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Evolutionary Conservation of Bacterial Essential Metabolic Genes across All Bacterial Culture Media.

Ish-Am O, Kristensen DM, Ruppin E - PLoS ONE (2015)

Bottom Line: One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance.Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media.We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied.

View Article: PubMed Central - PubMed

Affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance. Essential genes, whose knockout leads to a lethal phenotype are considered of high functional importance, yet whether they are truly more conserved than nonessential genes has been the topic of much debate, fuelled by a host of contradictory findings. Here we conduct the first large-scale study utilizing genome-scale metabolic modeling and spanning many bacterial species, which aims to answer this question. Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media. We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied. The results show that bacteria do exhibit an overall tendency for differential conservation of their essential genes vs. their non-essential ones, yet this tendency is highly variable across species. We show that the model bacterium E. coli K12 may or may not exhibit differential conservation of essential genes depending on its growth medium, shedding light on previous experimental studies showing opposite trends.

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Algorithm for finding a medium with the maximal separation between dN/dS values of essential and nonessential genes.Metabolic models (a) are first preprocessed and databases added to them, to support fast computation of essential genes (b). Simulated Annealing (c) is the first stage of optimization and the resulting medium found is further purified from redundant compounds (d), resulting in the two desired media: those which maximize the differential conservation of essential genes (e) and those which maximize the differential conservation of the nonessential genes (f).
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pone.0123785.g001: Algorithm for finding a medium with the maximal separation between dN/dS values of essential and nonessential genes.Metabolic models (a) are first preprocessed and databases added to them, to support fast computation of essential genes (b). Simulated Annealing (c) is the first stage of optimization and the resulting medium found is further purified from redundant compounds (d), resulting in the two desired media: those which maximize the differential conservation of essential genes (e) and those which maximize the differential conservation of the nonessential genes (f).

Mentions: Media Variation Analysis (MVA) is a novel generic approach for investigating the behavior of a metabolic model trait, by searching for its minimal and maximal values across all possible media—thus identifying the trait’s feasible range. Applied to the question at hand, Differential Conservation MVA will look for media that maximize and media that minimize the differential conservation of essential genes for a given species. Our algorithm for implementing Differential Conservation MVA is termed Evolutionary Conservation Of Essentiality Driven Search (ECOEDS). The algorithm consists of two optimization stages; it receives as inputs a genome scale metabolic model (GSMM), a random starting medium and evolutionary conservation scores for the model genes. ECOEDS outputs a medium, such that the essential and nonessential gene sets identified on it, have the maximal possible separation between their evolutionary conservation scores. ECOEDS searches for such a separation in both directions; once to find media where essential genes are most differentially conserved vs. the nonessential ones, and once, in the inverse direction, finding media where the nonessential genes are maximally conserved vs. the essential ones (Fig 1, Methods 5.1). As part of ECOEDS we have greatly accelerated the running time of existing methods for calculating the set of GSMM essential genes. Among other things, this has enabled us to identify all model genes that are essential under at least one medium (see APE in Methods 5.3 and S1 File 1.2)—a problem for which we are not aware of any current solutions.


Evolutionary Conservation of Bacterial Essential Metabolic Genes across All Bacterial Culture Media.

Ish-Am O, Kristensen DM, Ruppin E - PLoS ONE (2015)

Algorithm for finding a medium with the maximal separation between dN/dS values of essential and nonessential genes.Metabolic models (a) are first preprocessed and databases added to them, to support fast computation of essential genes (b). Simulated Annealing (c) is the first stage of optimization and the resulting medium found is further purified from redundant compounds (d), resulting in the two desired media: those which maximize the differential conservation of essential genes (e) and those which maximize the differential conservation of the nonessential genes (f).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403854&req=5

pone.0123785.g001: Algorithm for finding a medium with the maximal separation between dN/dS values of essential and nonessential genes.Metabolic models (a) are first preprocessed and databases added to them, to support fast computation of essential genes (b). Simulated Annealing (c) is the first stage of optimization and the resulting medium found is further purified from redundant compounds (d), resulting in the two desired media: those which maximize the differential conservation of essential genes (e) and those which maximize the differential conservation of the nonessential genes (f).
Mentions: Media Variation Analysis (MVA) is a novel generic approach for investigating the behavior of a metabolic model trait, by searching for its minimal and maximal values across all possible media—thus identifying the trait’s feasible range. Applied to the question at hand, Differential Conservation MVA will look for media that maximize and media that minimize the differential conservation of essential genes for a given species. Our algorithm for implementing Differential Conservation MVA is termed Evolutionary Conservation Of Essentiality Driven Search (ECOEDS). The algorithm consists of two optimization stages; it receives as inputs a genome scale metabolic model (GSMM), a random starting medium and evolutionary conservation scores for the model genes. ECOEDS outputs a medium, such that the essential and nonessential gene sets identified on it, have the maximal possible separation between their evolutionary conservation scores. ECOEDS searches for such a separation in both directions; once to find media where essential genes are most differentially conserved vs. the nonessential ones, and once, in the inverse direction, finding media where the nonessential genes are maximally conserved vs. the essential ones (Fig 1, Methods 5.1). As part of ECOEDS we have greatly accelerated the running time of existing methods for calculating the set of GSMM essential genes. Among other things, this has enabled us to identify all model genes that are essential under at least one medium (see APE in Methods 5.3 and S1 File 1.2)—a problem for which we are not aware of any current solutions.

Bottom Line: One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance.Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media.We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied.

View Article: PubMed Central - PubMed

Affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
One of the basic postulates of molecular evolution is that functionally important genes should evolve slower than genes of lesser significance. Essential genes, whose knockout leads to a lethal phenotype are considered of high functional importance, yet whether they are truly more conserved than nonessential genes has been the topic of much debate, fuelled by a host of contradictory findings. Here we conduct the first large-scale study utilizing genome-scale metabolic modeling and spanning many bacterial species, which aims to answer this question. Using the novel Media Variation Analysis, we examine the range of conservation of essential vs. nonessential metabolic genes in a given species across all possible media. We are thus able to obtain for the first time, exact upper and lower bounds on the levels of differential conservation of essential genes for each of the species studied. The results show that bacteria do exhibit an overall tendency for differential conservation of their essential genes vs. their non-essential ones, yet this tendency is highly variable across species. We show that the model bacterium E. coli K12 may or may not exhibit differential conservation of essential genes depending on its growth medium, shedding light on previous experimental studies showing opposite trends.

Show MeSH
Related in: MedlinePlus