Abstract
BackgroundGene copy number variants (CNVs), which consist of deletions and amplifications of single or sets of contiguous genes, contribute to the great diversity in the Plasmodium falciparum genome. In vitro studies in the laboratory have revealed their important role in parasite fitness phenotypes such as red cell invasion, transmissibility and cytoadherence. Studies of natural parasite populations indicate that CNVs are also common in the field and thus may facilitate adaptation of the parasite to its local environment.ResultsIn a survey of 183 fresh field isolates from three populations in Eastern Africa with different malaria transmission intensities, we identified 94 CNV loci using microarrays. All CNVs had low population frequencies (minor allele frequency < 5%) but each parasite isolate carried an average of 8 CNVs. Nine CNVs showed high levels of population differentiation (FST > 0.3) and nine exhibited significant clines in population frequency across a gradient in transmission intensity. The clearest example of this was a large deletion on chromosome 9 previously reported only in laboratory-adapted isolates. This deletion was present in 33% of isolates from a population with low and highly seasonal malaria transmission, and in < 9% of isolates from populations with higher transmission. Subsets of CNVs were strongly correlated in their population frequencies, implying co-selection.ConclusionsThese results support the hypothesis that CNVs are the target of selection in natural populations of P. falciparum. Their environment-specific patterns observed here imply an important role for them in conferring adaptability to the parasite thus enabling it to persist in its highly diverse ecological environment.
Highlights
Gene copy number variants (CNVs), which consist of deletions and amplifications of single or sets of contiguous genes, contribute to the great diversity in the Plasmodium falciparum genome
Surveys of parasite lines adapted to in vitro culture conditions in the laboratory, both long-term [11,12,13,14,15,16,17] and short-term [18], have revealed many CNVs in the P. falciparum genome. Common among these are two large deletions that abrogate traits which are crucial to survival in vivo but dispensable in vitro. These are the deletion of a region on chromosome 9 that contains several genes required for formation of gametocytes, the life stage required for transmission to new hosts via mosquitoes [19, 20], and a region on chromosome 2 containing a gene encoding the knob associated histidine rich protein (KAHRP) that mediates binding of the infected red blood cell to other host cells thereby allowing the parasite to avoid circulation through the spleen where it would otherwise be destroyed [21]
We test the hypothesis that CNVs provide the source of adaptive variation used by the parasite to evolve in response to natural environmental variation. Empirical support for this hypothesis would have implications for malaria control programmes that change the epidemiological setting of the parasite. We examine this hypothesis by analysing CNV variation among geographically and temporally separated populations of P. falciparum in Eastern Africa that differ widely in malaria transmission intensity and related selection pressures
Summary
Gene copy number variants (CNVs), which consist of deletions and amplifications of single or sets of contiguous genes, contribute to the great diversity in the Plasmodium falciparum genome. In vitro selection for drug resistance has uncovered further CNVs. Examples include amplification of genes encoding multidrug resistance protein 1 (Pfmdr1) that associates with resistance to multiple drugs in in vitro studies [24]; amplifications in the genes encoding the cysteine proteases falcipain 2 (FP2a and FP2b) and falcipain 3 (FP3) in which mutations have been associated with resistance to the antimalarial compound artemisinin [25], and which help breakdown haemoglobin in the food vacuole [26], a process that is required for artemisinin to be effective [27]; a deletion of 15 consecutive genes on chromosome 10 in parasites bearing mutations in the chloroquine resistance transporter gene (Pfcrt) [28]; deletion of 23 adjacent genes in chromosome 14 in strains resistant to the anti-malarial compound, fosmidomycin [13]; and amplification of the gene encoding GTP cyclohydrolase 1 (gch1) [12, 18], an enzyme high in the folate synthesis pathway and a potential target for the antifolate class of anti-malarial drugs. The evidence from in vitro studies strongly supports the hypothesis that CNVs play an important role in parasite adaptation to novel environments
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