Authors

E Gómez-Díaz¹; M Parrés-Mercader¹; B Díaz-Terenti²; S Pradhan³; LC Ranford-Cartwright³; M Diakite⁴; TD Otto⁵;  ¹ Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC),, Spain;  ² Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Spain;  ³ School of Biodiversity, One Health and Veterinary medicine, UK;  ⁴ University of Science, Techniques, and Technologies of Bamako, Mali;  ⁵ Bernhard Nocht Institute of Tropical Medicine, Germany

Discussion

One of the greatest global health challenges we face is understanding the mechanisms of rapid adaptation of pathogens to changing environments. Malaria parasites exhibit remarkable phenotypic and genomic plasticity, enabling rapid adaptation to fluctuating within host conditions. Although this plasticity is central to parasite survival and transmission, the regulatory mechanisms remain poorly understood. To fill this knowledge gap, we first produced high-quality, chromosome-level genome assemblies from eight field-derived Plasmodium clones that retain their adaptive potential, leveraging long-read PacBio HiFi sequencing. These assemblies provide a robust genomic framework for interrogating natural parasite variation, particularly within highly polymorphic gene families involved in host interactions. Building on this resource, we profiled and compared single-cell transcriptomes of parasites from heterogeneous versus homogeneous transmission environments. This combined approach enabled high-resolution dissection of transcriptional heterogeneity and the identification of gene regulatory networks and regulatory elements associated with plastic responses in the transmissible sexual stage of the gametocytes. Our analyses uncovered a set of genes that consistently exhibit transcriptional plasticity across biological replicates. Many of these genes encode known or predicted parasite surface proteins and mediators of host–parasite interactions. Their plastic expression supports a bet-hedging strategy that is actively modulated during sexual differentiation, equipping parasites to cope with the unpredictable environmental conditions of transmission. Together, our findings provide new insight into the genomic and transcriptional bases of adaptive plasticity in eukaryotic pathogens.