title: Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites.
abstract: Here, we fully characterize the genomes of 14 Plasmodium falciparum patient isolates taken recently from the Iquitos region using genome scanning, a microarray-based technique that delineates the majority of single-base changes, indels, and copy number variants distinguishing the coding regions of two clones. We show that the parasite population in the Peruvian Amazon bears a limited number of genotypes and low recombination frequencies. Despite the essentially clonal nature of some isolates, we see high frequencies of mutations in subtelomeric highly variable genes and internal var genes, indicating mutations arising during self-mating or mitotic replication. The data also reveal that one or two meioses separate different isolates, showing that P. falciparum clones isolated from different individuals in defined geographical regions could be useful in linkage analyses or quantitative trait locus studies. Through pairwise comparisons of different isolates we discovered point mutations in the apicoplast genome that are close to known mutations that confer clindamycin resistance in other species, but which were hitherto unknown in malaria parasites. Subsequent drug sensitivity testing revealed over 100-fold increase of clindamycin EC(50) in strains harboring one of these mutations. This evidence of clindamycin-resistant parasites in the Amazon suggests that a shift should be made in health policy away from quinine + clindamycin therapy for malaria in pregnant women and infants, and that the development of new lincosamide antibiotics for malaria should be reconsidered.
authors.affiliation: Department of Cell Biology, ICND 202, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Neekesh V
authors.initials: NV
authors.lastname: Dharia
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Selina E R
authors.initials: SE
authors.lastname: Bopp
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: González-Páez
authors.forename: Carmen
authors.initials: C
authors.lastname: Lucas
authors.forename: Carola
authors.initials: C
authors.lastname: Salas
authors.forename: Valeria
authors.initials: V
authors.lastname: Soberon
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Tadeusz J
authors.initials: TJ
authors.lastname: Kochel
authors.forename: David J
authors.initials: DJ
authors.lastname: Bacon
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D001483:Base Sequence; D043171:Chromosomal Instability / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D002981:Clindamycin / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018503:Genome, Protozoan; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology*; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D010568:Peru; D010963:Plasmodium falciparum / Q000235:genetics*; D011247:Pregnancy; D016615:Telomere / Q000235:genetics
chemical_list: D000962:Antimalarials; D002981:Clindamycin