Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The geographic overlap between the prevalence of erythrocyte polymorphisms and malaria endemicity is thought to be an example of natural selection on human populations. In Papua New Guinea (PNG), the Gerbich-negative phenotype is caused by an exon 3 deletion in the glycophorin C gene (GYPCDeltaex3) while heterozygosity for a 27-base pair deletion in the SLC4A1 gene (anion exchanger 1 or erythrocyte membrane protein, band 3), SLC4A1Delta27, results in Southeast Asian ovalocytosis. Two geographically and ethnically distinct malaria endemic regions of PNG (the Wosera [East Sepik Province] and Liksul [Madang Province]) were studied to illustrate the distribution of two prominent deletion polymorphisms (GYPCDeltaex3 and SLC4A1Delta27) and to determine if the genetic load associated with SLC4A1Delta27 would constrain independent assortment of GYPCDeltaex3 heterozygous and homozygous genotypes. The frequency of the GYPCDeltaex3 allele was higher in the Wosera (0.463) than Liksul (0.176) (chi(2); P < 0.0001). Conversely, the frequency of the SLC4A1Delta27 allele was higher in Liksul (0.0740) than the Wosera (0.0005) (chi(2); P < 0.0001). No individuals were homozygous for SLC4A1Delta27. In 355 Liksul residents, independent assortment of these two deletion polymorphisms resulted in 14 SLC4A1Delta27 carriers heterozygous for GYPCDeltaex3 and one SLC4A1Delta27 carrier homozygous for GYPCDeltaex3 (Fisher's exact test; P = 0.8040). While homozygosity for SLC4A1Delta27 appears to be nonviable, the GYPCDeltaex3 allele is not lethal when combined with SLC4A1Delta27. Neither mutation was associated with altered susceptibility to asymptomatic Plasmodium falciparum or P. vivax infection. While these erythrocyte polymorphisms apparently have no effect on blood-stage malaria infection, their contribution to susceptibility to clinical malaria morbidity requires further study.
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PMID:Glycophorin C (Gerbich antigen blood group) and band 3 polymorphisms in two malaria holoendemic regions of Papua New Guinea. 1469 25

Malaria is a major cause of childhood death throughout much of the tropical world. As a result, it has exerted a powerful force for the evolutionary selection of genes that confer a survival advantage. Identifying which genes are involved, and how they affect malaria risk, is a potentially useful way of exploring the host-parasite relationship. To date, some of the best-described malaria-protective polymorphisms relate to genes that affect the structure or function of red blood cells (RBC). Recent years have seen significant advances in our understanding of the importance of some of these genes, including glycophorin C (GYPC); complement receptor 1 (CR1); band 3 (SLC4A1); pyruvate kinase (Pklr); and the genes for alpha-(HBA) and beta-globin (HBB). The challenge for the future must be to convert these advances into fresh approaches to the prevention and treatment of malaria.
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PMID:Red blood cell defects and malaria. 1679 41

Southeast Asian ovalocytosis (SAO) is an erythrocyte abnormality that protects affected individuals from cerebral malaria. This trait is caused by a 27-bp deletion in the SLC4A1 gene, which is lethal when homozygous. We reseqeunced approximately 5 kb of SLC4A1 in an Indonesian population where SAO is prevalent to better understand the evolution of this clinically important trait. The four SAO chromosomes we resequenced share a single haplotype that differs from a sampled non-SAO haplotype only by the 27-bp deletion. Comparison of Indonesian sequence data to that from two other Asian populations (aboriginal Taiwanese and Japanese) shows Indonesian SLC4A1 to be strongly differentiated from the Taiwanese, but not the Japanese. Indeed, the Taiwanese sample contains only chromosomes that are highly divergent from all sampled SAO chromosomes. Because earlier studies have found an association between Austronesian-speakers (who most likely originated in Taiwan) and SAO, our failure to find SAO-like chromosomes in Taiwan is unexpected. Finally, our data find a strong excess of high-frequency derived alleles in all three populations. These alleles include the non-synonymous 'Memphis' variant, which is known to affect anion transport across the erythrocyte membrane. Our data suggest a role for recent natural selection acting on Memphis or a linked variant.
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PMID:Molecular population genetics of SLC4A1 and Southeast Asian ovalocytosis. 1922 54

Erythroid biology research involving rhesus macaques has been applied to several topics including malaria, hemoglobinopathy and gene therapy research. However, analyses of the rhesus red blood cells are limited by the inability to identify and sort those cells in research blood samples using flow cytometry. Here it is reported that the BRIC 6 hybridoma clone raised to the human erythroid surface molecule (referred to as CD233, Band 3, AE1, or SLC4A1) produces cross-reactive and erythroid-specific antibodies for flow cytometric detection and sorting of rhesus macaque erythrocytes.
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PMID:Identification of a cross-reacting, monoclonal anti-human CD233 antibody for identification and sorting of rhesus macaque erythrocytes. 2217 Aug 15

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.
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PMID:The SLC4A1 gene is under differential selective pressure in primates infected by Plasmodium falciparum and related parasites. 2242 10

Southeast Asian Ovalocytosis (SAO) is a common red blood cell disorder that is maintained as a balanced polymorphism in human populations. In individuals heterozygous for the SAO-causing mutation there are minimal detrimental effects and well-documented protection from severe malaria caused by Plasmodium vivax and Plasmodium falciparum; however, the SAO-causing mutation is fully lethal in utero when homozygous. The present-day high frequency of SAO in Island Southeast Asia indicates the trait is maintained by strong heterozygote advantage. Our study elucidates the evolutionary origin of SAO by characterizing DNA sequence variation in a 9.5 kilobase region surrounding the causal mutation in the SLC4A1 gene. We find substantial haplotype diversity among SAO chromosomes and estimate the age of the trait to be approximately 10,005 years (95% CI: 4930-23,200 years). This date is far older than any other human malaria-resistance trait examined previously in Southeast Asia, and considerably pre-dates the widespread adoption of agriculture associated with the spread of speakers of Austronesian languages some 4000 years ago. Using a genealogy-based method we find no evidence of historical positive selection acting on SAO (s=0.0, 95% CI: 0.0-0.03), in sharp contrast to the strong present-day selection coefficient (e.g., 0.09) estimated from the frequency of this recessively lethal trait. This discrepancy may be due to a recent increase in malaria-driven selection pressure following the spread of agriculture, with SAO targeted as a standing variant by positive selection in malarial populations.
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PMID:The evolutionary origins of Southeast Asian Ovalocytosis. 2604 85

Plasmodium parasites exerted a strong selective pressure on primate genomes and mutations in genes encoding erythrocyte cytoskeleton proteins (ECP) determine protective effects against Plasmodium infection/pathogenesis. We thus hypothesized that ECP-encoding genes have evolved in response to Plasmodium-driven selection. We analyzed the evolutionary history of 15 ECP-encoding genes in primates, as well as of their Plasmodium-encoded ligands (KAHRP, MESA and EMP3). Results indicated that EPB42, SLC4A1, and SPTA1 evolved under pervasive positive selection and that episodes of positive selection tended to occur more frequently in primate species that host a larger number of Plasmodium parasites. Conversely, several genes, including ANK1 and SPTB, displayed extensive signatures of purifying selection in primate phylogenies, Homininae lineages, and human populations, suggesting strong functional constraints. Analysis of Plasmodium genes indicated adaptive evolution in MESA and KAHRP; in the latter, different positively selected sites were located in the spectrin-binding domains. Because most of the positively selected sites in alpha-spectrin localized to the domains involved in the interaction with KAHRP, we suggest that the two proteins are engaged in an arms-race scenario. This observation is relevant because KAHRP is essential for the formation of "knobs", which represent a major virulence determinant for P. falciparum.
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PMID:Genetic conflicts with Plasmodium parasites and functional constraints shape the evolution of erythrocyte cytoskeletal proteins. 3027 39