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Ancient DNA Analysis Links Malaria Adaptation to Agricultural Adoption in Eastern Arabia

Aedes aegypti

NEW YORK – A well-known malaria resistance variant known as the "Mediterranean mutation" appears to have been present at high frequencies in ancient individuals from Eastern Arabia, pointing to its potential origins in South Asia or Mesopotamia, according to an analysis appearing in Cell Genomics on Tuesday.

"Our study highlights the association between malaria proliferation and agriculture, alerting to the importance of water and environmental management for preventing malaria transmission," first and co-corresponding author Rui Martiniano, a researcher at Liverpool John Moores University, said in an email. He added that the malaria resistance mutation identified can also influence side effects of antimalarial therapy and, consequently, affect treatment selection.

For their study, Martiniano and his colleagues focused on a malaria endemic region in present-day Bahrain in an effort to explore disease exposure and past human adaptations to malaria in Arabian populations.

Shotgun whole-genome sequencing on ancient DNA samples from petrous bone samples dated to around 1,400 to more than 2,300 years old from Tylos-period sites on the island of Bahrain revealed a malaria-protective variant in the glucose-6-phosphate dehydrogenase enzyme-coding gene G6PD in three out of four individuals studied.

In addition, by analyzing the genome sequence data alongside additional ancient and modern-day samples from the Middle East, Europe, and South Asia, the team went on to explore the roots of this so-called "Mediterranean" variant — from its apparent ties to the rise of agriculture to the ancestral populations that may have carried it to the region.

"According to our estimates, the G6PD Mediterranean mutation rose in frequency in Eastern Arabia when agriculture appeared there, [approximately 5,000] years ago," Martiniano noted.

"This makes sense because the onset of agriculture led to increased sedentarization, larger settlements, and proximity to water, which may have led to increased malaria transmission," he explained, adding that "[i]ncreased malaria presence would have created a positive selection favoring variants with a protective effect against malaria, leading to a rise in frequency."

While past genetic studies centered on present-day populations hinted that the Mediterranean G6PD mutation might have arrived in Europe during the Neolithic period, the variant has not turned up in any significant way in ancient individuals from relevant sites in Europe or the Levant.

In contrast, its appearance in ancient Bahrain suggests the variant was found at very high frequencies in this region in the "Tylos" period, potentially arriving with migrants from parts of South Asia such as Pakistan, where the variant is found in a significant subset of individuals today.

"Given that this variant occurs at high frequencies in South Asia (e.g., Pakistan) and Eastern Arabian populations with high South Asian ancestry, we think this variant may have been introduced into Arabia through admixture with ancient groups carrying substantial South Asian-related ancestry," Martiniano explained.

Because the malaria resistance variant has been linked to serious side effects such as hemolysis in individuals receiving certain antimalarial drugs such as 8-aminoquinoline and primaquine, the results also pointed to the importance of screening individuals for G6PD mutations prior to antimalarial treatment, he said, particularly those from populations where the variant is found at high frequency.

The work "goes beyond historical understanding, providing predictive capabilities for disease susceptibility, spread, and treatment, thus promoting better health outcomes," coauthor Marc Haber, a researcher at the University of Birmingham Dubai's Institute of Cancer and Genomic Sciences, said in a statement.

By considering the genetic results in this cultural and environmental context, the team was able to get a look at the collection of influences involved in the rise of malaria in the region, along with the human population features that arose to respond to such disease pressures.

Beyond that, the current work "paves the way for future research that will shed light on human population movements in Arabia and other regions with harsh climates where it is difficult to find well-preserved sources of DNA," noted Salman Almahari, director of the Bahrain Authority for Culture and Antiquities' Antiquities and Museums.