Genetic variation of glycophorins and infectious disease

Abstract

Glycophorins are transmembrane proteins of red blood cells (RBCs), heavily glycosylated on their external-facing surface. In humans, there are four glycophorin proteins, glycophorins A, B, C and D. Glycophorins A and B are encoded by two similar genes GYPA and GYPB, and glycophorin C and glycophorin D are encoded by a single gene, GYPC. The exact function of glycophorins remains unclear. However, given their abundance on the surface of RBCs, it is likely that they serve as a substrate for glycosylation, giving the RBC a negatively charged, complex glycan "coat". GYPB and GYPE (a closely related pseudogene) were generated from GYPA by two duplication events involving a 120-kb genomic segment between 10 and 15 million years ago. Non-allelic homologous recombination between these 120-kb repeats generates a variety of duplication alleles and deletion alleles, which have been systematically catalogued from genomic sequence data. One allele, called DUP4, encodes the Dantu NE blood type and is strongly protective against malaria as it alters the surface tension of the RBC membrane. Glycophorins interact with other infectious pathogens, including viruses, as well as the malarial parasite Plasmodium falciparum, but the role of glycophorin variation in mediating the effects of these pathogens remains underexplored.

Keywords: Copy number variation; Genetic variation; Glycophorins; Infectious disease; Malaria.

Fig. 1

Summary of the role of glycophorins and infectious disease. Overview of the central concepts discussed in this review. Structural variation affects two distinct loci carrying the GYPC gene and GYPA/GYPB/GYPE. Different variants encode distinct glycophorin variants on the red blood cell surface. These glycophorins interact with a variety of different pathogens, including viruses, bacteria and malaria. Created with Biorender.com

Fig. 2

Evolution of glycophorins in great apes. a The tree shows the phylogeny of great apes, with branches annotated with the changes in glycophorin genes along the branches. b Fibre-FISH representative image of the human glycophorin region showing the reference haplotype. 120-kb repeats carrying GYPE, GYPB and GYPA are represented by coloured bars green, orange and purple, respectively. Each one of the genes was identified by a specific FISH pattern using region-specific fosmid clones (details in Louzada et al. 2020). c Structural variation in the glycophorin region in chimpanzee revealed by fibre-FISH, highlighting the presence of three copies of GYPE (fibre-FISH details in Louzada et al. 2020)