First large-scale study uncovers malaria gene function and potential drug targets

The success of the malaria parasite could be attributed to it only having essential genes, according to research from Wellcome Trust Sanger Institute (Cambridge, UK) and collaborators. In the first large-scale study of malaria gene function the team analyzed more than half of the genes in malaria genome, discovering potential new targets for malaria drugs.

Malaria’s genetics has previously been challenging to decipher, as almost half of its genes have no homologs in other organisms making it difficult to determine their function. This study, published recently in Cell, is the first to provide experimental evidence suggesting the function of many of these genes, thanks to a new method.

The team studied the parasite Plasmodium bergheigenes, knocking out more than half of the genome – 2578 genes in total – and giving each knockout a specific DNA barcode. DNA barcoding tags specific genes with molecular barcodes, enabling the team to identify individual mutants and measure the growth of the modified pathogen via next-generation sequencing.

Author, Oliver Billker, from the Wellcome Trust Sanger Institute, explained: “This work was made possible by a new method that enabled us to investigate more than 2500 genes in a single study – more than the entire research community has studied over the past two decades. We believe that this method can be used to build a deep understanding of many unknown aspects of malaria biology, and radically speed up our understanding of gene function and prioritization of drug targets.”

The team discovered that two-thirds of the genes they identified were essential for survival, the largest proportion reported in any organism to date. In addition, they systematically demonstrated that Plasmodium bergheigenes can easily switch off genes that might produce proteins alerting the host’s immune system to its presence, presenting a challenging issue for those working on malaria vaccine development to overcome.

Author Julian Rayner (Wellcome Trust Sanger Institute) concluded: “We knew from previous work that on its surface the malaria parasite has many dispensable parts. Our study found that below the surface the parasite is more of a Formula 1 race car than a clunky people carrier. The parasite is fine-tuned and retains the absolute essential genes needed for growth. This is both good and bad: the bad news is it can easily get rid of the genes behind the targets we are trying to design vaccines for, but the flip side is there are many more essential gene targets for new drugs than we previously thought.”



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