Complex signatures of natural selection at GYPA
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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.
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Conflict of interest
The authors declare that they have no conflict of interest.
- 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. https://doi.org/10.1002/humu.1380060302 CrossRefPubMedGoogle Scholar
- 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
- 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. https://doi.org/10.1016/j.ajhg.2011.05.005 CrossRefPubMedPubMedCentralGoogle Scholar
- Mourant AE (1954) The distribution of the human blood groups. Blackwell Scientific Publications, OxfordGoogle Scholar
- 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
- Race RR, Sanger R (1975) The MNS blood groups, 6th edn. Blackwell, Oxford, pp 92–138Google Scholar
- 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. https://doi.org/10.1016/j.meegid.2016.07.044 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1126/science.1061573 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1086/344345 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1086/491748 CrossRefPubMedPubMedCentralGoogle Scholar