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Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes
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Summary
Malaria parasites have around 5,000 genes. Only a small proportion of these genes have homologs in well-studied model systems, and as a result the function of many is unclear. We performed the first genome-scale genetic screen in a malaria parasite.
We used linear DNA vectors which integrate into the Plasmodium genome. We were able to create vectors to target around half of all Plasmodium berghei genes. Each vector integrates into the parasite genome in the place of its target gene. It carries a drug resistance marker that enables us to select only parasites in which a gene has been deleted. The vectors also carry a "genetic barcode" into the parasite genome. We can amplify all of the barcodes from a mixture of thousands of parasites and read them out using DNA sequencing. This allowed us to measure the growth of many different mutants in a mixed population of parasites. By doing so we could work out whether deleting a gene had a profound effect on parasite growth ("essential" gene), a more moderate effect ("slow" gene) or no evidence of a change in growth rate ("dipsensable gene").
We unexpectedly found that most genes are important for parasite growth, even in a single stage of parasite growth - in the blood of an infected host. This is a higher proportion of essential genes than has been seen in any other organism screens and suggests that there may be more multi-stage drug targets encoded by the parasite than was previously supposed.
All phenotypes are available on the PlasmoGEM site: http://plasmogem.sanger.ac.uk/phenotypes
Summary
The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.
Graphical Abstract
Highlights
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Two-thirds of Plasmodium berghei genes contribute to normal blood stage growth
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The core genome of malaria parasites is highly optimized for rapid host colonization
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Essential parasite genes and pathways are identified for drug target prioritization
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Low functional redundancy reflects the constant environment encountered by a parasite
Abstract
An in vivo genetic screen in a mouse model of malaria reveals the essential genes and pathways required by Plasmodium parasite, with a surprising two-thirds of the genome being required for normal parasite growth in the blood.
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Most cited references37
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