Identification and Functional Validation of the Novel Antimalarial
Resistance Locus in
The Plasmodium falciparum parasite's ability to adapt to
environmental pressures, such as the human immune system and antimalarial drugs,
makes malaria an enduring burden to public health. Understanding the genetic
basis of these adaptations is critical to intervening successfully against
malaria. To that end, we created a high-density genotyping array that assays
over 17,000 single nucleotide polymorphisms (∼1 SNP/kb), and applied it to
57 culture-adapted parasites from three continents. We characterized genome-wide
genetic diversity within and between populations and identified numerous loci
with signals of natural selection, suggesting their role in recent adaptation.
In addition, we performed a genome-wide association study (GWAS), searching for
loci correlated with resistance to thirteen antimalarials; we detected both
known and novel resistance loci, including a new halofantrine resistance locus,
PF10_0355. Through functional testing we demonstrated that
PF10_0355 overexpression decreases sensitivity to
halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated
antimalarials, and that increased gene copy number mediates resistance. Our GWAS
and follow-on functional validation demonstrate the potential of genome-wide
studies to elucidate functionally important loci in the malaria parasite
genome.
Vyšlo v časopise:
Identification and Functional Validation of the Novel Antimalarial
Resistance Locus in. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1001383
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001383
Souhrn
The Plasmodium falciparum parasite's ability to adapt to
environmental pressures, such as the human immune system and antimalarial drugs,
makes malaria an enduring burden to public health. Understanding the genetic
basis of these adaptations is critical to intervening successfully against
malaria. To that end, we created a high-density genotyping array that assays
over 17,000 single nucleotide polymorphisms (∼1 SNP/kb), and applied it to
57 culture-adapted parasites from three continents. We characterized genome-wide
genetic diversity within and between populations and identified numerous loci
with signals of natural selection, suggesting their role in recent adaptation.
In addition, we performed a genome-wide association study (GWAS), searching for
loci correlated with resistance to thirteen antimalarials; we detected both
known and novel resistance loci, including a new halofantrine resistance locus,
PF10_0355. Through functional testing we demonstrated that
PF10_0355 overexpression decreases sensitivity to
halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated
antimalarials, and that increased gene copy number mediates resistance. Our GWAS
and follow-on functional validation demonstrate the potential of genome-wide
studies to elucidate functionally important loci in the malaria parasite
genome.
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