title: Natural selection on the erythrocyte surface.
abstract: Surface glycoproteins are principal receptors used by pathogens to invade target cells. It has been suggested that mammalian erythrocyte surface glycoproteins function as decoy receptors attracting pathogens to the anucleated erythrocyte and away from their target tissues. Glycophorin A (GYPA) is solely expressed on the erythrocyte surface where it is the most abundant sialoglycoprotein, although its function is unknown. The pathogen decoy hypothesis may be relevant here, as GYPA has been shown in vitro to bind numerous viruses and bacteria, which do not infect erythrocytes. However, it is also a receptor for erythrocyte invasion by the malarial parasite Plasmodium falciparum. Analyses of gypa sequence variation among six higher primates and within a human population show that there is a large excess of replacement (nonsynonymous) substitutions along each primate lineage (particularly on exons 2-4 encoding the extracellular glycosylated domain of GYPA) and a significant excess of polymorphisms in exon 2 (encoding the terminal portion of the extracellular domain) within humans. These two signatures suggest that there has been exceptionally strong positive selection on this receptor driving GYPA divergence during primate evolution and balancing selection maintaining allelic variation within human populations. The pathogen decoy hypothesis alone is adequate to explain both these signatures of between-species and within-species diversifying selection. This has implications for understanding the functions of erythrocyte surface components and their roles in health and disease.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine. Institute of Biological Anthropology, University of Oxford. jacob.baum@lshtm.ac.uk
authors.forename: Jake
authors.initials: J
authors.lastname: Baum
authors.forename: Ryk H
authors.initials: RH
authors.lastname: Ward
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004912:Erythrocytes / Q000378:metabolism*; D006021:Glycophorins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics; D011323:Primates / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012641:Selection, Genetic; D017385:Sequence Homology
chemical_list: D006021:Glycophorins; D008562:Membrane Glycoproteins