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Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

ABSTRACT: The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs) in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant expression quantitative trait locus. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to an increased copy number of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites.

SUBMITTER: Gonzales JM

PROVIDER: S-EPMC2553844 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

Gonzales Joseph M JM Patel Jigar J JJ Ponmee Napawan N Jiang Lei L Tan Asako A Maher Steven P SP Wuchty Stefan S Rathod Pradipsinh K PK Ferdig Michael T MT

PLoS biology 20080901 9

The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dic ...[more]

PMID: 18828674

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Project description:BackgroundIn malaria endemic areas, identifying spatio-temporal hotspots is becoming an important element of innovative control strategies targeting transmission bottlenecks. The aim of this work was to describe the spatio-temporal variation of malaria hotspots in central Senegal and to identify the meteorological, environmental, and preventive factors that influence this variation.MethodsThis study analysed the weekly incidence of malaria cases recorded from 2008 to 2012 in 575 villages of central Senegal (total population approximately 500,000) as part of a trial of seasonal malaria chemoprevention (SMC). Data on weekly rainfall and annual vegetation types were obtained for each village through remote sensing. The time series of weekly malaria incidence for the entire study area was divided into periods of high and low transmission using change-point analysis. Malaria hotspots were detected during each transmission period with the SaTScan method. The effects of rainfall, vegetation type, and SMC intervention on the spatio-temporal variation of malaria hotspots were assessed using a General Additive Mixed Model.ResultsThe malaria incidence for the entire area varied between 0 and 115.34 cases/100,000 person weeks during the study period. During high transmission periods, the cumulative malaria incidence rate varied between 7.53 and 38.1 cases/100,000 person-weeks, and the number of hotspot villages varied between 62 and 147. During low transmission periods, the cumulative malaria incidence rate varied between 0.83 and 2.73 cases/100,000 person-weeks, and the number of hotspot villages varied between 10 and 43. Villages with SMC were less likely to be hotspots (OR?=?0.48, IC95%: 0.33-0.68). The association between rainfall and hotspot status was non-linear and depended on both vegetation type and amount of rainfall. The association between village location in the study area and hotspot status was also shown.ConclusionIn our study, malaria hotspots varied over space and time according to a combination of meteorological, environmental, and preventive factors. By taking into consideration the environmental and meteorological characteristics common to all hotspots, monitoring of these factors could lead targeted public health interventions at the local level. Moreover, spatial hotspots and foci of malaria persisting during LTPs need to be further addressed.Trial registrationThe data used in this work were obtained from a clinical trial registered on July 10, 2008 at www.clinicaltrials.gov under NCT00712374.

Project description:BackgroundDuring intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.ResultsWe generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.ConclusionsThis study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.

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Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

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Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

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