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.
London School of Hygiene & Tropical Medicine, Department of Infectious Tropical Diseases, London, UK.
Richard J
RJ
Pearce
Hirva
H
Pota
Marie-Solange B
MS
Evehe
El-Hadj
el-H
Bâ
Ghyslain
G
Mombo-Ngoma
Allen L
AL
Malisa
Rosalynn
R
Ord
Walter
W
Inojosa
Alexandre
A
Matondo
Diadier A
DA
Diallo
Wilfred
W
Mbacham
Ingrid V
IV
van den Broek
Todd D
TD
Swarthout
Asefaw
A
Getachew
Seyoum
S
Dejene
Martin P
MP
Grobusch
Fanta
F
Njie
Samuel
S
Dunyo
Margaret
M
Kweku
Seth
S
Owusu-Agyei
Daniel
D
Chandramohan
Maryline
M
Bonnet
Jean-Paul
JP
Guthmann
Sian
S
Clarke
Karen I
KI
Barnes
Elizabeth
E
Streat
Stark T
ST
Katokele
Petrina
P
Uusiku
Chris O
CO
Agboghoroma
Olufunmilayo Y
OY
Elegba
Badara
B
Cissé
Ishraga E
IE
A-Elbasit
Hayder A
HA
Giha
S Patrick
SP
Kachur
Caroline
C
Lynch
John B
JB
Rwakimari
Pascalina
P
Chanda
Moonga
M
Hawela
Brian
B
Sharp
Inbarani
I
Naidoo
Cally
C
Roper
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