A shared Asian origin of the triple-mutant dhfr allele in Plasmodium falciparum from sites across Africa.
BACKGROUND
Usefulness of sulfadoxine-pyrimethamine as first-line therapy for uncomplicated Plasmodium falciparum malaria and intermittent preventive treatment in pregnancy throughout sub-Saharan Africa is compromised by the spread of dhfr alleles associated with pyrimethamine resistance. A predominant haplotype associated with the N51I+C59R+S108N triple-mutant dhfr allele has been reported recently in 4 African countries. A more comprehensive picture of the evolution of this mutant allele in Africa is lacking.


METHODS
Seventy-five P. falciparum isolates carrying the wild-type dhfr allele and 204 carrying the triple-mutant dhfr allele from 11 African countries were selected. The genetic diversity of the chromosomes bearing these alleles was analyzed with 4 microsatellite markers closely linked to the dhfr gene.


RESULTS
Seventy-three different 4-locus haplotypes carrying the wild-type dhfr allele were found. By contrast, 175 (85%) of 204 isolates carrying the triple-mutant dhfr allele shared a unique haplotype, identical to the one identified in Thailand. For the remaining triple-mutant isolates and one isolate with the quadruple-mutant dhfr allele (N51I+C59R+S108N+I164L), haplotypes were closely related to the predominant haplotype by mutation or recombination.


CONCLUSIONS
Migration of parasites carrying an ancestral triple-mutant dhfr allele drives the spread of dhfr alleles associated with pyrimethamine resistance throughout West and Central Africa.
Maïga
Oumou
O
Université Paris Descartes, Paris, France.
Djimdé
Abdoulaye A
AA
Hubert
Veronique
V
Renard
Emmanuelle
E
Aubouy
Agnes
A
Kironde
Fred
F
Nsimba
Basile
B
Koram
Kwadwo
K
Doumbo
Ogobara K
OK
Le   Bras
Jacques
J
Clain
Jérôme
J
D000349:Africa; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology*; D018895:Microsatellite Repeats / Q000235:genetics; D017720:Molecular Epidemiology; D020125:Mutation, Missense / Q000235:genetics; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D000962:Antimalarials; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine