Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Angkor Wat, Cambodia © Roberto Amato
Angkor Wat, Cambodia

Largest genome-wide study of parasite provides clearest picture yet of genetic changes driving artemisinin resistance.

The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance.

The global research collaboration analysed 1612 samples from 15 locations in Southeast Asia and Africa finding 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in four other genes to support artemisinin resistance.

“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 in Statistical Genomics at the Wellcome Trust Sanger Institute and Oxford University’s Wellcome Trust Centre for Human Genetics. “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 variety of kelch13 mutations associated with artemisinin resistance, with new variants continually emerging, makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background – in this case, a fixed set of four well-defined mutations in the fd, arps10, mdr2, and crt genes – could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions even before resistant parasites take hold.

“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 Nick 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.”

Researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar and Bangladesh, scientists found that the distribution of different kelch13 mutations are localised within relatively well-defined geographical areas.

Whilst artemisinin resistant parasites do appear to have migrated across national borders, this only happened on a limited scale and, in fact, the most widespread kelch13 mutation, C580Y, appeared to have emerged independently on several occasions. Notably parasites along the Thailand-Myanmar border appear to have acquired this mutation separately from those in Cambodia and Vietnam. Crucially, parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

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.”

Mutations in the kelch13 gene were present, yet rare, in Africa but weren't associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programmes are,” says Professor Dominic Kwiatkowski, who is head of the Malaria Programme at the Wellcome Trust Sanger Institute and Professor of Genomics and 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.

Further information

Similar stories

New study shows higher rate of fractures in people with intellectual disability

In the most comprehensive study of its kind, researchers at the University of Oxford and Oxford Health NHS Foundation Trust found a substantially higher rate of fractures in people with intellectual disability compared with people of the same age and gender without an intellectual disability.

New evidence for how our brains handle surprise

A new study from the Bruno Group is challenging our perceptions of how the different regions of the cerebral cortex function. A group of ‘quiet’ cells in the somatosensory cortex that rarely respond to touch have been found to react mainly to surprising circumstances. The results suggest their function is not necessarily driven by touch, but may indicate an important and previously unidentified role across all the major cortices.

Language learning difficulties in children linked to brain differences

A new study using MRI has revealed structural brain changes in children with developmental language disorder (DLD), a common but under-recognised difficulty in language learning. Children with DLD aged 10-15 showed reduced levels of myelin in areas of the brain associated with speaking and listening to others, and areas involved in learning new skills. This finding is a significant advance in our understanding of DLD and these brain differences may explain the poorer language outcomes in this group.

New research reveals relationship between particular brain circuits and different aspects of mental wellbeing

Researchers at the University of Oxford have uncovered previously unknown details about how changes in the brain contribute to changes in wellbeing.

Night-time blood pressure assessment is found to be important in diagnosing hypertension

Around 15% of people aged 40-75 may have a form of undiagnosed high blood pressure (hypertension) that occurs only at night-time. Because they do not know about this, and therefore are not being treated for it, they are at a higher risk of cardiovascular disease such as stroke, heart failure, and even death, suggests new research from the University of Oxford published in the British Journal of General Practice.