highly specialized and unique for the parasite’s calcium homeostasis. Interestingly, it has been recently suggested that highly specialized genes in the Plasmodium genome are more likely to undergo accelerated selective processes. However, neither Tajima’s nor Fu & Li’s tests provided evidence of departures from neutrality and calculations of the McDonaldKreitman test identified only marginally significant departures in French Guiana and in Senegal. These were associated with NI values.February Polymorphism of Pf-SERCA Guinea, while they were not detected at all in Senegal or French Guiana. Although we cannot exclude that such synonymous mutations may not be phenotypically silent as some synonymous mdr mutations were shown to influence the rate of translation, protein folding and substrate specificity, we tentatively conclude that it is likely that neutral evolution operating on possible multiple colonising events is currently shaping polymorphism at the pfserca gene of P. falciparum at this stage in history 
i.e. before massive worldwide deployment of artemisinin derivatives. Multiple colonisation events by ancestral parasites spreading out of Africa to the other continents have been suggested by the analysis of mitochondrial DNA. The most obvious and statistically significant association regarding artemisinin susceptibility was that of the February Polymorphism of Pf-SERCA in the set of samples from French Guiana. The mutation is located in the vicinity of the predicted hinge domain of the protein, which influences binding of the calcium ion. As the inhibitory effect of thapsigargin depends on the engagement of the first calcium ion in the binding site, it is possible that the tion. This could furthermore offer new insights on factors possibly contributing to the high level of polymorphism of PfSERCA. Interestingly, the areas where the highest PfSERCA diversity was observed in this work and in previous studies are those with an elevated ARRY-380 prevalence of haemoglobinopathies such as HbS, namely African populations and South American countries with a substantial population of African origin. Sickle cell anaemia and betathalassaemia are associated with an elevation of total red cell calcium content. This abnormally high cytosolic calcium content could be a selective force for mutant PfSERCA as an enhanced activity of this pump is needed in such environments to restore physiological intracellular calcium stores. This possibility is currently under investigation. Materials and Methods For more details see also Materials and Methods S Ethics Statement This program received ethical clearance from all the National Ethical Committees of the countries involved in the study. All the patients enrolled gave a written informed consent for the protocol. Sample Collection Blood samples were obtained from consenting patients attending dispensaries with uncomplicated P. falciparum malaria. The following isolates were used as characteristic haplotypes: F Sequencing of Field Isolates Parasite DNA was extracted from red blood cells by standard phenol/chloroform method. Primers used were synthesized based on the published sequence of PfatpFebruary Polymorphism of Pf-SERCA inspection of the corresponding chromatogram, using PhredPhrap. Bioinformatic Analysis Sequences have been aligned using CLUSTALX software and BOXSHADE. Functional areas were predicted using PROSITE. Prediction of the PfSERCA domains was performed by alignment with a set of other eukaryotic se