Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.
BACKGROUND
Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution.


RESULTS
We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations.


CONCLUSIONS
Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.
Pearce
Richard J
RJ
London School of Hygiene & Tropical Medicine, Department of Infectious Tropical Diseases, London, UK.
Pota
Hirva
H
Evehe
Marie-Solange B
MS
Bâ
El-Hadj
el-H
Mombo-Ngoma
Ghyslain
G
Malisa
Allen L
AL
Ord
Rosalynn
R
Inojosa
Walter
W
Matondo
Alexandre
A
Diallo
Diadier A
DA
Mbacham
Wilfred
W
van den Broek
Ingrid V
IV
Swarthout
Todd D
TD
Getachew
Asefaw
A
Dejene
Seyoum
S
Grobusch
Martin P
MP
Njie
Fanta
F
Dunyo
Samuel
S
Kweku
Margaret
M
Owusu-Agyei
Seth
S
Chandramohan
Daniel
D
Bonnet
Maryline
M
Guthmann
Jean-Paul
JP
Clarke
Sian
S
Barnes
Karen I
KI
Streat
Elizabeth
E
Katokele
Stark T
ST
Uusiku
Petrina
P
Agboghoroma
Chris O
CO
Elegba
Olufunmilayo Y
OY
Cissé
Badara
B
A-Elbasit
Ishraga E
IE
Giha
Hayder A
HA
Kachur
S Patrick
SP
Lynch
Caroline
C
Rwakimari
John B
JB
Chanda
Pascalina
P
Hawela
Moonga
M
Sharp
Brian
B
Naidoo
Inbarani
I
Roper
Cally
C
D000349:Africa / Q000453:epidemiology; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D016054:DNA, Protozoan / Q000235:genetics; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology / Q000517:prevention & control; D026901:Membrane Transport Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D012641:Selection, Genetic; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use
D000962:Antimalarials; D016054:DNA, Protozoan; D004338:Drug Combinations; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine