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      Generation of Antigenic Diversity in Plasmodium falciparum by Structured Rearrangement of Var Genes During Mitosis

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          Abstract

          The most polymorphic gene family in P. falciparum is the ∼60 var genes distributed across parasite chromosomes, both in the subtelomeres and in internal regions. They encode hypervariable surface proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) that are critical for pathogenesis and immune evasion in Plasmodium falciparum. How var gene sequence diversity is generated is not currently completely understood. To address this, we constructed large clone trees and performed whole genome sequence analysis to study the generation of novel var gene sequences in asexually replicating parasites. While single nucleotide polymorphisms (SNPs) were scattered across the genome, structural variants (deletions, duplications, translocations) were focused in and around var genes, with considerable variation in frequency between strains. Analysis of more than 100 recombination events involving var exon 1 revealed that the average nucleotide sequence identity of two recombining exons was only 63% (range: 52.7–72.4%) yet the crossovers were error-free and occurred in such a way that the resulting sequence was in frame and domain architecture was preserved. Var exon 1, which encodes the immunologically exposed part of the protein, recombined in up to 0.2% of infected erythrocytes in vitro per life cycle. The high rate of var exon 1 recombination indicates that millions of new antigenic structures could potentially be generated each day in a single infected individual. We propose a model whereby var gene sequence polymorphism is mainly generated during the asexual part of the life cycle.

          Author Summary

          Malaria kills >600,000 people each year, with most deaths caused by Plasmodium falciparum. A family of proteins known as P. falciparum erythrocyte membrane protein 1, PfEMP1, is expressed on the surface of infected erythrocytes and plays an important role in pathogenesis. Each P. falciparum genome contains approximately 60 highly polymorphic var genes encoding the PfEMP1 proteins, and monoallelic expression with periodic switching results in immune evasion. Var gene polymorphism is thus critical to this survival strategy. We investigated how var gene diversity is generated by performing an in vitro evolution experiment, tracking var gene mutation in ‘real-time’ with whole genome sequencing. We found that genome structural variation is focused in and around var genes. These genetic rearrangements created new ‘chimeric’ var gene sequences during the mitotic part of the life cycle, and were consistent with processes of mitotic non-allelic homologous recombination. The recombinant var genes were always in frame and with conserved overall var gene architecture, and the recombination rate implies that many millions of rearranged var gene sequences are produced every 48-hour life cycle within infected individuals. In conclusion, we provide a detailed description of how new var gene sequences are continuously generated in the parasite genome, helping to explain long-term parasite survival within infected human hosts.

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          Most cited references 38

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            Genome sequence of the human malaria parasite Plasmodium falciparum.

            The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.
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              Global malaria mortality between 1980 and 2010: a systematic analysis.

              During the past decade, renewed global and national efforts to combat malaria have led to ambitious goals. We aimed to provide an accurate assessment of the levels and time trends in malaria mortality to aid assessment of progress towards these goals and the focusing of future efforts. We systematically collected all available data for malaria mortality for the period 1980-2010, correcting for misclassification bias. We developed a range of predictive models, including ensemble models, to estimate malaria mortality with uncertainty by age, sex, country, and year. We used key predictors of malaria mortality such as Plasmodium falciparum parasite prevalence, first-line antimalarial drug resistance, and vector control. We used out-of-sample predictive validity to select the final model. Global malaria deaths increased from 995,000 (95% uncertainty interval 711,000-1,412,000) in 1980 to a peak of 1,817,000 (1,430,000-2,366,000) in 2004, decreasing to 1,238,000 (929,000-1,685,000) in 2010. In Africa, malaria deaths increased from 493,000 (290,000-747,000) in 1980 to 1,613,000 (1,243,000-2,145,000) in 2004, decreasing by about 30% to 1,133,000 (848,000-1,591,000) in 2010. Outside of Africa, malaria deaths have steadily decreased from 502,000 (322,000-833,000) in 1980 to 104,000 (45,000-191,000) in 2010. We estimated more deaths in individuals aged 5 years or older than has been estimated in previous studies: 435,000 (307,000-658,000) deaths in Africa and 89,000 (33,000-177,000) deaths outside of Africa in 2010. Our findings show that the malaria mortality burden is larger than previously estimated, especially in adults. There has been a rapid decrease in malaria mortality in Africa because of the scaling up of control activities supported by international donors. Donor support, however, needs to be increased if malaria elimination and eradication and broader health and development goals are to be met. The Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Affiliations
                [1 ]Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
                [2 ]MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom
                Weill Medical College of Cornell University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AC WLH JCR DK. Performed the experiments: AC WLH MK AF. Analyzed the data: AC WLH JCR DK. Contributed reagents/materials/analysis tools: TDO. Wrote the paper: AC WLH TDO JCR DK.

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                December 2014
                18 December 2014
                : 10
                : 12
                PGENETICS-D-14-01590
                10.1371/journal.pgen.1004812
                4270465
                25521112

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 16
                Funding
                This work was supported by the Wellcome Trust (098051) and the Medical Research Council (G0600718). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Biochemistry
                DNA
                DNA recombination
                Homologous Recombination
                Proteins
                Immune System Proteins
                Antigens
                Antigenic Variation
                Genetics
                Genomics
                Immunology
                Parasitology
                Parasite Groups
                Apicomplexa
                Plasmodium
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. Data has been uploaded to the European Nucleotide Archive under the accession numbers found in Table S1.

                Genetics

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