A combination of genes results in malaria drug resistance

The largest genome-wide study of the malaria parasite finds that the drug resistance occurs because of a key mutation happening on top of 'background' mutations which make the parasite more likely to develop drug resistance later.

The study, involving researchers at the University of Oxford, found kelch13 gene mutations that seem to work with a set of 'background' mutations in four other genes to support resistance to artemisinin, the drug that currently works best against malaria.

There are many kelch13 mutations associated with artemisinin resistance, with new variants emerging all the time. This makes it difficult to use kelch13 alone to track the emergence of drug-resistant strains.

Instead, the study (published in Nature Genetics) suggests that monitoring populations of the malaria parasite Plasmodium falciparum for specific mutations in four other genes - fd, arps10, mdr2, and crt genes - could be more useful. This information can help target high-risk regions before resistant parasites take hold.

'Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance - until mutations occurred in the kelch13 gene,' explains Dr Roberto Amato, a first author and Research Associate at Oxford University's Wellcome Trust Centre for Human Genetics and the the Wellcome Trust Sanger Institute. 'It's similar to what we see with pre-cancerous cells which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.'

The global research collaboration analysed 1612 samples from 15 locations in Southeast Asia and Africa to find these results. By comparing parasites from multiple Southeast Asian countries, the scientists also found that different kelch13 mutations are localised within relatively well-defined geographical areas.

Instead, the most widespread kelch13 mutation, C580Y, appears to have emerged independently on several occasions. For example, parasites along the Thailand-Myanmar border appear to have acquired this C580Y mutation separately from those in Cambodia and Vietnam. However, even though these strains are genetically distinct, they both have the same genetic background mutations.

By contrast, kelch13 mutations were rare in Africa, and not associated with artemisinin resistance. This was because they did not have genetic background which appears to be the prerequisite for drug-resistance. This is reassuring for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur.

There remain many unanswered questions. 'We don't yet know the role of these background mutations,' says Dr Olivo Miotto, a first author and Senior Informatics Fellow at MORU and the Centre for Genomics and Global Health. 'Some may not affect drug resistance directly, but rather provide an environment where drug resistance mutations are tolerated. Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.'

A report of the research, entitled Genetic architecture of artemisinin resistant Plasmodium falciparum, is published in Nature Genetics.