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Integrative analysis of intraerythrocytic differentially expressed transcripts yields novel insights into the biology of Plasmodium falciparum
Raphael D Isokpehi, Winston A Hide
Malaria Journal , 2003, DOI: 10.1186/1475-2875-2-38
Abstract: In order to resolve genes associated with stage differentially expressed transcripts, we have developed and implemented an integrative approach that combines evidence from P. falciparum expressed sequence tags (ESTs), genomic, microarray, proteomic and gene ontology data.A total of 143 gametocyte-overexpressed and 51 asexual-overexpressed transcripts were identified. A subset of 74 genes associated with these transcripts showed evidence of stage-correlated protein expression, of which 53 have not been experimentally characterised. Our study has revealed (1) possible regulatory mechanisms in malaria parasites' gametocyte maturation, (2) correlation between EST and microarray data for a P. falciparum gene family to present unique EST-derived information, (3) candidate drug and antigenic targets on which computational and experimental studies can be performed, and (4) the need for more empirical studies on gene and protein expression in malaria parasites.Applying different domains of data to the same underlying gene set has yielded novel insights into the biology of the parasite and presents an approach to appraise critically the data quality of post-genomic datasets from malaria parasites.Pathogen bioinformatics have been developed and applied as a vehicle to discover novel genes and the search for virulence-associated genes combining approaches that assay gene expression, adaptive evolution and gene transfer [1-3]. In this study, layers of data about Plasmodium falciparum, obtained with gene transcript and genome sequencing as well as gene and protein expression profiling technologies, were integrated to reveal insights into previously undiscovered regulation during intraerythrocytic development. Genes that merit further analysis are described. This integrative approach uses an evidence-based assessment of disparate datasets similar to gene structure prediction approaches that rely on accumulation of evidence such as similarity to known genes, nucleotide compositiona
Telomeric Heterochromatin in Plasmodium falciparum
Rosaura Hernandez-Rivas,Karla Pérez-Toledo,Abril-Marcela Herrera Solorio,Dulce María Delgadillo,Miguel Vargas
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/290501
Abstract: Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions in Plasmodium falciparum. In yeast and Drosophila melanogaster, chromatin structure has long been known to be an important aspect in the regulation and functioning of these regions. Telomeres and subtelomeric regions are enriched in epigenetic marks that are specific to heterochromatin, such as methylation of lysine 9 of histone H3 and lysine 20 of histone H4. In P. falciparum, histone modifications and the presence of both the heterochromatin “writing” (PfSir2, PKMT) and “reading” (PfHP1) machinery at telomeric and subtelomeric regions indicate that these regions are likely to have heterochromatic structure that is epigenetically regulated. This structure may be important for telomere functions such as the silencing of the var gene family implicated in the cytoadherence and antigenic variation of these parasites.
The Plasmodium falciparum genome  [cached]
Jonathan B Weitzman
Genome Biology , 2002, DOI: 10.1186/gb-spotlight-20021003-01
Abstract: Malaria kills over one million people a year and some estimates predict that the number of cases may double in the next two decades. P. falciparum is the most lethal of the human Plasmodium species and an international effort to sequence its genome began six years ago.Gardner et al. carried out whole chromosome shotgun sequencing of P. falciparum clone 3D7 and observed that the genome is 22.8 Mb long, organized into 14 chromosomes and has an unusually high A+T composition (averaging 80.6% and rising to 90% in introns and intergenic regions). They predict that there are around 5,300 protein-coding genes, half of which contain introns. About half of the predicted genes match with results from proteomic and EST analyses. The P. falciparum genome exhibits minimal redundancy of tRNAs, lacks long tandem repeats of rRNA genes and has a complex subtelomeric repeat structure.Unsurprisingly the P. falciparum genome contains large numbers of genes implicated in cell adhesion and evasion of the host immune system, but a relative dearth of genes encoding enzymes and transporters, and around 60% of the predicted genes could not be assigned a function - more than found in other eukaryotes. The malaria parasite harbors an 'apicoplast' (an organelle thought to be plant derived) that is necessary for survival, and which has a 35 kb genome that encodes about 30 proteins that may be supplemented by as many as 551 nuclear-encoded proteins. Perhaps as a consequence of this, the P. falciparum genome is more similar to that of Arabidopsis than to any other sequenced eukaryotic genome.The authors report extensive analysis of genes involved in metabolism, membrane transport, DNA metabolism, secretory pathways and immune evasion. They expect the genome sequence to stimulate the identification of potential antigens for vaccine development programmes and the design of high-throughput immunological assay systems.The availability of parasite, vector and host genomes offers a unique opportunity to
Gametocytogenesis : the puberty of Plasmodium falciparum
Arthur M Talman, Olivier Domarle, F McKenzie, Frédéric Ariey, Vincent Robert
Malaria Journal , 2004, DOI: 10.1186/1475-2875-3-24
Abstract: Plasmodium falciparum has the morbid characteristic of being the deadliest protozoan parasite of humans. Like all malaria parasites, it is an organism with an obligatory sexual reproduction which takes place in the mosquito midgut. After several development stages, the parasite migrates to the salivary glands to be injected into the next human host. However, before it can succeed sexually in the mosquito host, P. falciparum undergoes a puberty-like process in the human blood: an asexual parasite goes through a series of changes, which will lead to the generation of a sexually competent parasite. This maturation has been termed gametocytogenesis, whereby male and female gametocytes (i.e. pre-gametes) are produced to later fertilize in the invertebrate host.One of the intriguing facts about sex is that it has been established and maintained regardless of how expensive it might be to the organism bearing it [1]. Several costs are associated with sexual reproduction. There is a two-fold disadvantage as compared to asexual proliferation: the investment in securing a mate and the risk of mixing genes with another, possibly burdened, individual [2]. The fusion of genomes (syngamy), followed by meiosis, whereby chromosomal segregation and recombination occur, seems, however, to confer sufficiently powerful advantages to have driven and maintained sexual reproduction in a vast majority of eukaryotes.Gametocytogenesis delivers a gametocyte, the only transmission stage from the human to the mosquito. Moreover, it allows sexual achievement and therefore recombination with other genotypes. The present review focuses on specific points of commitment to sexual development – gametocytogenesis and gametocyte biology–especially those relevant to transmission and evolution of P. falciparum transmission strategies.A gametocyte is a cell specializing in the transition between the human and the mosquito host. In order to adjust to life in such drastically different environments, many cha
Detectability of Plasmodium falciparum clones
Michael T Bretscher, Francesca Valsangiacomo, Seth Owusu-Agyei, Melissa A Penny, Ingrid Felger, Tom Smith
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-234
Abstract: A longitudinal molecular study was conducted in the Kassena-Nankana district in northern Ghana. From each of the 80 participants, four finger prick samples were collected over a period of 8 days, and tested for presence of different Merozoite Surface Protein (msp) 2 genotypes. Implications for estimating q were derived from these data by comparing the fit of statistical models of serial dependence and over-dispersion.The distribution of the frequencies of detection for msp2 genotypes was close to binomial if the time span between consecutive blood samples was at least 7 days. For shorter intervals the probabilities of detection were positively correlated, i.e. the shorter the interval between two blood collections, the more likely the diagnostic results matched for a particular genotype. Estimates of q were rather insensitive to the statistical model fitted.A simple algorithm based on analysing blood samples collected 7 days apart is justified for generating robust estimates of detectability. The finding of positive correlation of detection probabilities for short time intervals argues against imperfect detection being directly linked to the 48-hour periodicity of P. falciparum. The results suggest that the detectability of a given parasite clone changes over time, at an unknown rate, but fast enough to regard blood samples taken one week apart as statistically independent.In areas of high endemicity of Plasmodium falciparum, human hosts are often superinfected with multiple clones of the parasite [1]. Identification of these concurrent infections is important for understanding patterns of drug resistance [2] and of the transmission of the parasite. PCR-based methods for detecting parasites not only have lower detection limits than blood smear microscopy, but also make it possible to distinguish genetically distinct clones, and hence to compute multiplicity of infection. But at least two diagnostic problems remain: i) the same host might be infected with more than o
Genetic diversity of Plasmodium vivax and Plasmodium falciparum in Honduras
Lopez Ana,Ortiz Andres,Coello Jorge,Sosa-Ochoa Wilfredo
Malaria Journal , 2012, DOI: 10.1186/1475-2875-11-391
Abstract: Background Understanding the population structure of Plasmodium species through genetic diversity studies can assist in the design of more effective malaria control strategies, particularly in vaccine development. Central America is an area where malaria is a public health problem, but little is known about the genetic diversity of the parasite’s circulating species. This study aimed to investigate the allelic frequency and molecular diversity of five surface antigens in field isolates from Honduras. Methods Five molecular markers were analysed to determine the genotypes of Plasmodium vivax and Plasmodium falciparum from endemic areas in Honduras. Genetic diversity of ama-1, msp-1 and csp was investigated for P. vivax, and msp-1 and msp-2 for P. falciparum. Allelic frequencies were calculated and sequence analysis performed. Results and conclusion A high genetic diversity was observed within Plasmodium isolates from Honduras. A different number of genotypes were elucidated: 41 (n = 77) for pvama-1; 23 (n = 84) for pvcsp; and 23 (n = 35) for pfmsp-1. Pvcsp sequences showed VK210 as the only subtype present in Honduran isolates. Pvmsp-1 (F2) was the most polymorphic marker for P. vivax isolates while pvama-1 was least variable. All three allelic families described for pfmsp-1 (n = 30) block 2 (K1, MAD20, and RO33), and both allelic families described for the central domain of pfmsp-2 (n = 11) (3D7 and FC27) were detected. However, K1 and 3D7 allelic families were predominant. All markers were randomly distributed across the country and no geographic correlation was found. To date, this is the most complete report on molecular characterization of P. vivax and P. falciparum field isolates in Honduras with regards to genetic diversity. These results indicate that P. vivax and P. falciparum parasite populations are highly diverse in Honduras despite the low level of transmission.
Recombination Hotspots and Population Structure in Plasmodium falciparum  [PDF]
Jianbing Mu,Philip Awadalla,Junhui Duan,Kate M. McGee,Deirdre A. Joy,Gilean A. T. McVean,Xin-zhuan Su
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0030335
Abstract: Understanding the influences of population structure, selection, and recombination on polymorphism and linkage disequilibrium (LD) is integral to mapping genes contributing to drug resistance or virulence in Plasmodium falciparum. The parasite's short generation time, coupled with a high cross-over rate, can cause rapid LD break-down. However, observations of low genetic variation have led to suggestions of effective clonality: selfing, population admixture, and selection may preserve LD in populations. Indeed, extensive LD surrounding drug-resistant genes has been observed, indicating that recombination and selection play important roles in shaping recent parasite genome evolution. These studies, however, provide only limited information about haplotype variation at local scales. Here we describe the first (to our knowledge) chromosome-wide SNP haplotype and population recombination maps for a global collection of malaria parasites, including the 3D7 isolate, whose genome has been sequenced previously. The parasites are clustered according to continental origin, but alternative groupings were obtained using SNPs at 37 putative transporter genes that are potentially under selection. Geographic isolation and highly variable multiple infection rates are the major factors affecting haplotype structure. Variation in effective recombination rates is high, both among populations and along the chromosome, with recombination hotspots conserved among populations at chromosome ends. This study supports the feasibility of genome-wide association studies in some parasite populations.
Recombination Hotspots and Population Structure in Plasmodium falciparum  [PDF]
Jianbing Mu,Philip Awadalla ,Junhui Duan,Kate M McGee,Deirdre A Joy,Gilean A. T McVean,Xin-zhuan Su
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030335
Abstract: Understanding the influences of population structure, selection, and recombination on polymorphism and linkage disequilibrium (LD) is integral to mapping genes contributing to drug resistance or virulence in Plasmodium falciparum. The parasite's short generation time, coupled with a high cross-over rate, can cause rapid LD break-down. However, observations of low genetic variation have led to suggestions of effective clonality: selfing, population admixture, and selection may preserve LD in populations. Indeed, extensive LD surrounding drug-resistant genes has been observed, indicating that recombination and selection play important roles in shaping recent parasite genome evolution. These studies, however, provide only limited information about haplotype variation at local scales. Here we describe the first (to our knowledge) chromosome-wide SNP haplotype and population recombination maps for a global collection of malaria parasites, including the 3D7 isolate, whose genome has been sequenced previously. The parasites are clustered according to continental origin, but alternative groupings were obtained using SNPs at 37 putative transporter genes that are potentially under selection. Geographic isolation and highly variable multiple infection rates are the major factors affecting haplotype structure. Variation in effective recombination rates is high, both among populations and along the chromosome, with recombination hotspots conserved among populations at chromosome ends. This study supports the feasibility of genome-wide association studies in some parasite populations.
Plasmodium falciparum virulence determinants unveiled
Brendan S Crabb, Alan F Cowman
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-11-reviews1031
Abstract: Despite intensive efforts over the last century to understand and control malaria, the causative agent of the most severe form of the disease - Plasmodium falciparum - remains firmly entrenched as a leading cause of morbidity and mortality in humans. Approximately 300-500 million clinical episodes and 2.7 million deaths are attributed to P. falciparum infections each year and, with the emergence of widespread drug-resistant parasite populations and insecticide-resistant mosquitoes, this situation is predicted to worsen [1]. New cost-effective strategies for controlling malaria, such as the development of a vaccine, are urgently required. The complete sequence of the 14 linear chromosomes that comprise the P. falciparum genome has recently been determined [2,3,4,5]. It is perhaps not surprising for such a successful pathogen that these studies have revealed that a high proportion of the 5,300 predicted genes encode proteins known or predicted to play a role in pathogenic processes, such as invasion of red blood cells, cytoadherence and immune evasion. We have reviewed elsewhere the impact of the genome sequence on red blood cell invasion [6]; in this article, we comment on our increased understanding of the virulence genes that encode proteins involved in cytoadherence and immune evasion. Insight into the function, diversity and regulation of these genes promises to reveal new strategies for fighting malarial disease [7].The adhesion of parasite-infected red blood cells to vascular endothelium leads to sequestration of P. falciparum in the deep microvasculature of various tissues and organs, and is associated with certain severe disease outcomes (reviewed in [8,9,10]). A parasite protein inserted into the infected red blood cell surface, known as P. falciparum erythrocyte membrane protein 1 (PfEMP1), is considered to be a key adhesive ligand mediating sequestration. In a process known as antigenic variation, clonal P. falciparum parasites can vary the type of PfEMP1
In vivo transcriptional profiling of Plasmodium falciparum
Johanna P Daily, Karine G Le Roch, Ousmane Sarr, Xuemin Fang, Yingyao Zhou, Omar Ndir, Soulyemane Mboup, Ali Sultan, Elizabeth A Winzeler, Dyann F Wirth
Malaria Journal , 2004, DOI: 10.1186/1475-2875-3-30
Abstract: A custom made oligonucleotide array with probes based on the P. falciparum 3D7 laboratory strain chromosome 2 sequence was used to detect in vivo P. falciparum transcripts. This study analyzed transcripts from total RNA derived from small blood samples of P. falciparum infected patients and compared the in vivo expression profile to the in vitro cultivated 3D7 strain transcriptome.The data demonstrated that in vivo transcription can be studied from a small blood sample, despite the abundance of human RNA. The in vivo transcriptome is similar to the 3D7 ring stage transcriptome, but there are significant differences in genes encoding a sexual stage antigen and surface proteins.Whole genome transcription analysis of P. falciparum can be carried out successfully and further studies in selected patient cohorts may provide insight into parasite in vivo biology and defense against host immunity.Plasmodium falciparum infection remains a major health problem worldwide. Its complex life cycle has hampered standard methods for the study of pathogenesis. New approaches to elucidate parasite biology using whole genomic methods have provided insight into gene function, transcriptional regulation and stage specific biology [1-4]. Characterization of the in vivo biology of this pathogen, through adaptation of a whole genome approach, would provide insight into the host-parasite relationship, parasite virulence factors and inform new strategies for intervention. Genomic scale transcriptional profiling of P. falciparum during a natural infection is presented. Small amounts of parasite RNA, isolated from a few milliliters of a blood sample are found to be sufficient for whole genome transcriptional analysis. This data show that several genes are differentially expressed in vivo, indicating differences between the transcriptional program of 3D7 laboratory strain parasites growing in culture and naturally occurring infections in the human host.Whole genome expression has been used in s
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