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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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Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


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