Transcriptional variation in the malaria parasitePlasmodium falciparum

Abstract

Malaria genetic variation has been extensively characterized, but the level of epigenetic plasticity remains largely unexplored. Here we provide a comprehensive characterization of transcriptional variation in the most lethal malaria parasite, Plasmodium falciparum, based on highly accurate transcriptional analysis of isogenic parasite lines grown under homogeneous conditions. This analysis revealed extensive transcriptional heterogeneity within genetically homogeneous clonal parasite populations. We show that clonally variant expression controlled at the epigenetic level is an intrinsic property of specific genes and gene families, the majority of which participate in host-parasite interactions. Intrinsic transcriptional variability is not restricted to genes involved in immune evasion, but also affects genes linked to lipid metabolism, protein folding, erythrocyte remodeling, or transcriptional regulation, among others, indicating that epigenetic variation results in both antigenic and functional variation. We observed a general association between heterochromatin marks and clonally variant expression, extending previous observations for specific genes to essentially all variantly expressed gene families. These results suggest that phenotypic variation of functionally unrelated P. falciparum gene families is mediated by a common mechanism based on reversible formation of H3K9me3-based heterochromatin. In changing environments, diversity confers fitness to a population. Our results support the idea that P. falciparum uses a bethedging strategy, as an alternative to directed transcriptional responses, to adapt to common fluctuations in its environment. Consistent with this idea, we found that transcriptionally different isogenic parasite lines markedly differed in their survival to heat-shock mimicking febrile episodes and adapted to periodic heat-shock with a pattern consistent with natural selection of pre-existing parasites.

Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling

“…It is speculated that it contains an interaction epitope for binding of iRBC membrane/cytoskeleton components (12). Here it is also noteworthy that PF3D7_0936800 has been found to be variantly expressed in 3D7 (55) and that there has been no reported PF3D7_0936800 knockout (PF3D7_ 0936800-KO) parasite.…”

“…Genes annotated "phista-like" or as "phist" genes were grouped together as "phist others." Yellow boxes to the right of the heat map indicate PHIST proteins present in the early gametocyte proteome (35), differentially expressed phist genes in pregnancy-associated malaria (29,49,50,84,92,112) and in cerebral malaria (32,34), or if variant expression has been reported (55). Green to red colors represent fold changes (log fold changes from Ϫ3 to 3).…”

Variation in Plasmodium falciparum Erythrocyte Invasion Phenotypes and Merozoite Ligand Gene Expression across Different Populations in Areas of Malaria Endemicity

“…Expression of genes encoding P. falciparum merozoite ligands involved with invasion is tightly regulated as part of the parasite developmental cycle (30,31), and variation between parasites is known to be under epigenetic regulation (32)(33)(34), but the selective determinants of transcript profiles seen in vivo are not well understood. A diversity of eba and Rh gene expression profiles has been previously seen in separate studies of clinical isolates from individual populations, but epidemiological correlations with function or host immunity remain to be established (21,24,25,29).…”

Evolution in changing environments: Modifiers of mutation, recombination, and migration

“…However, in natural populations selection may not be constant over time due, for example, to ecological changes, spatial variability, changes in environment, or even shifts in the genetic background (1). Under temporal and spatial heterogeneity in the direction and strength of selection, a population may evolve mechanisms that create and maintain phenotypic diversity, thus increasing the long-term adaptability of the population (2)(3)(4)(5)(6)(7). These mechanisms may include changes in the rates at which genetic variability is produced, such as the rates of recombination, mutation, and migration (8).…”