Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia.
Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.
Mita
Toshihiro
T
Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, 9-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. hiro-tm@research.twmu.ac.jp
Tanabe
Kazuyuki
K
Takahashi
Nobuyuki
N
Tsukahara
Takahiro
T
Eto
Hideaki
H
Dysoley
Lek
L
Ohmae
Hiroshi
H
Kita
Kiyoshi
K
Krudsood
Srivicha
S
Looareesuwan
Sornchai
S
Kaneko
Akira
A
Björkman
Anders
A
Kobayakawa
Takatoshi
T
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005075:Biological Evolution; D003430:Cross-Sectional Studies; D016054:DNA, Protozoan / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D017125:Genes, Protozoan; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008542:Melanesia; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D016054:DNA, Protozoan; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine