title: Geographic structuring of the Plasmodium falciparum sarco(endo)plasmic reticulum Ca2+ ATPase (PfSERCA) gene diversity.
abstract: Artemisinin, a thapsigargin-like sesquiterpene has been shown to inhibit the Plasmodium falciparum sarco/endoplasmic reticulum calcium-ATPase PfSERCA. To collect baseline pfserca sequence information before field deployment of Artemisinin-based Combination therapies that may select mutant parasites, we conducted a sequence analysis of 100 isolates from multiple sites in Africa, Asia and South America. Coding sequence diversity was large, with 29 mutated codons, including 32 SNPs (average of one SNP/115 bp), of which 19 were novel mutations. Most SNP detected in this study were clustered within a region in the cytosolic head of the protein. The PfSERCA functional domains were very well conserved, with non synonymous mutations located outside the functional domains, except for the S769N mutation associated in French Guiana with elevated IC(50) for artemether. The S769N mutation is located close to the hinge of the headpiece, which in other species modulates calcium affinity and in consequence efficacy of inhibitors, possibly linking calcium homeostasis to drug resistance. Genetic diversity was highest in Senegal, Brazil and French Guiana, and few mutations were identified in Asia. Population genetic analysis was conducted for a partial fragment of the gene encompassing nucleotide coordinates 87-2862 (unambiguous sequence available for 96 isolates). This supported a geographic clustering, with a separation between Old and New World samples and one dominant ancestral haplotype. Genetic drift alone cannot explain the observed polymorphism, suggesting that other evolutionary mechanisms are operating. One possible contributor could be the frequency of haemoglobinopathies that are associated with calcium dysregulation in the erythrocyte.
authors.affiliation: Institut Pasteur de Dakar, BP 220, Dakar, Senegal. rjambou@pasteur.fr
authors.forename: Ronan
authors.initials: R
authors.lastname: Jambou
authors.forename: Axel
authors.initials: A
authors.lastname: Martinelli
authors.forename: João
authors.initials: J
authors.lastname: Pinto
authors.forename: Simonetta
authors.initials: S
authors.lastname: Gribaldo
authors.forename: Eric
authors.initials: E
authors.lastname: Legrand
authors.forename: Makhtar
authors.initials: M
authors.lastname: Niang
authors.forename: Nimol
authors.initials: N
authors.lastname: Kim
authors.forename: Lim
authors.initials: L
authors.lastname: Pharath
authors.forename: Béatrice
authors.initials: B
authors.lastname: Volnay
authors.forename: Marie Therese
authors.initials: MT
authors.lastname: Ekala
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.forename: Pedro
authors.initials: P
authors.lastname: Berzosa
authors.forename: Agustin
authors.initials: A
authors.lastname: Benito
authors.forename: Isabel Dinis
authors.initials: ID
authors.lastname: Ferreira
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ferreira
authors.forename: Pedro Paulo
authors.initials: PP
authors.lastname: Vieira
authors.forename: Maria das Graças
authors.initials: Md
authors.lastname: Alecrim
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.forename: Pedro
authors.initials: P
authors.lastname: Cravo
mesh_terms: D000349:Africa; D000569:Americas; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D001208:Asia; D001665:Binding Sites / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D014644:Genetic Variation; D005843:Geography; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
chemical_list: C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D000252:Calcium-Transporting ATPases