A study, published this week in Nature, has identified a new locus of resistance to severe malaria. Variations in DNA in this region of the human genome can help protect African children from developing severe malaria, in some cases nearly halving a child’s risk of developing life-threatening illness.
“The fundamental question that we’re trying to answer is, ‘Why, in places where malaria is common, are some children better able to resist the illness? Our findings identify a particular genetic variant that makes children who carry it considerably less likely to develop severe malaria,” explained Dr. Gavin Band, one of the lead authors on the paper, from the Wellcome Trust Centre for Human Genetics, University of Oxford.
The newly-discovered locus is near a cluster of genes which code for proteins called ‘glycophorins’ that are involved in the malaria parasite’s invasion of red blood cells. Although many different malaria resistance loci have been postulated over the years, this is one of very few that have stood up to stringent testing in a large multi-centre study; others include the genes for sickle cell and the O blood group.
To identify the new locus, researchers conducted a large genome-wide association study (GWAS) using data from eight African countries: Kenya, Malawi, The Gambia, Burkina Faso, Mali, Cameroon, Tanzania and Ghana. They first compared the DNA of 5,633 children with severe malaria with the DNA of 5,919 children without severe malaria; then replicated their key findings in a further 14,000 children.
This work is the latest publication to come from MalariaGEN’s Consortial Project , an international collaboration that was initiated in 2005, as part of the Grand Challenges in Global Health , and involves partners in several malaria-endemic countries.
“When we formed this collaboration a decade ago, we had in mind that we could do genomics in Africa. We’ve now achieved this vision on a scale and at a resolution beyond what we could have imagined at the time — and we are seeing how this can drive our understanding of the biology and evolutionary mechanisms of malaria,” explained Dr. Kirk Rockett, MalariaGEN Scientific Research Manager and co-author, who is based at the Wellcome Trust Centre for Human Genetics and the Wellcome Trust Sanger Institute.
“This type of discovery is made possible by a strong collaboration between malaria investigators in the field and northern collaborators who have the technology platform and the capacity to analyse big data,” said Professor Ogobara K. Doumbo one of the co-authors from the Malaria Research and Training Center at the University of Bamako in Mali, also reflecting on the importance of the underlying collaboration.
A particularly strongly-protective variant, or allele, was found most commonly among children in Kenya in East Africa. Having this allele reduces the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied. The difference between populations could be due to the genetic features of the local malaria parasite in East Africa.
Researchers have known for decades that the glycophorin cluster of genes is highly variable, but it was not possible to show that this genetic variation was responsible for protecting people against severe malaria. Now, with improved GWAS methodology, and the ability to collect samples from across different African countries, researchers are better able to understand the complexity in the patterns of DNA and, crucially, accurately measure their effects on an individual’s level of resistance to the disease.
Surprisingly, these DNA variants are also near one of only a handful of locations in the genome where humans and chimpanzees have the same combination of alleles, suggesting they have been around for millions of years – and that balancing selection may be maintaining these variations throughout a long-standing evolutionary battle between humans and malaria parasites.
One way balancing selection arises is when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences. The classic example is the sickle cell gene – people with one copy of the gene are strongly protected against malaria but those with two copies of the gene develop a life-threatening condition known as sickle-cell disease.
“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Professor Dominic Kwiatkowski, one of the lead authors of the paper, from the Wellcome Trust Sanger Institute and the Wellcome Trust Centre for Human Genetics.
And, these findings also provide important clues to guide future research. “This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterise these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act,” said Professor Kwiatkowski.
Professor Kevin Marsh, a co-author of the study from the Kemri-Wellcome Research Programme in Kilifi, Kenya, said: “This work is an excellent example of how genuine large-scale collaboration can tap into the power of modern genomic science. The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell. This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”