Tracing malaria’s historical impact and distribution through ancient genome analysis

A recent paper sheds light on the historical distribution and genetic diversity of malaria-causing Plasmodium species through ancient DNA analysis from human skeletal remains, providing insights into the evolution, transmission, and impact of malaria on human populations over millennia.

Malaria, caused by protozoa parasites of the genus Plasmodium and transmitted by female Anopheles mosquitoes, is a major threat to human health worldwide. An estimated 247 million cases and 619,000 deaths were reported in 2023.

Among the five main Plasmodium species that infect humans, P. falciparum and P. vivax are the most prevalent and widely distributed today; P. falciparum is the major cause of malaria across Africa (and some parts of Caribbean) and P. vivax across Latin American, Asia (and small parts of Africa).

Knowledge of the parasite’s historical infection distribution beyond its current endemic areas and evolutionary history, particularly how they spread and influenced human populations, remains largely unknown and there is currently debate over when, where and how Plasmodium emerged as a human pathogen.

Many factors (such as evolutionary constraints, human genetics and motility, mosquito viability, and climate) restrict the geographic distributions of these parasites, both today and historically. Biomolecular research suggests that P. falciparum emerged as a zoonosis from gorillas in sub-Saharan Africa somewhere between a few thousand and half a million years ago. The evolutionary origins of P. vivax are even less understood, however, with its geographical origins contested between Southeast Asia and Africa, but it is believed to have emerged before P. falciparum.

Extracting ‘ancient’ DNA (aDNA) of pathogens preserved in human bones is deepening our knowledge of the evolutionary histories and global spread of key pathogens; however, retrieving ancient DNA from Plasmodium species has largely been unsuccessful, until now.

Sequencing ancient Plasmodium genomes from human skeletal remains 

A recent Nature paper published by a collection of 94 researchers from over 50 institutions sought to overcome the pitfalls associated with Plasmodium aDNA genomics, and shed light on the evolution and historical distribution of these hugely important human pathogens.

To achieve this, a metagenomic analysis of over 10,000 ancient human remains was conducted. Ancient samples found to contain traces of parasite DNA were then enriched using two newly designed in-solution hybridisation capture bait sets. This enabled generation of high-coverage ancient mitochondrial and nuclear genomes of the three major Plasmodium species (P. falciparum, P. vivax, and P. malariae) across 5,500 years of human history and 16 countries.

(A) Archeological sites containing malaria-positive human skeletal remains and (B) the time period these individuals are thoguht to have lived. Michel et al., 2024.

Overall, 36 ancient malaria infections were identified, comprising all three targeted Plasmodium species, consisting of 21 P. vivax infections, 10 P. falciparum and 2 P. malariae infections.

This high-coverage ancient Plasmodium genome data was then comprehensively analysed alongside several historical Plasmodium datasets from 1940s Spain (one of the last malaria-affected European areas), as well as 1,000s of modern Plasmodium genome datasets, allowing them to examine the geographic and temporal distribution of these parasites.

Uncovering the early presence of malaria in Eurasia

Modern and ancient P. vivax genome principal component analysis. Modified from Michel et al., 2024.

The study reveals significant findings regarding the ancient presence and dissemination of P. vivax and P. falciparum across regions of Eurasia, dating back to the fourth and first millennia BCE, respectively. This discovery notably pre-dates existing textual references by several millennia

The identification of P. vivax in Europe during the 12th-14th centuries CE aligns with historical accounts of its adaptation to colder climates, and endemic presence throughout Europe at that time. Notably, ancient P. vivax-infected individuals were also identified across Eurasia (Germany (Middle Neolithic Baalberge), Spain (Cueva de las Lechuzas), and Russia (Gundorovka)) much earlier than previously documented, suggesting it had a much earlier and widespread impact on human populations than previously understood.

Ancient P. falciparum data from the Himalayan site of Chokhopani (804–765 BCE) and the Central European Iron Age site of Göttlesbrunn (350–250 BCE) provided new insights into the spread of malaria facilitated by trade and mobility – Chokhopani’s documented trade with the Indian subcontinent and Göttlesbrunn’s trans-regional networks highlight the role of movement and trade in malaria transmission beyond historically known endemic areas. All ancient P. falciparum genomes also fall into a gap in ‘genetic space’, highlighting the genetic uniqueness of ancient European strains.

 Plasmodium and the Americas: origins and transmission

Plasmodium vivax genomic data was generated from an individual associated with the Chachapoya culture in Peru (1437-1617 CE) that showed complete indigenous ancestry.

Modern and ancient P. falciparum genome principal component analysis. Michel et al., 2024.

The research also provides evidence for distinct histories of P. falciparum and P. vivax in the Americas. Based on genetic similarities between ancient European and South American strains of P. vivax, the authors suggest that European (Spanish) colonisers and explorers likely introduced P. vivax to the Americas (~1492-1600 CE). It’s well known that Spanish invaders (among others) spread infectious diseases to the Americas, and this appears to extend to malaria.

On the other hand, modern South American P. falciparum strains were found closely related to those from West, Central, and East Africa, supporting suggestions that the trans-Atlantic slave trade brought P. falciparum to the Americas.

Impact and implications

This research provides valuable insights into ancient Plasmodium populations and broadens our understanding of malaria’s evolutionary history and global reach. It collectively highlights the deep historical roots and widespread impact of malaria, emphasising the importance of human mobility, trade, and conflict on its ancient dispersal.

Beyond this, the ability to reconstruct ancient malaria genomes opens new research avenues and enables further palaeo-epidemiological studies on the historical impact of Plasmodium parasites. Enhanced modern sampling and sequencing of malaria genomes are, however, needed for a better understanding of malarias’ ancient and modern global diversity.

Integrating ancient DNA evidence, historical records, osteological markers, and archaeological data can be a powerful combination to gain new insights into malaria genomics

I’ve barely scratched the surface of this publication, so if you’d like to hear more please check out their paper!


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