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Multiple var2csa-type PfEMP1 genes located at different chromosomal loci occur in many Plasmodium falciparum isolates.

Sander AF, Salanti A, Lavstsen T, Nielsen MA, Magistrado P, Lusingu J, Ndam NT, Arnot DE - PLoS ONE (2009)

Bottom Line: This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates.One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates.Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria.

View Article: PubMed Central - PubMed

Affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, Faculty of Health Sciences, University of Copenhagen & Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.

ABSTRACT

Background: The var2csa gene encodes a Plasmodium falciparum adhesion receptor which binds chondroitin sulfate A (CSA). This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates. In isolates 3D7, FCR3/It4 and HB3, var2csa is transcribed from a sub-telomeric position on the left arm of chromosome 12, but it is not known if this location is conserved in all parasites. Genome sequencing indicates that the var2csa gene is duplicated in HB3, but whether this is true in natural populations is uncertain.

Methodology/principal findings: To assess global variation in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant women and from the peripheral circulation of other malaria patients. Sequence analysis, gene mapping and copy number quantitation in P.falciparum isolates indicate that there are at least two loci and that both var2csa-like genes can be transcribed. All VAR2CSA DBL2X domains fall into one of two distinct phylogenetic groups possessing one or the other variant of a large (approximately 26 amino acid) dimorphic motif, but whether either motif variant is linked to a specific locus is not known.

Conclusions/significance: Two or more related but distinct var2csa-type PfEMP1/var genes exist in many P. falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria.

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Phylogenetic relationships between 44 VAR2CSA DBL2X sequences.A. Neighbor joining tree illustrating the phylogenetic relationship between the sequences, with representatives of each of the two DSM variants marked in separate colors. 3D7-type sequences are shown in red and FCR3/It4-type in green. The bootstrap value is shown at the main bifurcation. B. Neighbor joining tree based on the same sequences, after excision of the DSM region. The 3D7/red, FCR3/It4/green variant-type coding is maintained.
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pone-0006667-g004: Phylogenetic relationships between 44 VAR2CSA DBL2X sequences.A. Neighbor joining tree illustrating the phylogenetic relationship between the sequences, with representatives of each of the two DSM variants marked in separate colors. 3D7-type sequences are shown in red and FCR3/It4-type in green. The bootstrap value is shown at the main bifurcation. B. Neighbor joining tree based on the same sequences, after excision of the DSM region. The 3D7/red, FCR3/It4/green variant-type coding is maintained.

Mentions: The dimorphism of DBL2X domains was investigated by a standard type of phylogenetic analysis based on the assumption that sequences are evolving largely by mutation. This has been cogently criticized as underestimating the role of very high levels of recombination in generating hyper-variable sequence blocks in P.falciparum PfEMP1/var genes [47]. However, by the standards of PfEMP1/var genes, the VAR2CSA DBL2X domain is not a hypervariable region and in fact shows some highly conserved features, as discussed below. Figure 4 shows the constructed neighbor-joining trees, based on 54 P.falciparum and one P.reichenowi var2csa DBL2X sequences. Figure 4A confirms that these DBL2X sequences will cluster into two distinct phylogenetic subgroups (bootstrap value 97). Sequences fall into one of two reference groups, the 3D7 DSM type, shown in green, or the FCR3/It4 DSM type, shown in red. To test whether this is due to the DSM, or other less obvious variation, the sequences were re-tested, after excising the DSM sequence from the alignments. The neighbor joining tree shows that the division of the sequences into two groups disappears and the branching of the tree is similar to the relationship observed between variants of other DBL domains [48]. Unsurprisingly, the branch lengths support a more distant relationship between the P.reichenowi sequence and all P.falciparum sequences but the conservation of the DSM still results in this particular P.reichenowi sequence clustering with FCR3/It4 sub-type sequences.


Multiple var2csa-type PfEMP1 genes located at different chromosomal loci occur in many Plasmodium falciparum isolates.

Sander AF, Salanti A, Lavstsen T, Nielsen MA, Magistrado P, Lusingu J, Ndam NT, Arnot DE - PLoS ONE (2009)

Phylogenetic relationships between 44 VAR2CSA DBL2X sequences.A. Neighbor joining tree illustrating the phylogenetic relationship between the sequences, with representatives of each of the two DSM variants marked in separate colors. 3D7-type sequences are shown in red and FCR3/It4-type in green. The bootstrap value is shown at the main bifurcation. B. Neighbor joining tree based on the same sequences, after excision of the DSM region. The 3D7/red, FCR3/It4/green variant-type coding is maintained.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2723927&req=5

pone-0006667-g004: Phylogenetic relationships between 44 VAR2CSA DBL2X sequences.A. Neighbor joining tree illustrating the phylogenetic relationship between the sequences, with representatives of each of the two DSM variants marked in separate colors. 3D7-type sequences are shown in red and FCR3/It4-type in green. The bootstrap value is shown at the main bifurcation. B. Neighbor joining tree based on the same sequences, after excision of the DSM region. The 3D7/red, FCR3/It4/green variant-type coding is maintained.
Mentions: The dimorphism of DBL2X domains was investigated by a standard type of phylogenetic analysis based on the assumption that sequences are evolving largely by mutation. This has been cogently criticized as underestimating the role of very high levels of recombination in generating hyper-variable sequence blocks in P.falciparum PfEMP1/var genes [47]. However, by the standards of PfEMP1/var genes, the VAR2CSA DBL2X domain is not a hypervariable region and in fact shows some highly conserved features, as discussed below. Figure 4 shows the constructed neighbor-joining trees, based on 54 P.falciparum and one P.reichenowi var2csa DBL2X sequences. Figure 4A confirms that these DBL2X sequences will cluster into two distinct phylogenetic subgroups (bootstrap value 97). Sequences fall into one of two reference groups, the 3D7 DSM type, shown in green, or the FCR3/It4 DSM type, shown in red. To test whether this is due to the DSM, or other less obvious variation, the sequences were re-tested, after excising the DSM sequence from the alignments. The neighbor joining tree shows that the division of the sequences into two groups disappears and the branching of the tree is similar to the relationship observed between variants of other DBL domains [48]. Unsurprisingly, the branch lengths support a more distant relationship between the P.reichenowi sequence and all P.falciparum sequences but the conservation of the DSM still results in this particular P.reichenowi sequence clustering with FCR3/It4 sub-type sequences.

Bottom Line: This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates.One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates.Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria.

View Article: PubMed Central - PubMed

Affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, Faculty of Health Sciences, University of Copenhagen & Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.

ABSTRACT

Background: The var2csa gene encodes a Plasmodium falciparum adhesion receptor which binds chondroitin sulfate A (CSA). This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates. In isolates 3D7, FCR3/It4 and HB3, var2csa is transcribed from a sub-telomeric position on the left arm of chromosome 12, but it is not known if this location is conserved in all parasites. Genome sequencing indicates that the var2csa gene is duplicated in HB3, but whether this is true in natural populations is uncertain.

Methodology/principal findings: To assess global variation in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant women and from the peripheral circulation of other malaria patients. Sequence analysis, gene mapping and copy number quantitation in P.falciparum isolates indicate that there are at least two loci and that both var2csa-like genes can be transcribed. All VAR2CSA DBL2X domains fall into one of two distinct phylogenetic groups possessing one or the other variant of a large (approximately 26 amino acid) dimorphic motif, but whether either motif variant is linked to a specific locus is not known.

Conclusions/significance: Two or more related but distinct var2csa-type PfEMP1/var genes exist in many P. falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria.

Show MeSH
Related in: MedlinePlus