Abstract
Mechanisms for differential regulation of gene expression may underlie much of the phenotypic variation and adaptability of malaria parasites. Here we describe transcriptional variation among culture-adapted field isolates of Plasmodium falciparum, the species responsible for most malarial disease. It was found that genes coding for parasite protein export into the red cell cytosol and onto its surface, and genes coding for sexual stage proteins involved in parasite transmission are up-regulated in field isolates compared with long-term laboratory isolates. Much of this variability was associated with the loss of small or large chromosomal segments, or other forms of gene copy number variation that are prevalent in the P. falciparum genome (copy number variants, CNVs). Expression levels of genes inside these segments were correlated to that of genes outside and adjacent to the segment boundaries, and this association declined with distance from the CNV boundary. This observation could not be explained by copy number variation in these adjacent genes. This suggests a local-acting regulatory role for CNVs in transcription of neighboring genes and helps explain the chromosomal clustering that we observed here. Transcriptional co-regulation of physical clusters of adaptive genes may provide a way for the parasite to readily adapt to its highly heterogeneous and strongly selective environment.
Highlights
Malaria is a global health problem that imposes major strain on the development of many tropical countries [1]
Functional classification of genes that differ between field and laboratory isolates We found that genes coding for proteins involved in sexual stage parasites, those known to be expressed on the surface of the parasite, and those thought to be exported to the red cell surface membrane were significantly over-represented among the genes significantly different between field and laboratory strains (Figure 2B)
Examples of differentially expressed genes discovered in multiple independent studies include those involved in a range of biological processes important to parasite fitness in vivo such as export of proteins to the red cell surface, transmission, and colonization of the pregnant woman, transcriptional regulation factors, nutrient biosynthesis and metabolic pathways involved in drug resistance
Summary
Malaria is a global health problem that imposes major strain on the development of many tropical countries [1]. A further theme that has emerged from these studies is the remarkable degree of coordinated regulation in the transcription of P. falciparum genes, both within and between life stages [18,19,20,21,22]. This is evident from the strong co-regulation through time within the asexual cycle of genes with related function [19,20,22,23], but has been observed for genes that share similar location in the genome [9,20,22,24,25]. The contribution of transcriptional regulation to whole-organism phenotypes such as virulence and transmissibility in natural parasite populations has not yet been investigated
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