RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics

2020

Preprint

Self Cite

Background : The Plasmodium genus of malaria parasites encodes several families of antigen-encoding genes. These genes tend to be hyper-variable, highly recombinogenic and variantly expressed. The best-characterized family is the var genes, exclusively found in the Laveranian subgenus of malaria parasites infecting humans and great apes. Var genes encode major virulence factors involved in immune evasion and the maintenance of chronic infections. In the human parasite P. falciparum , var gene recombination and diversification appear to be promoted by G-quadruplex (G4) DNA motifs, which are strongly associated with var genes in P. falciparum . Here, we investigated how this association might have evolved across Plasmodium species – both Laverania and also more distantly related species which lack var s but encode other, more ancient variant gene families. Results : The association between var genes and G4-forming motifs was conserved across Laverania, spanning ~1 million years of evolutionary time, with suggestive evidence for evolution of the association occurring within this subgenus. In rodent malaria species, G4-forming motifs were somewhat associated with pir genes, but this was not conserved in the Laverania, nor did we find a strong association of these motifs with any gene family in a second outgroup of avian malaria parasites. Secondly, we compared two different G4 prediction algorithms in their performance on extremely A/T-rich Plasmodium genomes, and also compared these predictions with experimental data from G4-seq, a DNA sequencing method for identifying G4-forming motifs. We found a surprising lack of concordance between the two algorithms and also between the algorithms and G4-seq data. Conclusions: G4-forming motifs are uniquely strongly associated with Plasmodium var genes, suggesting a particular role for G4s in recombination and diversification of these genes. Secondly, in the A/T-rich genomes of Plasmodium species, the choice of prediction algorithm may be particularly influential when studying G4s in these important protozoan pathogens.

Section: Introductionmentioning

confidence: 87%

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

2020

Preprint

Self Cite

“…The motifs strongly associate with recombination breakpoints that were observed in var genes when parasites were cultured over many mitotic cycles, evolving new gene variants [23]. Furthermore, the knockdown of a RecQ helicase homolog called PfWRN dramatically increased the rate of var gene recombination, as would be expected if this helicase was responsible for unwinding G4s and modulating their recombinogenic effects [24].…”

Section: Introductionmentioning

confidence: 95%

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

2020

BMC Genomics

Self Cite

Background: The Plasmodium genus of malaria parasites encodes several families of antigen-encoding genes. These genes tend to be hyper-variable, highly recombinogenic and variantly expressed. The best-characterized family is the var genes, exclusively found in the Laveranian subgenus of malaria parasites infecting humans and great apes. Var genes encode major virulence factors involved in immune evasion and the maintenance of chronic infections. In the human parasite P. falciparum, var gene recombination and diversification appear to be promoted by G-quadruplex (G4) DNA motifs, which are strongly associated with var genes in P. falciparum. Here, we investigated how this association might have evolved across Plasmodium speciesboth Laverania and also more distantly related species which lack vars but encode other, more ancient variant gene families. Results: The association between var genes and G4-forming motifs was conserved across Laverania, spanning~1 million years of evolutionary time, with suggestive evidence for evolution of the association occurring within this subgenus. In rodent malaria species, G4-forming motifs were somewhat associated with pir genes, but this was not conserved in the Laverania, nor did we find a strong association of these motifs with any gene family in a second outgroup of avian malaria parasites. Secondly, we compared two different G4 prediction algorithms in their performance on extremely A/T-rich Plasmodium genomes, and also compared these predictions with experimental data from G4-seq, a DNA sequencing method for identifying G4-forming motifs. We found a surprising lack of concordance between the two algorithms and also between the algorithms and G4-seq data. Conclusions: G4-forming motifs are uniquely strongly associated with Plasmodium var genes, suggesting a particular role for G4s in recombination and diversification of these genes. Secondly, in the A/T-rich genomes of Plasmodium species, the choice of prediction algorithm may be particularly influential when studying G4s in these important protozoan pathogens.

“…The motifs strongly associate with recombination breakpoints that were observed in var genes when parasites were cultured over many mitotic cycles, evolving new gene variants [21]. Furthermore, the knockdown of a RecQ helicase homolog called PfWRN dramatically increased the rate of var gene recombination, as would be expected if this helicase was responsible for unwinding G4s and modulating their recombinogenic effects [22].…”

mentioning

confidence: 95%

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

2020

Preprint

Self Cite

Background: The Plasmodium genus of malaria parasites encodes several families of antigenencoding genes. These genes tend to be hyper-variable, highly recombinogenic and variantly expressed. The best-characterized family is the var genes, exclusively found in the Laveranian subgenus of malaria parasites infecting humans and great apes. Var genes encode major virulence factors involved in immune evasion and the maintenance of chronic infections. In the human parasite P. falciparum, var gene recombination and diversification appear to be promoted by G-quadruplex (G4) DNA motifs, which are strongly associated with var genes in P. falciparum. Here, we investigated how this association might have evolved across Plasmodium species -both Laverania and also more distantly related species which lack vars but encode other, more ancient variant gene families.Results: The association between var genes and G4-forming motifs was conserved across Laverania, spanning ~1 million years of evolutionary time, with suggestive evidence for evolution of the association occurring within this subgenus. In rodent malaria species, G4-forming motifs were somewhat associated with pir genes, but this was not conserved in the Laverania, nor did we find a strong association of these motifs with any gene family in a second outgroup of avian malaria parasites. Secondly, we compared two different G4 prediction algorithms in their performance on extremely A/T-rich Plasmodium genomes, and also compared these predictions with experimental data from G4-seq, a DNA sequencing method for identifying G4-forming motifs. We found a surprising lack of concordance between the two algorithms and also between the algorithms and G4-seq data.Conclusions: G4-forming motifs are uniquely strongly associated with Plasmodium var genes, suggesting a particular role for G4s in recombination and diversification of these genes. Secondly, in the A/T-rich genomes of Plasmodium species, the choice of prediction algorithm may be particularly influential when studying G4s in these important protozoan pathogens. BackgroundMalaria is caused by protozoan Plasmodium parasites: in humans it causes considerable morbidity and is still responsible for almost half a million deaths each year [1]. Most severe cases of human malaria are caused by Plasmodium falciparum, but a further five parasite species can infect humans 3 and there are many more species that infect rodents, birds and other vertebrates. In all vertebrate hosts, the disease involves cyclical infection of erythrocytes by Plasmodium parasites. The infected cells are exposed to circulating immune factors and also to splenic clearance, yet many malarias can lead to both chronic and repeated infections, indicating that the parasites have considerable capacities for immune evasion. These capacities have been linked, in several species, to the variant expression of virulence factors that are exposed on the infected erythrocyte surface and are encoded by highly variable families of variantly-expressed virulence genes.Such gene fa...