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Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions.

Lavstsen T, Salanti A, Jensen AT, Arnot DE, Theander TG - Malar. J. (2003)

Bottom Line: Two sequences belonging to the var1 and var2 subfamilies formed independent groups.A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged.This organization appeared to be unique for the group A var genes The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Medical Parasitology at Institute for Medical Microbiology and Immunology, University of Copenhagen, Denmark. thomaslavstsen@vip.cybercity.dk

ABSTRACT

Background: The variant surface antigen family Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) is an important target for protective immunity and is implicated in the pathology of malaria through its ability to adhere to host endothelial receptors. The sequence diversity and organization of the 3D7 PfEMP1 repertoire was investigated on the basis of the complete genome sequence.

Methods: Using two tree-building methods we analysed the coding and non-coding sequences of 3D7 var and rif genes as well as var genes of other parasite strains.

Results: var genes can be sub-grouped into three major groups (group A, B and C) and two intermediate groups B/A and B/C representing transitions between the three major groups. The best defined var group, group A, comprises telomeric genes transcribed towards the telomere encoding PfEMP1s with complex domain structures different from the 4-domain type dominant of groups B and C. Two sequences belonging to the var1 and var2 subfamilies formed independent groups. A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged. This organization appeared to be unique for the group A var genes

Conclusion: The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.

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Distance tree of DBLαCIDR1 domains of 3D7 PfEMP1 and pseudogene PFE1640w generated using the p-distance/NJ method. The clusters A through E were supported by both bootstrapping and maximum parsimony tree (not shown). Numbers at the nodes represent bootstrap proportions (BP) on 1000 replicates. The scale bar represents the proportion of different amino acids compared. PlasmoDB accession numbers are shown. Genes with assigned cluster are collected in figure 7.
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Figure 3: Distance tree of DBLαCIDR1 domains of 3D7 PfEMP1 and pseudogene PFE1640w generated using the p-distance/NJ method. The clusters A through E were supported by both bootstrapping and maximum parsimony tree (not shown). Numbers at the nodes represent bootstrap proportions (BP) on 1000 replicates. The scale bar represents the proportion of different amino acids compared. PlasmoDB accession numbers are shown. Genes with assigned cluster are collected in figure 7.

Mentions: Because most PfEMP1 molecules contain a semi-conserved head structure comprising of DBL1α and CIDR1, and all contain the acidic terminal segment (ATS) encoded by exon II, we restricted the analysis of coding sequences to these domains. In 3D7 all but one var gene encode a DBLlα as the first domain and in all but four genes DBL1 is followed by a CIDR1. Since alignment and tree constructions of DBL1 and CIDR1 domains individually yielded almost identical clusters, we decided to analyse the head structure sequences from the N terminal region of DBL1 to a conserved motif in the C-terminal region of CIDR1 (figure 3). Fifty-two sequences, including that of pseudogene PFE1640w, could be grouped into five clusters, and four sequences could not be assigned any of these. When all CIDR sequences are aligned most CIDR1s fall into separate clusters of CIDRα or CIDRα1 domains[20]. The exceptions are three sequences (PF08_0141, PF11_0008, PF13_0003), which fall into a CIDRγ cluster. In figure 3, the head structures of these genes fall into group A. Robinson et al. [20] found that most CIDR domains bind CD36 but identified nine, which did not. These constitute cluster A. In the analysis of DBLα domains three small almost identical PfEMP1s (PFA0015c, MAL6P1.314, PFI1820w) clustered with the DBL1α of group A (data not shown). Thus, we named their DBL1 "A*" (Figure 7). Alignments and tree construction of all var ATS sequences (figure 4) identified four clusters. Though less well defined by bootstrap proportions the clusters were supported by both NJ and MP tree making methods. Four sequences could not be assigned to any of these clusters.


Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions.

Lavstsen T, Salanti A, Jensen AT, Arnot DE, Theander TG - Malar. J. (2003)

Distance tree of DBLαCIDR1 domains of 3D7 PfEMP1 and pseudogene PFE1640w generated using the p-distance/NJ method. The clusters A through E were supported by both bootstrapping and maximum parsimony tree (not shown). Numbers at the nodes represent bootstrap proportions (BP) on 1000 replicates. The scale bar represents the proportion of different amino acids compared. PlasmoDB accession numbers are shown. Genes with assigned cluster are collected in figure 7.
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Related In: Results  -  Collection

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Figure 3: Distance tree of DBLαCIDR1 domains of 3D7 PfEMP1 and pseudogene PFE1640w generated using the p-distance/NJ method. The clusters A through E were supported by both bootstrapping and maximum parsimony tree (not shown). Numbers at the nodes represent bootstrap proportions (BP) on 1000 replicates. The scale bar represents the proportion of different amino acids compared. PlasmoDB accession numbers are shown. Genes with assigned cluster are collected in figure 7.
Mentions: Because most PfEMP1 molecules contain a semi-conserved head structure comprising of DBL1α and CIDR1, and all contain the acidic terminal segment (ATS) encoded by exon II, we restricted the analysis of coding sequences to these domains. In 3D7 all but one var gene encode a DBLlα as the first domain and in all but four genes DBL1 is followed by a CIDR1. Since alignment and tree constructions of DBL1 and CIDR1 domains individually yielded almost identical clusters, we decided to analyse the head structure sequences from the N terminal region of DBL1 to a conserved motif in the C-terminal region of CIDR1 (figure 3). Fifty-two sequences, including that of pseudogene PFE1640w, could be grouped into five clusters, and four sequences could not be assigned any of these. When all CIDR sequences are aligned most CIDR1s fall into separate clusters of CIDRα or CIDRα1 domains[20]. The exceptions are three sequences (PF08_0141, PF11_0008, PF13_0003), which fall into a CIDRγ cluster. In figure 3, the head structures of these genes fall into group A. Robinson et al. [20] found that most CIDR domains bind CD36 but identified nine, which did not. These constitute cluster A. In the analysis of DBLα domains three small almost identical PfEMP1s (PFA0015c, MAL6P1.314, PFI1820w) clustered with the DBL1α of group A (data not shown). Thus, we named their DBL1 "A*" (Figure 7). Alignments and tree construction of all var ATS sequences (figure 4) identified four clusters. Though less well defined by bootstrap proportions the clusters were supported by both NJ and MP tree making methods. Four sequences could not be assigned to any of these clusters.

Bottom Line: Two sequences belonging to the var1 and var2 subfamilies formed independent groups.A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged.This organization appeared to be unique for the group A var genes The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Medical Parasitology at Institute for Medical Microbiology and Immunology, University of Copenhagen, Denmark. thomaslavstsen@vip.cybercity.dk

ABSTRACT

Background: The variant surface antigen family Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) is an important target for protective immunity and is implicated in the pathology of malaria through its ability to adhere to host endothelial receptors. The sequence diversity and organization of the 3D7 PfEMP1 repertoire was investigated on the basis of the complete genome sequence.

Methods: Using two tree-building methods we analysed the coding and non-coding sequences of 3D7 var and rif genes as well as var genes of other parasite strains.

Results: var genes can be sub-grouped into three major groups (group A, B and C) and two intermediate groups B/A and B/C representing transitions between the three major groups. The best defined var group, group A, comprises telomeric genes transcribed towards the telomere encoding PfEMP1s with complex domain structures different from the 4-domain type dominant of groups B and C. Two sequences belonging to the var1 and var2 subfamilies formed independent groups. A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged. This organization appeared to be unique for the group A var genes

Conclusion: The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.

Show MeSH
Related in: MedlinePlus