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Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in plasmodium falciparum
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نویسنده
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van tyne d. ,park d.j. ,schaffner s.f. ,neafsey d.e. ,angelino e. ,cortese j.f. ,barnes k.g. ,rosen d.m. ,lukens a.k. ,daniels r.f. ,milner jr. d.a. ,johnson c.a. ,shlyakhter i. ,grossman s.r. ,becker j.s. ,yamins d. ,karlsson e.k. ,ndiaye d. ,sarr o. ,mboup s. ,happi c. ,furlotte n.a. ,eskin e. ,kang h.m. ,hartl d.l. ,birren b.w. ,wiegand r.c. ,lander e.s. ,wirth d.f. ,volkman s.k. ,sabeti p.c.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 4
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چکیده
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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. © 2011 van tyne et al.
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آدرس
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department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, broad institute,cambridge,ma,united states,organismic and evolutionary biology,harvard university,cambridge,ma, United States, broad institute,cambridge,ma, United States, broad institute,cambridge,ma, United States, fas center for systems biology,harvard university,cambridge,ma,united states,harvard medical school,boston,ma, United States, broad institute,cambridge,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, broad institute,cambridge,ma,united states,biological and biomedical sciences,harvard university,cambridge,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, broad institute,cambridge,ma, United States, broad institute,cambridge,ma,united states,organismic and evolutionary biology,harvard university,cambridge,ma,united states,fas center for systems biology,harvard university,cambridge,ma, United States, broad institute,cambridge,ma,united states,organismic and evolutionary biology,harvard university,cambridge,ma,united states,fas center for systems biology,harvard university,cambridge,ma,united states,harvard medical school,boston,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma, United States, fas center for systems biology,harvard university,cambridge,ma, United States, broad institute,cambridge,ma,united states,organismic and evolutionary biology,harvard university,cambridge,ma,united states,fas center for systems biology,harvard university,cambridge,ma, United States, faculty of medicine and pharmacy,cheikh anta diop university,dakar, Senegal, faculty of medicine and pharmacy,cheikh anta diop university,dakar, Senegal, faculty of medicine and pharmacy,cheikh anta diop university,dakar, Senegal, malaria research laboratories,college of medicine,university of ibadan,ibadan, Nigeria, department of computer science and department of human genetics,university of california los angeles,los angeles,ca, United States, department of computer science and department of human genetics,university of california los angeles,los angeles,ca, United States, department of biostatistics,university of michigan,ann arbor,mi, United States, organismic and evolutionary biology,harvard university,cambridge,ma, United States, broad institute,cambridge,ma, United States, broad institute,cambridge,ma, United States, broad institute,cambridge,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma,united states,broad institute,cambridge,ma, United States, department of immunology and infectious diseases,harvard school of public health,boston,ma,united states,broad institute,cambridge,ma,united states,school for health sciences,simmons college,boston,ma, United States, broad institute,cambridge,ma,united states,organismic and evolutionary biology,harvard university,cambridge,ma,united states,fas center for systems biology,harvard university,cambridge,ma, United States
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Authors
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