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Genomics illuminates parasite biology

An esteemed colleague recently commented that “genomics has failed biology”, and parasitology in particular1. As genome biologists, we would like to respectfully disagree. Here, we present some recent examples in which, in our opinion, genomics and associated technologies have provided important new insights into the biology of Plasmodium spp.

Artemisinin derivatives are highly effective at treating malaria in humans, and early signs of emerging resistance in South East Asia are cause for grave concern. Until recently, the molecular basis of this drug resistance was unknown. Based on the genomic analysis of drug-adapted parasites that had been generated in vitro, Ariey and colleagues managed to identify a single gene, kelch13, of previously unknown function in Plasmodium falciparum, as apparently being involved in conferring reduced drug susceptibility2. The association of genomic variation in this gene with emerging artemisinin resistance was confirmed by DNA sequencing of malaria parasites from hundreds of patient samples2. Genomic variation in kelch13 has since been used as a crucial molecular marker to track and investigate the spread of emerging artemisinin resistance in the field3. Moreover, it has already been possible to conclude that relevant mutations in this gene have arisen independently in multiple locations4.

In addition, the causal relationship between a particular single-nucleotide mutation in kelch13 and artemisinin resistance has recently been demonstrated by genome editing using the newly established CRISPR–Cas9 (clustered, regularly interspaced short palindromic repeats–CRISPR-associated protein 9) system in P. falciparum5. This experimental technique is a powerful new 'weapon' in the experimental genomics 'arsenal', and knowledge of the genome sequence of an organism obviously facilitates the design of appropriate guide RNAs. Genome editing seems to be poised to greatly simplify and accelerate the elucidation of gene function in malaria parasites. This is particularly important as alternative, established approaches such as allele replacement are exceedingly difficult and time consuming.

Credit: NPG

A different example of the ability of genomics to provide insights into malaria biology is seen in recent reports on the dynamics and biology of recurrent and mixed concurrent malaria infections. Bright and co-workers6 generated whole-genome sequence data from three successive Plasmodium vivax infections from a single patient and concluded that the initial infection was polyclonal, whereas the two recurrent infections were monoclonal and were most probably caused by reactivated hypnozoites that had been dormant in the liver. Notably, the analysis of eight microsatellite and other genetic markers would have led to the incorrect conclusion that the populations of the two relapse infections were nearly identical. By contrast, whole-genome sequence data provided information about thousands of variant positions and showed that the parasites in all three infections were meiotic siblings that developed in the infected mosquito after fertilization. A total of 21 recombination breakpoints were identified across the genome. In another study, single-cell genomic techniques were used to dissect multigenotype infections of P. falciparum or P. vivax from individual patients7. Together, these studies show that genomics techniques can: distinguish malaria relapse infections from reinfections; ascertain the within-host diversity of parasites in both recurrent and concurrent infections; be used to examine the in vivo composition of mixed infections directly from patient samples and without the potential bias that is introduced by subsequent in vitro cultivation; and be used to investigate non-cultivable parasites.

As a discipline, genomics has its limitations, and its benefits may be greatest when it is combined with smart experimental designs and 'old school' biological experimentation. But in our opinion, far from having stopped studying what genes do, as suggested by Viney1, genomics and the diverse applications of its principal technology — high-throughput sequencing — have already been proven to wield the power to greatly accelerate and directly enable the discovery of new biology in malaria parasites and other microorganisms.

References

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    Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371, 411–423 (2014).

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Correspondence to Bernardo J. Foth or Thomas D. Otto.

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Foth, B., Otto, T. Genomics illuminates parasite biology. Nat Rev Microbiol 12, 727 (2014). https://doi.org/10.1038/nrmicro3368

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