Molecular Evolution of Glycophorins


Humans and closely related apes have four glycophorin‐encoding genes, three of which form a small paralogous gene family. These genes encode sialoglycoproteins that localise to the plasma membrane of the red blood cell. Although the biological function of these proteins is not well understood, and their presence does not appear necessary for human viability or normal health, all four glycophorin‐encoding genes show evidence of accelerated evolution through positive natural selection. This selection is likely caused by a coevolutionary dynamic between glycophorins and Plasmodium falciparum receptors that use these molecules to gain entry into the red blood cell.

Key Concepts:

  • Gene duplication, followed by DNA sequence divergence and non‐homologous recombination, has shaped the GYPA‐GYPB‐GYPC gene family.

  • Positive natural selection, likely mediated by Plasmodium falciparum, has caused accelerated amino acid evolution at all glycophorin‐encoding genes.

Keywords: glycophorins; sialoglycoproteins; malaria; natural selection; gene duplication

Figure 1.

Two successive duplication events created the GYPAGYPBGYPE gene family in gorillas, chimpanzees and humans. GYPA represents the ancestral gene, which initially duplicated to form a precursor GYPB/E gene. Subsequently, this precursor duplicated to form GYPB and GYPE. Several additional structural changes have also affected these genes. A, The GYPB/E precursor gene acquired a novel 3′ sequence through nonhomologous recombination. This novel sequence replaced ancestral exons 6 and 7. B, In gorillas, GYPA contains two alleles that differ with respect to whether exon 3 is included in the final messenger ribonucleic acid (mRNA) transcript. C, In humans, ancestral exon 3 has been eliminated from the GYPB transcript. D, In all species, ancestral exon 3 has been eliminated from the final GYPE transcript. Ancestral exon 4 is also eliminated in humans and chimpanzees.

Figure 2.

Schematic representation of glycophorins C and D (GYPC and GYPD). The two proteins are encoded by separate in‐frame start codons from a single transcript. GYPC is encoded by the upstream start codon and has 63 amino acid residues on the exterior of the red blood cell (and a total of 128 amino acid residues in the entire protein). GYPD has 42 amino acids outside of the cell (and a total of 107 amino acid residues). The two proteins differ with respect to the extent of extracellular glycosylation (O‐linked glycans are indicated by red dots, N‐linked glycans in blue). Within the cell, the two proteins are identical, and both bind with protein 4.1.



Baum J, Ward RH and Conway DJ (2002) Natural selection on the erythrocyte surface. Molecular Biology and Evolution 19: 223–229.

Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437: 69–87.

Cortés A (2008) Switching Plasmodium falciparum genes on and off for erythrocyte invasion. Trends in Parasitology 24: 517–524.

Gagneux P and Varki A (1999) Evolutionary considerations in relating oligosaccharide diversity to biological function. Glycobiology 9: 747–755.

Hobolth A, Christensen OF, Mailund T and Schierup MH (2007) Genomic relationships and speciation times of human, chimpanzee, and gorilla inferred from a coalescent hidden Markov model. PLoS Genetics 3: e7.

Huang C‐H and Blumenfeld OO (1995) MNSs blood groups and major glycophorins: molecular basis for allelic variation. In: Cartron JP and Rouger P (eds) Blood Cell Biochemistry, Volume 6: Molecular Basis of Major Human Blood Group Antigens, pp. 153–188. New York: Plenum Press.

Huang CH, Xie SS, Socha W and Blumenfeld OO (1995) Sequence diversification and exon inactivation in the glycophorin a gene family from chimpanzee to human. Journal of Molecular Evolution 41: 478–486.

Kozak M (2002) Pushing the limits of the scanning mechanism for initiation of translation. Gene 299: 1–34.

Kudo S and Fukuda M (1990) Identification of a novel human glycophorin, glycophorin E, by isolation of genomic clones and complementary DNA clones utilizing polymerase chain reaction. Journal of Biological Chemistry 265: 1102–1110.

Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. American Journal of Human Genetics 77: 171–192.

Le Van Kim C, Piller V, Cartron JP and Colin Y (1996) Glycophorins C and D are generated by the use of alternative translation initiation sites. Blood 88: 2364–2365.

Li WH and Saunders MA (2005) News and views: the chimpanzee and us. Nature 437: 50–51.

Luna EJ and Hitt AL (1992) Cytoskeleton–plasma membrane interactions. Science 258: 955–964.

Mayer DC, Jiang L, Achur RN et al. (2006) The glycophorin C N‐linked glycan is a critical component of the ligand for the Plasmodium falciparum erythrocyte receptor BAEBL. Proceedings of the National Academy of Sciences of the USA 103: 2358–2362.

Onda M, Kudo S, Rearden A, Mattei MG and Fukuda M (1993) Identification of a precursor genomic segment that provided a sequence unique to glycophorin B and E genes. Proceedings of the National Academy of Sciences of the USA 90: 7220–7224.

Rearden A, Magnet A, Kudo S and Fukuda M (1993) Glycophorin B and glycophorin E genes arose from the glycophorin A ancestral gene via two duplications during primate evolution. Journal of Biological Chemistry 268: 2260–2267.

Rearden A, Phan H, Kudo S and Fukuda M (1990) Evolution of the glycophorin gene family in the hominoid primates. Biochemical Genetics 28: 209–222.

Satta Y, Hickerson M, Watanabe H, O'hUigin C and Klein J (2004) Ancestral population sizes and species divergence times in the primate lineage on the basis of intron and BAC end sequences. Journal of Molecular Evolution 59: 478–487.

Schenkel‐Brunner H (2000) Human Blood Groups: Chemical and Biochemical Basis of Antigen Specificity. Wien, New York: Springer.

Tanner MJ, High S, Martin PG et al. (1988) Genetic variants of human red‐cell membrane sialoglycoprotein beta. Study of the alterations occurring in the sialoglycoprotein‐beta gene. Biochemical Journal 250: 407–414.

Telen MJ, Le Van Kim C, Chung A, Cartron JP and Colin Y (1991) Molecular basis for elliptocytosis associated with glycophorin C and D deficiency in the Leach phenotype. Blood 78: 1603–1606.

Tokunaga E, Sasakawa S, Tamaka K et al. (1979) Two apparently healthy Japanese individuals of type MkMk have erythrocytes which lack both the blood group MN and Ss‐active sialoglycoproteins. Journal of Immunogenetics 6: 383–390.

Wang HY, Tang H, Shen CK and Wu CI (2003) Rapidly evolving genes in human. I. The glycophorins and their possible role in evading malaria parasites. Molecular Biology and Evolution 20: 1795–1804.

Wilder JA, Hewett EK and Gansner ME (2009) Molecular evolution of GYPC: evidence for recent structural innovation and positive selection in humans. Molecular Biology and Evolution 26: 2679–2687.

Xie SS, Huang CH, Reid ME, Blancher A and Blumenfeld OO (1997) The glycophorin A gene family in gorillas: structure, expression, and comparison with the human and chimpanzee homologues. Biochemical Genetics 35: 59–76.

Further Reading

Barreiro LB and Quintana‐Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nature Reviews. Genetics 11: 17–30.

Lisowska E (2001) Antigenic properties of human glycophorins – an update. Advances in Experimental Medicine and Biology 491: 155–169.

Pasvol G (2003) How many pathways for invasion of the red blood cell by the malaria parasite? Trends in Parasitology 19: 430–432.

Race RR and Sanger R (1975) Blood Groups in Man. Oxford, Philadelphia: Blackwell Scientific Publications.

Reid ME and Lomas‐Francis C (2004) The Blood Group Antigen Factsbook. Amsterdam, Boston: Elsevier/Academic Press.

Williams TN (2006) Red blood cell defects and malaria. Molecular and Biochemical Parasitology 149: 121–127.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Wilder, Jason A(Sep 2010) Molecular Evolution of Glycophorins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022861]