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Genetic architecture of resistance

22 January 2015

Study identifies 26 independent mutations on the kelch 13 gene, from 15 different locations in Southeast Asia, were associated with a delayed rate of malaria parasite clearance – a clear indicator of malaria drug resistance.

In January 2014, researchers found that genetic mutations on the kelch13 gene of the malaria parasite genome act as key indicators of resistance to the antimalarial, artemisinin. Later in 2014, results from the Tracking Resistance to Artemisinin Collaborations found that resistant-parasites with these kelch13 mutations were firmly established in many parts of Southeast Asia. Today (19 January 2015), a study published in Nature Genetics reveals the complicated genetic architecture that enables the p. falciparum malaria parasite to acquire this drug resistance.

The team identified that 26 independent mutations on the kelch 13 gene, from 15 different locations in Southeast Asia, were associated with a delayed rate of malaria parasite clearance – a clear indicator of malaria drug resistance. A closer look at the parasite genomes found that these mutations function hand-in-hand with a set of background mutations on four other genes across the genome, thus enabling the parasite to acquire resistance to artemisinin combination therapies (ACTs).

“These data serve as a reminder of how crucial surveillance and elimination programmes are,” says Professor Dominic Kwiatkowski, Head of the Malaria Programme at the Wellcome Trust Sanger Institute and Professor of Genomics & Global Health at Oxford University. “At present artemisinin resistance appears to be largely confined to Southeast Asia but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

The paper highlights that the distribution of the different kelch 13 mutations are localised within well-defined geographical regions including SouthEast and Eastern Asia and Western Asia, including Bangladesh. This indicates that resistance may not have necessarily spread across country borders, but emerged independently on several occasions.

WWARN is working with partners to help improve strategies and resources that support monitoring and tracking of antimalarial drug resistance. Tools such as the WWARN Molecular Surveyor are providing a global picture of the changes in the prevalence of molecular markers associated with antimalarial drug resistance over time and location, helping to inform key international, regional and national monitoring strategies.

“We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective,” says Professor Nicholas Day, Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. “We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

Publication details:

Miotto O, Amato R, et al. (2015). Genetic architecture of artemisinin resistant Plasmodium falciparum.Nature Genetics. Advanced online publication 19 January 2014. DOI: 10.1038/ng.3189 PMID:25599401

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