title: The SLC4A1 gene is under differential selective pressure in primates infected by Plasmodium falciparum and related parasites.
abstract: Malaria is a disease caused by Plasmodium parasites and is responsible for high mortality in humans. This disease is caused by four different species of Plasmodium though the main source of mortality is Plasmodium falciparum. Humans have a number of genetic adaptations that act to combat Plasmodium. One adaptation is a deletion in the SLC4A1 gene that leads to Southeast Asian ovalocytosis (SAO). There is evidence that SAO erythrocytes are resistant to multiple Plasmodium species. Here we analyze SLC4A1 in 23 primates and mammals to test for differential selective pressures among different primate lineages. Because primates are infected with both human Plasmodium parasites and their relatives, this analysis can be used to test which human Plasmodium parasite is the likely target of SAO. A significantly different pattern of molecular evolution was found in humans and African apes, species that are infected by P. falciparum and its relatives. This effect was restricted to the cytosolic domain of the SLC4A1 gene. The evidence is consistent with a different selective regime operating on this gene domain in humans and African apes, when compared to other primates and mammals. Alternatively, this pattern is consistent with a relaxation of selection or weak adaptive evolution operating on a small number of amino acids. The adaptive interpretation of the results is consistent with the SAO allele of the SLC4A1 gene interacting with P. falciparum in humans, rather than other Plasmodium parasites. However, additional investigation of the relationship between SLC4A1 variants and Plasmodium in humans and African apes is required to test whether the different selective regime in humans and African apes is due to natural selection or relaxed constraint.
authors.affiliation: Department of Anthropology, Hunter College of the City University of New York, 695 Park Avenue, NY, NY 10065, USA. msteiper@hunter.cuny.edu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Steiper
authors.forename: Fiona
authors.initials: F
authors.lastname: Walsh
authors.forename: Julia M
authors.initials: JM
authors.lastname: Zichello
mesh_terms: D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D001483:Base Sequence; D004612:Elliptocytosis, Hereditary / Q000235:genetics; D019143:Evolution, Molecular; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D010963:Plasmodium falciparum; D011323:Primates; D051381:Rats; D012641:Selection, Genetic; D016415:Sequence Alignment
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; C454201:SLC4A1 protein, human