Human Genetics

, Volume 137, Issue 2, pp 151–160 | Cite as

Complex signatures of natural selection at GYPA

  • Abigail W. BighamEmail author
  • Kevin Magnaye
  • Diane M. Dunn
  • Robert B. Weiss
  • Michael Bamshad
Original Investigation


The human MN blood group antigens are isoforms of glycophorin A (GPA) encoded by the gene, GYPA, and are the most abundant erythrocyte sialoglycoproteins. The distribution of MN antigens has been widely studied in human populations yet the evolutionary and/or demographic factors affecting population variation remain elusive. While the primary function of GPA is yet to be discovered, it serves as the major binding site for the 175-kD erythrocyte-binding antigen (EB-175) of the malarial parasite, Plasmodium falciparum, a major selective pressure in recent human history. More specifically, exon two of GYPA encodes the receptor-binding ligand to which P. falciparum binds. Accordingly, there has been keen interest in understanding what impact, if any, natural selection has had on the distribution of variation in GYPA and exon two in particular. To this end, we resequenced GYPA in individuals sampled from both P. falciparum endemic (sub-Saharan Africa and South India) and non-endemic (Europe and East Asia) regions of the world. Observed patterns of variation suggest that GYPA has been subject to balancing selection in populations living in malaria endemic areas and in Europeans, but no such evidence was found in samples from East Asia, Oceania, and the Americas. These results are consistent with malaria acting as a selective pressure on GYPA, but also suggest that another selective force has resulted in a similar pattern of variation in Europeans. Accordingly, GYPA has perhaps a more complex evolutionary history, wherein on a global scale, spatially varying selective pressures have governed its natural history.



AWB was supported by a training fellowship from the NIH–National Human Genome Research Institute (T32HG00035). The authors thank Anita Beck, Kati Buckingham, and Heidi Gildersleeve for thoughtful discussions on the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2018_1866_MOESM1_ESM.docx (67 kb)
Supplementary material 1 (DOCX 66 kb)
439_2018_1866_MOESM2_ESM.xlsx (112 kb)
Supplementary material 2 (XLSX 112 kb)


  1. Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nat Rev Genet 4:99–111. CrossRefPubMedGoogle Scholar
  2. Bandelt HJ, Forster P, Sykes BC, Richards MB (1995) Mitochondrial portraits of human populations using median networks. Genetics 141:743–753PubMedPubMedCentralGoogle Scholar
  3. Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11:17–30. CrossRefPubMedGoogle Scholar
  4. Baseman JB, Banai M, Kahane I (1982) Sialic acid residues mediate Mycoplasma pneumoniae attachment to human and sheep erythrocytes. Infect Immun 38:389–391PubMedPubMedCentralGoogle Scholar
  5. Baum J, Ward RH, Conway DJ (2002) Natural selection on the erythrocyte surface. Mol Biol Evol 19:223–229CrossRefPubMedGoogle Scholar
  6. Blumenfeld OO, Huang CH (1995) Molecular genetics of the glycophorin gene family, the antigens for MNSs blood groups: multiple gene rearrangements and modulation of splice site usage result in extensive diversification. Hum Mutat 6:199–209. CrossRefPubMedGoogle Scholar
  7. Brooks DE, Cavanagh J, Jayroe D, Janzen J, Snoek R, Trust TJ (1989) Involvement of the MN blood group antigen in shear-enhanced hemagglutination induced by the Escherichia coli F41 adhesin. Infect Immun 57:377–383PubMedPubMedCentralGoogle Scholar
  8. Burness AT, Pardoe IU (1981) Effect of enzymes on the attachment of influenza and encephalomyocarditis viruses to erythrocytes. J Gen Virol 55:275–288. CrossRefPubMedGoogle Scholar
  9. Camus D, Hadley TJ (1985) A Plasmodium falciparum antigen that binds to host erythrocytes and merozoites. Science 230:553–556CrossRefPubMedGoogle Scholar
  10. Cann HM, de Toma C, Cazes L, Legrand MF, Morel V, Piouffre L, Bodmer J, Bodmer WF, Bonne-Tamir B, Cambon-Thomsen A, Chen Z, Chu J, Carcassi C, Contu L, Du R, Excoffier L, Ferrara GB, Friedlaender JS, Groot H, Gurwitz D, Jenkins T, Herrera RJ, Huang X, Kidd J, Kidd KK, Langaney A, Lin AA, Mehdi SQ, Parham P, Piazza A, Pistillo MP, Qian Y, Shu Q, Xu J, Zhu S, Weber JL, Greely HT, Feldman MW, Thomas G, Dausset J, Cavalli-Sforza LL (2002) A human genome diversity cell line panel. Science 296:261–262CrossRefPubMedGoogle Scholar
  11. Chitnis CE, Miller LH (1994) Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J Exp Med 180:497–506CrossRefPubMedGoogle Scholar
  12. Excoffier L, Laval G, Schneider S (2005) Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50CrossRefGoogle Scholar
  13. Gagneux P, Varki A (1999) Evolutionary considerations in relating oligosaccharide diversity to biological function. Glycobiology 9:747–755CrossRefPubMedGoogle Scholar
  14. Hamblin MT, Di Rienzo A (2000) Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am J Hum Genet 66:1669–1679CrossRefPubMedPubMedCentralGoogle Scholar
  15. Karlsson KA (1995) Microbial recognition of target-cell glycoconjugates. Curr Opin Struct Biol 5:622–635CrossRefPubMedGoogle Scholar
  16. Ko WY, Kaercher KA, Giombini E, Marcatili P, Froment A, Ibrahim M, Lema G, Nyambo TB, Omar SA, Wambebe C, Ranciaro A, Hirbo JB, Tishkoff SA (2011) Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations. Am J Hum Genet 88:741–754. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452. CrossRefPubMedGoogle Scholar
  18. Mourant AE (1954) The distribution of the human blood groups. Blackwell Scientific Publications, OxfordGoogle Scholar
  19. Nielsen R, Hellmann I, Hubisz M, Bustamante C, Clark AG (2007) Recent and ongoing selection in the human genome. Nat Rev Genet 8:857–868. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Nishimura H, Sugawara K, Kitame F, Nakamura K (1988) Attachment of influenza C virus to human erythrocytes. J Gen Virol 69(Pt 10):2545–2553CrossRefPubMedGoogle Scholar
  21. Okoyeh JN, Pillai CR, Chitnis CE (1999) Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A. Infect Immun 67:5784–5791PubMedPubMedCentralGoogle Scholar
  22. Onda M, Kudo S, Fukuda M (1994) Genomic organization of glycophorin A gene family revealed by yeast artificial chromosomes containing human genomic DNA. J Biol Chem 269:13013–13020PubMedGoogle Scholar
  23. Ozwara H, Kocken CH, Conway DJ, Mwenda JM, Thomas AW (2001) Comparative analysis of Plasmodium reichenowi and P. falciparum erythrocyte-binding proteins reveals selection to maintain polymorphism in the erythrocyte-binding region of EBA-175. Mol Biochem Parasitol 116:81–84CrossRefPubMedGoogle Scholar
  24. Pasvol G, Wainscoat JS, Weatherall DJ (1982) Erythrocytes deficiency in glycophorin resist invasion by the malarial parasite Plasmodium falciparum. Nature 297:64–66CrossRefPubMedGoogle Scholar
  25. Paul RW, Lee PW (1987) Glycophorin is the reovirus receptor on human erythrocytes. Virology 159:94–101CrossRefPubMedGoogle Scholar
  26. Polzin T, Daneshmand SV (2003) On Steiner trees and minimum spanning trees in hypergraphs. Op Res Lett 31:12–20CrossRefGoogle Scholar
  27. Race RR, Sanger R (1975) The MNS blood groups, 6th edn. Blackwell, Oxford, pp 92–138Google Scholar
  28. Rearden A, Magnet A, Kudo S, Fukuda M (1993) Glycophorin B and glycophorin E genes arose from the glycophorin A ancestral gene via two duplications during primate evolution. J Biol Chem 268:2260–2267PubMedGoogle Scholar
  29. Rosenberg NA (2006) Standardized subsets of the HGDP-CEPH Human Genome Diversity Cell Line Panel, accounting for atypical and duplicated samples and pairs of close relatives. Ann Hum Genet 70:841–847. CrossRefPubMedGoogle Scholar
  30. Saada AB, Terespolski Y, Adoni A, Kahane I (1991) Adherence of Ureaplasma urealyticum to human erythrocytes. Infect Immun 59:467–469PubMedPubMedCentralGoogle Scholar
  31. Salas A, Marco-Puche G, Trivino JC, Gomez-Carballa A, Cebey-Lopez M, Rivero-Calle I, Vilanova-Trillo L, Rodriguez-Tenreiro C, Gomez-Rial J, Martinon-Torres F (2016) Strong down-regulation of glycophorin genes: a host defense mechanism against rotavirus infection. Infect Genet Evol 44:403–411. CrossRefPubMedGoogle Scholar
  32. Sanchez G, Aragones L, Costafreda MI, Ribes E, Bosch A, Pinto RM (2004) Capsid region involved in hepatitis A virus binding to glycophorin A of the erythrocyte membrane. J Virol 78:9807–9813. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Saunders MA, Hammer MF, Nachman MW (2002) Nucleotide variability at G6pd and the signature of malarial selection in humans. Genetics 162:1849–1861PubMedPubMedCentralGoogle Scholar
  34. Schaffner SF, Foo C, Gabriel S, Reich D, Daly MJ, Altshuler D (2005) Calibrating a coalescent simulation of human genome sequence variation. Genome Res 15:1576–1583. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Scheet P, Stephens M (2006) A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78:629–644CrossRefPubMedPubMedCentralGoogle Scholar
  36. Sim BK, Chitnis CE, Wasniowska K, Hadley TJ, Miller LH (1994) Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264:1941–1944CrossRefPubMedGoogle Scholar
  37. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595PubMedPubMedCentralGoogle Scholar
  38. Tavakkol A, Burness AT (1990) Evidence for a direct role for sialic acid in the attachment of encephalomyocarditis virus to human erythrocytes. Biochemistry 29:10684–10690CrossRefPubMedGoogle Scholar
  39. Thornton K (2005) Recombination and the properties of Tajima’s D in the context of approximate-likelihood calculation. Genetics 171:2143–2148. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G, Destro-Bisol G, Drousiotou A, Dangerfield B, Lefranc G, Loiselet J, Piro A, Stoneking M, Tagarelli A, Tagarelli G, Touma EH, Williams SM, Clark AG (2001) Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293:455–462. CrossRefPubMedGoogle Scholar
  41. Tolia NH, Enemark EJ, Sim BK, Joshua-Tor L (2005) Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell 122:183–193. CrossRefPubMedGoogle Scholar
  42. Verrelli BC, McDonald JH, Argyropoulos G, Destro-Bisol G, Froment A, Drousiotou A, Lefranc G, Helal AN, Loiselet J, Tishkoff SA (2002) Evidence for balancing selection from nucleotide sequence analyses of human G6PD. Am J Hum Genet 71:1112–1128. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wang HY, Tang H, Shen CK, Wu CI (2003) Rapidly evolving genes in human. I. The glycophorins and their possible role in evading malaria parasites. Mol Biol Evol 20:1795–1804. CrossRefPubMedGoogle Scholar
  44. Wood ET, Stover DA, Slatkin M, Nachman MW, Hammer MF (2005) The beta-globin recombinational hotspot reduces the effects of strong selection around HbC, a recently arisen mutation providing resistance to malaria. Am J Hum Genet 77:637–642. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Wybenga LE, Epand RF, Nir S, Chu JW, Sharom FJ, Flanagan TD, Epand RM (1996) Glycophorin as a receptor for Sendai virus. Biochemistry 35:9513–9518. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of AnthropologyThe University of MichiganAnn ArborUSA
  2. 2.Department of Human GeneticsThe University of ChicagoChicagoUSA
  3. 3.Department of Human GeneticsThe University of UtahSalt Lake CityUSA
  4. 4.Departments of Pediatrics and Genome SciencesThe University of WashingtonSeattleUSA

Personalised recommendations