Genetic adaptation of parasites to new environments: Plasmodium vivax in Americas – GENAD

GENAD relied on an extensive international collaborative network to assemble P. vivax samples from Latin America and other regions of the world potentially involved in the colonization of the Americas, together with Plasmodium samples from non-human primates.

The project mobilized 388 P. vivax and 42 P. simium samples. Because parasite DNA was often available in limited quantities, selective whole-genome amplification was performed prior to high-throughput sequencing. Newly generated genomic data were combined with publicly available genomes to build datasets representative of the worldwide genetic diversity of P. vivax.

The study of the colonization history of Latin America analysed whole-genome variation from 620 P. vivax isolates, including 107 newly sequenced samples from West Africa, the Middle East and Latin America.

In parallel, 719 monkey samples from five Latin American countries were screened for Plasmodium infections. Newly generated data were integrated with whole-genome variation from 19 P. simium and 405 P. vivax isolates to investigate the evolutionary relationships between parasites infecting humans and non-human primates.

Analyses combined population genomics, phylogenetics, population structure and ancestry analyses, genetic diversity and differentiation, demographic reconstruction and formal comparison of alternative evolutionary scenarios. Complementary approaches for detecting natural selection were used to identify genomic regions potentially involved in adaptation to new hosts and environments.

GENAD addressed its three initial scientific objectives and revealed that the history of P. vivax in the Americas is substantially more complex than a single introduction followed by population expansion.

Analysis of 620 genomes showed that present-day Latin American P. vivax populations predominantly derive from ancestry related to a now-extinct European parasite lineage. Additional contributions, including a likely West African source, were also identified. The results support multiple waves of introduction, beginning during early European contact and followed by later introductions associated with post-colonial human migrations, particularly during the late nineteenth century.

GENAD also clarified the evolutionary history of P. simium. Genomic analyses support a recent host shift from human P. vivax to Neotropical primates, with divergence occurring approximately within the last two centuries. P. simium displays genetic structuring within Brazil, and recent genetic exchanges between P. vivax and P. simium were also detected.

Importantly, P. vivax, generally considered a human malaria parasite, was identified in monkeys from Colombia and Brazil. This finding suggests a broader host range than previously recognized and highlights the need to better understand parasite circulation between humans and non-human primates.

Finally, signatures of positive selection were detected in several genomic regions, including genes involved in parasite interactions with primate host cells and mosquito vectors, providing candidate mechanisms for adaptation associated with host shifts.

GENAD generated 10 peer-reviewed international publications, including two major studies directly addressing its core objectives (PLoS Pathogens, 2025; Evolutionary Applications, 2026), and formed the core of Margaux Lefebvre’s PhD thesis (2022–2024).

One of GENAD’s major findings is the demonstration that the evolutionary history of malaria parasites in the Americas involves not only repeated introductions and admixture, but also recent host shifts between humans and non-human primates. The detection of P. vivax in monkeys from Colombia and Brazil, together with evidence of recent genetic exchanges between P. vivax and P. simium, raises important questions about the existence and epidemiological significance of non-human primate reservoirs.

A major future priority is therefore to expand genomic sampling of Plasmodium circulating in Neotropical primates. Current P. simium genomic sampling remains limited and is largely concentrated in Brazil. Broader geographic sampling will be required to determine the frequency and extent of host shifts and parasite circulation between humans and non-human primates.

A second perspective is the integration of historical and ancient parasite genomes. GENAD indicates that present-day American populations largely derive from ancestry related to European P. vivax populations that are now extinct. Historical genomes could directly test the demographic scenarios identified by the project and improve reconstruction of successive introduction waves.

Genomic regions showing signatures of selection also provide priority candidates for functional studies aimed at determining whether specific variants facilitated adaptation to new primate hosts or mosquito vectors.

Finally, these findings have implications for malaria elimination in the Americas. Parasite circulation between humans and non-human primates could contribute to reservoirs that are difficult to control in some regions. Integrating genomics with primate ecology, parasite surveillance and vector studies will therefore be important for assessing this zoonotic potential.

The genomic datasets, metadata and analysis resources generated by GENAD and deposited in public repositories provide a foundation for these future studies and for the international collaborations established through the project.

GENAD contributed to 10 publications in international peer-reviewed journals, including 7 original research articles and 3 reviews, either directly resulting from the project or developed from the collaborations and genomic resources generated through GENAD.

Two publications directly address its central objectives: Lefebvre et al., PLoS Pathogens (2025), reconstructing the genomic history of P. vivax in Latin America, and Lefebvre et al., Evolutionary Applications (2026), investigating host shifts and the evolutionary history of P. vivax and P. simium. The project also contributed to research on adaptive evolution of P. falciparum during its invasion of the Americas (Molecular Biology and Evolution, 2023), together with broader reviews on malaria parasite evolution.

GENAD formed the core of Margaux Lefebvre's PhD thesis (2022–2024), and its results were presented at several international conferences, including invited presentations.

Genomic data and associated resources have been made publicly available, notably through NCBI (BioProject PRJNA116416) and DataSuds (DOI 10.23708/RCOGR6), together with resources supporting their reuse.

No patents were filed, as GENAD is a fundamental research project.

Plasmodium vivax, a human malaria parasite characterized by a succession of several colonization events, represents an interesting model to study how pathogens adapt themselves to new environments. Present in almost all inter-tropical regions, in the Americas two events of colonization happened for P. vivax: one when P. vivax arrived and infected new human populations and one with the transfer of P. vivax from humans to American monkeys (P. simium). In this context, the general questions of this project will be : How and when has P. vivax genetically adapted to these new environments in the Americas: in humans and in monkeys (Plasmodium simium)? Which genes have been involved? The first objective will be to reconstruct the origin of P. vivax in American humans and the second in American monkeys (P. simium). The third objective will be to identify mechanisms of adaptation of P. vivax in these environments (humans and monkeys). This project will increase our knowledge of how P. vivax emerged.