Arthropod disease vectors not only transmit malaria but many other serious diseases, many of which are, to a greater or lesser degree, neglected [...].
Mechanisms of transcriptional control in malaria parasites are still not fully understood. The positioning patterns of G-quadruplex (G4) DNA motifs in the parasite's AT-rich genome, especially within the var gene family which encodes virulence factors, and in the vicinity of recombination hotspots, points towards a possible regulatory role of G4 in gene expression and genome stability. Here, we carried out the most comprehensive genome-wide survey, to date, of G4s in the Plasmodium falciparum genome using G4Hunter, which identifies G4 forming sequences (G4FS) considering their G-richness and G-skewness. We show an enrichment of G4FS in nucleosome-depleted regions and in the first exon of var genes, a pattern that is conserved within the closely related Laverania Plasmodium parasites. Under G4-stabilizing conditions, i.e., following treatment with pyridostatin (a high affinity G4 ligand), we show that a bona fide G4 found in the non-coding strand of var promoters modulates reporter gene expression. Furthermore, transcriptional profiling of pyridostatin-treated parasites, shows large scale perturbations, with deregulation affecting for instance the ApiAP2 family of transcription factors and genes involved in ribosome biogenesis. Overall, our study highlights G4s as important DNA secondary structures with a role in Plasmodium gene expression regulation, sub-telomeric recombination and var gene biology.
- MeSH
- aminochinoliny farmakologie MeSH
- G-kvadruplexy * MeSH
- genom účinky léků MeSH
- kyseliny pikolinové farmakologie MeSH
- lidé MeSH
- malárie farmakoterapie genetika parazitologie MeSH
- nukleotidové motivy genetika MeSH
- Plasmodium falciparum genetika patogenita MeSH
- promotorové oblasti (genetika) genetika MeSH
- regulace genové exprese účinky léků MeSH
- ribozomy účinky léků genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Genome-wide studies of African populations have the potential to reveal powerful insights into the evolution of our species, as these diverse populations have been exposed to intense selective pressures imposed by infectious diseases, diet, and environmental factors. Within Africa, the Sahel Belt extensively overlaps the geographical center of several endemic infections such as malaria, trypanosomiasis, meningitis, and hemorrhagic fevers. We screened 2.5 million single nucleotide polymorphisms in 161 individuals from 13 Sahelian populations, which together with published data cover Western, Central, and Eastern Sahel, and include both nomadic and sedentary groups. We confirmed the role of this Belt as a main corridor for human migrations across the continent. Strong admixture was observed in both Central and Eastern Sahelian populations, with North Africans and Near Eastern/Arabians, respectively, but it was inexistent in Western Sahelian populations. Genome-wide local ancestry inference in admixed Sahelian populations revealed several candidate regions that were significantly enriched for non-autochthonous haplotypes, and many showed to be under positive selection. The DARC gene region in Arabs and Nubians was enriched for African ancestry, whereas the RAB3GAP1/LCT/MCM6 region in Oromo, the TAS2R gene family in Fulani, and the ALMS1/NAT8 in Turkana and Samburu were enriched for non-African ancestry. Signals of positive selection varied in terms of geographic amplitude. Some genomic regions were selected across the Belt, the most striking example being the malaria-related DARC gene. Others were Western-specific (oxytocin, calcium, and heart pathways), Eastern-specific (lipid pathways), or even population-restricted (TAS2R genes in Fulani, which may reflect sexual selection).
- MeSH
- acetyltransferasy genetika MeSH
- genom lidský * MeSH
- haplotypy MeSH
- hemoragické horečky virové genetika MeSH
- jednonukleotidový polymorfismus MeSH
- krevní skupiny - systém Duffy genetika MeSH
- lidé MeSH
- malárie genetika MeSH
- MCM komplex, komponenta 6 genetika MeSH
- meningitida genetika MeSH
- migrace lidstva * MeSH
- proteiny genetika MeSH
- receptory buněčného povrchu genetika MeSH
- receptory spřažené s G-proteiny genetika MeSH
- selekce (genetika) * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Afrika MeSH
