction (i.e. Mg2t3_2pp (magnesium (Mg+2) transport in/out through proton antiport (periplasm)). All the components of this cluster are responsible for magnesium transport under different mechanisms. Cluster H is an example of a 1-connected cluster, where the presence of at least one gene (i.e. pitA or pitB) can prevent lethality. As seen in Figure 3, unlike SL gene pairs, only a small number of SL gene triples participate in disjoint triples. Instead the majority of them form complex k-connected clusters (e.g. clusters K, L and M). We used the mixed-integer optimization formulation proposed by Burgard et al (2001) to identify the minimum required set of genes (and non-gene associated reactions) in each of these clusters to prevent lethality. Surprisingly, for clusters K and L we found that the minimal sets contained only a single member (i.e. k=1). For example, by maintaining only the activity of purT (b1849) in cluster K or the activity of either purU (b1232) or purN (b2500) in cluster L, we can prevent lethality. Unlike clusters K and L, cluster M has fourteen alternative minimal sets each containing nine members (i.e. k=9) that need to be active to prevent lethality (see Supplementary information for complete listing).

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