Abstract
BackgroundNew drug targets are urgently needed for parasites of socio-economic importance. Genes that are essential for parasite survival are highly desirable targets, but information on these genes is lacking, as gene knockouts or knockdowns are difficult to perform in many species of parasites. We examined the applicability of large-scale essentiality information from four model eukaryotes, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus and Saccharomyces cerevisiae, to discover essential genes in each of their genomes. Parasite genes that lack orthologues in their host are desirable as selective targets, so we also examined prediction of essential genes within this subset.ResultsCross-species analyses showed that the evolutionary conservation of genes and the presence of essential orthologues are each strong predictors of essentiality in eukaryotes. Absence of paralogues was also found to be a general predictor of increased relative essentiality. By combining several orthology and essentiality criteria one can select gene sets with up to a five-fold enrichment in essential genes compared with a random selection. We show how quantitative application of such criteria can be used to predict a ranked list of potential drug targets from Ancylostoma caninum and Haemonchus contortus - two blood-feeding strongylid nematodes, for which there are presently limited sequence data but no functional genomic tools.ConclusionsThe present study demonstrates the utility of using orthology information from multiple, diverse eukaryotes to predict essential genes. The data also emphasize the challenge of identifying essential genes among those in a parasite that are absent from its host.
Highlights
New drug targets are urgently needed for parasites of socio-economic importance
Because the genes chosen for knockout analysis in mice were selected to address specific phenotypic questions, it is possible that this nonrandom collection may introduce some bias towards or away from genes that are expected to be essential
To test whether having essential orthologues in S. cerevisiae predicted essentiality in the corresponding C. elegans genes, we identified orthology groups containing non-paralogous C. elegans and S. cerevisiae genes that had been subjected to essentiality analysis
Summary
New drug targets are urgently needed for parasites of socio-economic importance. Genes that are essential for parasite survival are highly desirable targets, but information on these genes is lacking, as gene knockouts or knockdowns are difficult to perform in many species of parasites. Essentiality, is difficult to define because its application is necessarily restricted to the experimental conditions being tested Despite this limitation, indispensability under a defined laboratory condition can be a useful starting point for identifying biological processes that are likely to be crucial for the survival of an organism under natural conditions. Few infectious agents are currently amenable to whole-genome approaches for the experimental testing of essentiality, such that promising candidate drug targets must be individually validated genetically. This is true of eukaryotic parasites, for which the genetic tools to characterize drug or vaccine targets are often limited, and absent for many others
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