In Simple Terms
Researchers have made much clearer maps of the genetic material of three malaria parasites using blood samples from infected people, without growing the parasites in a lab. The maps reveal hard-to-see regions that may help explain how parasites change and evade the body’s defenses. They could also support better testing and efforts to track changes that affect treatment.
Malaria is caused by more than one parasite. Although Plasmodium falciparum is responsible for most malaria deaths, other species—including Plasmodium ovale and Plasmodium vivax—can cause long-lasting infections and remain less well understood. One major obstacle is that these parasites are difficult to study in the lab: researchers do not have reliable methods for keeping them growing continuously in culture.
In a study published in PLOS Pathogens, a research team presented high-quality, chromosome-level genetic maps for three Plasmodium species that infect humans. Crucially, the work used blood from people who had naturally acquired malaria, rather than parasites grown in the lab. This approach gave the researchers access to parts of the parasites’ genetic material that had been difficult to see in earlier reference genomes.
Why Have Some Malaria Parasites Stayed in the Shadows?
Malaria research has focused heavily on P. falciparum, the species responsible for most malaria-related deaths. But the other species are not insignificant. P. ovale and P. vivax also contribute to the burden of disease and can be associated with chronic infections. They may also persist in places where P. falciparum infections are declining, making them important to understand when assessing malaria-control efforts.
Studying parasites usually requires detailed genetic information, but obtaining it from species that are hard to grow presents a challenge. When available genomes are broken into fragments, it can be difficult to work out how those pieces fit together or to identify some genes and gene families. A useful reference genome, then, is more than a long sequence: it needs to be organized well enough to show where genes lie and how they relate to one another within chromosomes.
The team set out to build more complete references for two less-studied species, while also producing high-quality references for P. falciparum. Including all three species allowed the researchers to compare parasites collected from the same geographical region and examine their similarities and differences side by side, rather than studying each species in isolation.
From Patients’ Blood to Chromosome Maps
Researchers from the Wellcome Sanger Institute and Mali’s Research and Training Center on Parasites and Microbes collected blood samples from people who had naturally contracted malaria in Faladè, Mali. Rather than starting with parasites grown in culture, the team extracted parasite genetic material directly from the clinical samples. In total, they assembled parasite genomes from eight participants.
Before the genetic material could be read, the team had to separate parasite DNA from other components of the blood. The researchers removed human white blood cells as well as uninfected red blood cells to increase the proportion of parasite DNA in each sample. This enrichment helps make the parasite’s genetic signals clearer, especially when only a limited amount of its genetic material is available.
The team then used PacBio Ultra-Low-Input HiFi, a long-read sequencing technology designed to work with small amounts of genetic material. Long reads make it easier to determine how separated sections of a sequence fit together: the equipment can read longer stretches at once, instead of producing short fragments that are difficult to connect in complex regions.
To complete the picture of chromosome structure, the researchers added Hi-C technology. This method detects regions of DNA that are close together inside a cell, providing clues about which pieces belong to the same chromosome and how they are positioned relative to one another. Combining long reads with information about DNA’s physical proximity allowed the team to move beyond assembling genome fragments and organize them into more complete chromosome maps.
What Turned Up at the Ends of the Chromosomes?
One of the study’s most notable achievements was resolving regions near the ends of chromosomes, known as subtelomeric regions. These areas had been out of reach in fragmented reference genomes, in part because their DNA contains repeated sequences and expanded gene families—features that make the genetic material difficult to read and assemble.
The importance of these chromosome ends goes beyond their location. They contain gene families involved in how parasites interact with humans, and studying them could help explain persistent infections, parasite transmission, and the ability to evade immune responses. With these regions more clearly mapped, researchers can examine genes that were missing or incomplete in previous references and compare them across species and samples.
In the genome of Plasmodium ovale wallikeri, the researchers identified more than 2,000 genes belonging to the PIR family. These genes make up about a quarter of the parasite’s genome, showing just how large this gene family is. The finding provides a starting point for investigating what these genes do and how their abundance relates to the parasite’s characteristics. It does not, by itself, establish the function of every gene.
Comparing parasites collected from the same geographical area also revealed extensive genetic changes near the ends of chromosomes. This pattern raised the possibility that rearrangements of genetic material help diversify the molecules parasites use when interacting with the human body. Such diversity may affect how the immune system recognizes parasites, but further research will be needed to determine the precise mechanisms.
Genetic Change Offers a Window into Parasite Evasion
Genes near chromosome ends can be thought of as particularly changeable parts of the genetic map. Comparisons among the samples showed that these regions are not entirely fixed: their organization and genetic material can shift. Lead author Sunil Daga noted that the more complete maps revealed how greatly gene families at chromosome ends have expanded, and suggested that changes in these locations may help parasites adapt and evade human defenses.
This interpretation matters because the interaction between a parasite and its host does not happen in isolation. If genes involved in that interaction change, the traits a parasite uses to interact with the immune system—or the way an infection persists—may change as well. But genetic maps alone cannot prove that a particular change directly enables immune evasion. Instead, they provide more precise data, point to questions that can be tested, and let researchers locate and compare differences across samples.
Having reference genomes for all three species also makes evolutionary and genetic comparisons more robust. Rather than leaving complex regions off the map, researchers can examine them in the context of entire chromosomes and track differences among P. ovale, P. vivax, and P. falciparum. This could support research into parasite persistence, transmission, and diversity—questions that are difficult to assess when genetic data are incomplete.
From Reference Genomes to Surveillance and Diagnosis
The value of these maps extends beyond basic biology. High-quality reference genomes could help improve molecular diagnostic tools: tests that look for a parasite’s genetic material in a sample. The more complete the reference sequence, the better researchers can assess which regions might be useful for detecting different species and avoid relying on information that represents only one malaria-causing parasite.
That matters because non-falciparum malaria can be difficult to diagnose, and these parasites may persist even in areas where transmission of P. falciparum has fallen. If surveillance systems do not clearly account for these species, they may fail to capture the full range of parasites circulating in a population. The new data could therefore broaden genetic surveillance and improve the ability to track parasite changes across communities and samples.
The reference genomes could also support the search for potential treatment targets and help researchers study how parasite populations respond to treatment and control measures. Comparing sequences over time or between samples may reveal changes worth monitoring, including changes that could be associated with drug resistance. The study does not report the discovery of new resistance or offer a ready-made treatment. Rather, it provides a genetic resource that future research can use to investigate these issues more effectively.
Study supervisor Mara Lawniczak of the Wellcome Sanger Institute says that creating standard reference genomes for these neglected parasites fills an important gap in malaria research. That gap matters for planning control efforts: knowing which species are circulating in a community, and being able to compare them genetically, can build a more complete picture than one focused on P. falciparum alone.
The Next Step in Malaria Research
The study provides a new resource, but it does not settle the many questions surrounding these parasites. The maps open up parts of the genome that were previously hidden, yet understanding what expanded gene families do and how they affect infection and immunity will take more work. And although comparing eight participants from one region offers an important genetic starting point, it cannot replace broader sampling to investigate parasite diversity in other places.
A key strength of the approach is that it shows chromosome maps can be built from naturally acquired infections without relying on parasites growing continuously in the lab. This does not remove the need for other tools and methods, but it offers a practical route to studying species that are difficult to grow. With improved references in hand, researchers can test new questions about parasite differences and monitor changes that could affect diagnosis or control.
Including less-studied species in genetic surveillance also carries a broader message: tackling malaria means paying attention to the diversity of the parasites that cause it, not just the best-known species. If P. ovale and P. vivax remain absent from reference data or monitoring systems, important aspects of how malaria persists and spreads may remain unclear. This study gives researchers a foundation for narrowing that gap with more complete genetic references they can build on.
The Bottom Line
A team from the Wellcome Sanger Institute and Mali’s Research and Training Center on Parasites and Microbes assembled high-quality genomes for three Plasmodium species using blood samples from eight people in Faladè. Long-read sequencing and Hi-C helped organize the parasites’ genetic material at the chromosome level and reveal hard-to-read regions near chromosome ends. Among the findings were more than 2,000 PIR-family genes—about a quarter of the P. ovale wallikeri genome—and extensive genetic changes near chromosome ends. The results are not an immediate solution to malaria, but they offer tools and knowledge to improve research on neglected species and support better diagnosis, surveillance, the search for treatment targets, and monitoring of parasite responses to control measures.