Regulatory Hotspots in the Malaria Parasite Genome Dictate Transcriptional Variation

Gonzales, Joseph M; Patel, Jigar; Ponmee, Napawan; Jiang, Lei; Tan, Aiping; Maher, Steven P.; Wuchty, Stefan; Rathod, Pradipsinh K.; Ferdig, Michael T.

doi:10.1371/journal.pbio.0060238

Cited by 66 publications

(96 citation statements)

References 63 publications

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“…To date, descriptions of transcriptional modification in Plasmodium sp. appear to be limited to associations with genomic structural variants, for example, gene amplification as in pfmdr1 and deletions or repeatlength polymorphisms in promoter regions (57,58). One could hypothesize that SNPs in an AP2 transcription factor DNAbinding domain may alter its motif binding and stage-specific expression of downstream genes.…”

Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…For the comparison of non-isogenic parasite lines (parentals comparison), which as expected showed higher levels of transcriptional variability (Supplemental Fig. S13) that may be explained by the effect of genetic differences on transcript levels (Gonzales et al 2008) or by technical aspects, only genes with aMAFC > 3.5 were retained in the list of variant genes. This represents only the top 2.1% of genes showing highest levels of transcriptional variability in this comparison, with observed expression fold-changes (MAFC) above 6.75.…”

Section: Epigenetic Variation In Malaria Parasitesmentioning

confidence: 99%

“…Furthermore, some of the transcript-level differences observed may be attributable to genetic polymorphism. A recent study established that transcriptional diversity in P. falciparum has a strong genetic component (Gonzales et al 2008). …”

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confidence: 99%

Transcriptional variation in the malaria parasitePlasmodium falciparum

Rovira-Graells¹,

Gupta²,

Planet³

et al. 2012

Genome Res.

207

342

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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.

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“…The amplicons reported vary in size from 14.7 to 50 kb, contain between 2 and 11 genes, and are arranged in tandem with various breakpoints in parasites of different geographical origins (reviewed in reference 2). Multiple copies of the amplicon may also affect the transcription of genes remote to the region, as suggested by the results of a recent study (10).…”

mentioning

confidence: 92%

Deamplification of pfmdr1 -Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

Chen¹,

Chavchich²,

Peters

et al. 2010

Antimicrob Agents Chemother

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Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives.

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Regulatory Hotspots in the Malaria Parasite Genome Dictate Transcriptional Variation

Cited by 66 publications

References 63 publications

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Transcriptional variation in the malaria parasitePlasmodium falciparum

Deamplification of pfmdr1 -Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

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