Human Genetics

, 126:729 | Cite as

The molecular genetics of blood group polymorphism

  • Geoff DanielsEmail author
Review Article


Over 300 blood group specificities on red cells have been identified, many of which are polymorphic. The molecular mechanisms responsible for these polymorphisms are diverse, though many simply represent single nucleotide polymorphisms (SNPs). Other mechanisms include the following: gene deletion; single nucleotide deletion and sequence duplication, which introduce reading-frame shifts; nonsense mutation; intergenic recombination between closely linked genes, giving rise to hybrid genes and hybrid proteins; and a SNP in the promoter region of a blood group gene. Examples of these various genetic mechanisms are taken from the ABO, Rh, Kell, and Duffy blood group systems. Null phenotypes, in which no antigens of a blood group system are expressed, are not generally polymorphic, but provide good examples of the effect of inactivating mutations on blood group expression. As natural human ‘knock-outs’, null phenotypes provide useful clues to the functions of blood group antigens. Knowledge of the molecular backgrounds of blood group polymorphisms provides a means to predict blood group phenotypes from genomic DNA. This has two main applications in transfusion medicine: determination of foetal blood groups to assess whether the foetus is at risk from haemolytic disease and ascertainment of blood group phenotypes in multiply transfused, transfusion-dependent patients, where serological tests are precluded by the presence of donor red cells. Other applications are being developed for the future.


Blood Group Vivax Malaria Blood Group Antigen Blood Group System Null Phenotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anstee DJ (2009) Red cell genotyping and the future of pretransfusion testing. Blood 114:248–256CrossRefPubMedGoogle Scholar
  2. Avent ND (2008) Large-scale blood group genotyping—clinical implications. Br J Haematol 144:3–13CrossRefPubMedGoogle Scholar
  3. Avent ND, Butcher SK, Liu W, Mawby WJ, Mallinson G, Parsons SF, Anstee DJ, Tanner MJ (1992) Localization of the C termini of the Rh (Rhesus) polypeptides to the cytoplasmic face of the human erythrocyte membrane. J Biol Chem 267:15134–15139PubMedGoogle Scholar
  4. Avent ND, Martinez A, Flegel WA, Olsson ML, Scott ML, Nogués N, Písăcka M, Daniels G, van der Schoot E, Muñiz-Diaz E, Madgett TE, Storry JR, Beiboer SH, Maaskant-van Wijk PA, von Zabern I, Jiménez E, Tejedor D, López M, Camacho E, Cheroutre G, Hacker A, Jinoch P, Svobodova I, de Haas M (2007) The BloodGen project: towards mass-scale comprehensive genotyping of blood donors in the European Union and beyond. Transfusion 47(1S):40S–46SCrossRefPubMedGoogle Scholar
  5. Bandyopadhyay S, Zhan R, Chaudhuri A, Watabe M, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Pauza ME, Hayashi S, Wang Y, Mohinta S, Mashimo T, Iiizumi M, Furuta E, Watabe K (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12:933–938CrossRefPubMedGoogle Scholar
  6. Bruce LJ, Beckmann R, Ribeiro ML, Peters LL, Chasis JA, Delaunay J, Mohandas N, Anstee DJ, Tanner MJ (2003) A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane. Blood 101:4180–4188CrossRefPubMedGoogle Scholar
  7. Burton NM, Anstee DJ (2008) Nature, function and significance of Rh proteins in red cells. Curr Opin Hematol 15:625–630CrossRefPubMedGoogle Scholar
  8. Chan KCA, Ding C, Gerovassili A, Yeung SW, Chiu RW, Leung TN, Lau TK, Chim SS, Chung GT, Nicolaides KH, Lo YM (2006) Hypermethylated RASSF1A in maternal plasma: a universal fetal DNA marker that improves the reliability of noninvasive prenatal diagnosis. Clin Chem 52:2211–2218CrossRefPubMedGoogle Scholar
  9. Cherif-Zahar B, Raynal V, Gane P, Mattei MG, Bailly P, Gibbs B, Colin Y, Cartron JP (1996) Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nat Genet 12:168–173CrossRefPubMedGoogle Scholar
  10. Chérif-Zahar B, Matassi G, Raynal V, Gane P, Mempel W, Perez C, Cartron JP (1998) Molecular defects of the RHCE gene in the Rh-deficient individuals of the amorph type. Blood 92:639–646PubMedGoogle Scholar
  11. Chester MA, Olsson ML (2001) The ABO blood group gene: a locus of considerable genetic diversity. Transfus Med Rev 15:177–200CrossRefPubMedGoogle Scholar
  12. Clapéron A, Rose C, Gane P, Collec E, Bertrand O, Ouimet T (2005) The Kell protein of the common K2 phenotype is a catalytically active metalloprotease, whereas the rare Kell K1 antigen is inactive. J Biol Chem 280:21272–21283CrossRefPubMedGoogle Scholar
  13. Cockburn IA, Mackinnon MJ, O’Donnell A, Allen SJ, Moulds JM, Baisor M, Bockarie M, Reeder JC, Rowe JA (2004) A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci USA 101:272–277CrossRefPubMedGoogle Scholar
  14. Conroy MJ, Bullough PA, Merrick M, Avent ND (2005) Modelling the human rhesus proteins: implications for structure and function. Br J Haematol 131:543–551CrossRefPubMedGoogle Scholar
  15. Cserti CM, Dzik WH (2007) The ABO blood group system and Plasmodium falciparum malaria. Blood 110:2250–2258CrossRefPubMedGoogle Scholar
  16. Danek A (ed) (2005) Neuroacanthocytosis syndromes. Springer, BerlinGoogle Scholar
  17. Daniels G (2002) Human blood groups, 2nd edn. Blackwell Science, OxfordGoogle Scholar
  18. Daniels G (2007) Functions of red cell surface proteins. Vox Sang 93:331–340CrossRefPubMedGoogle Scholar
  19. Daniels GL, Faas BHW, Green CA, Smart E, Maaskant-van Wijk PA, Avent ND, Zondervan HA, von dem Borne AE, van der Schoot CE (1998) The Rh VS and V blood group polymorphisms in Africans: a serological and molecular analysis. Transfusion 38:951–958CrossRefPubMedGoogle Scholar
  20. Daniels GL, Fletcher A, Garratty G et al (2004) Blood group terminology 2004. From the ISBT committee on terminology for red cell surface antigens. Vox Sang 87:304–316CrossRefPubMedGoogle Scholar
  21. Daniels G, Castilho L, Flegel WA et al (2009a) International society of blood transfusion committee on terminology for red cell surface antigens: Macao report. Vox Sang 96:153–156CrossRefPubMedGoogle Scholar
  22. Daniels G, Finning K, Martin P, Massey E (2009b) Non-invasive prenatal diagnosis of fetal blood group phenotypes: current practice and future prospects. Prenat Diagn 29:101–107CrossRefPubMedGoogle Scholar
  23. Endeward V, Cartron J-P, Ripoche P, Gros G (2008) RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane. FASEB J 22:64–73CrossRefPubMedGoogle Scholar
  24. Faas BHW, Beckers EAM, Wildoer P, Ligthart PC, Overbeeke MA, Zondervan HA, von dem Borne AE, van der Schoot CE (1997) Molecular background of VS and weak C expression in blacks. Transfusion 37:38–44CrossRefPubMedGoogle Scholar
  25. Finning K, Martin P, Summers J, Daniels G (2007) Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA from maternal plasma. Transfusion 47:2126–2133CrossRefPubMedGoogle Scholar
  26. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G (2008) Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. Br Med J 336:816–818CrossRefGoogle Scholar
  27. Hadley TJ, Peiper SC (1997) From malaria to chemokine receptor: the emerging physiologic role of the Duffy blood group antigen. Blood 89:3077–3091PubMedGoogle Scholar
  28. Hashmi G, Shariff T, Zhang Y, Cristobal J, Chau C, Seul M, Vissavajjhala P, Baldwin C, Hue-Roye K, Charles-Pierre D, Lomas-Francis C, Reid ME (2007) Determination of 24 minor red cell antigens for more then 2000 blood donors by high-throughput DNA analysis. Transfusion 47:736–747CrossRefPubMedGoogle Scholar
  29. Hellberg Å, Chester MA, Olsson ML (2005) Two previously proposed P1/P2-differentiating and nine novel polymorphisms at the A4GALT (Pk) locus do not correlated with the presence of the P1 blood group antigen. BMC Genet 6:49CrossRefPubMedGoogle Scholar
  30. Hillyer C, Shaz BH, Winkler AM, Reid M (2008) Integrating molecular technologies for red blood cell typing and compatibility testing into blood centers and transfusion services. Transfus Med Rev 22:117–132CrossRefPubMedGoogle Scholar
  31. Huang C-H, Chen Y, Reid ME, Seidl C (1998) Rhnull disease: the amorph type results from a novel double mutation in RhCe gene on D-negative background. Blood 92:664–671PubMedGoogle Scholar
  32. Karamatic Crew V, Mallinson G, Green C, Poole J, Uchikawa M, Tani Y, Geisen C, Oldenburg J, Daniels G (2007) Different inactivating mutations in the LU genes of three individuals with the Lutheran-null phenotype. Transfusion 47:492–498CrossRefPubMedGoogle Scholar
  33. Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB (1995) Sequence and expression of a candidate for the human Secretor blood group α(1, 2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem 270:4640–4649CrossRefPubMedGoogle Scholar
  34. King CL, Michon P, Shakri AR, Marcotty A, Stanisic D, Zimmerman PA, Cole-Tobian JL, Mueller I, Chitnis CE (2008) Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection. Proc Natl Acad Sci USA 105:8363–8368CrossRefPubMedGoogle Scholar
  35. Lee S (1997) Molecular basis of Kell blood group phenotypes. Vox Sang 73:1–11 (Erratum in: Vox Sang 1998;74:58)Google Scholar
  36. Lee S, Lin M, Mele A, Cao Y, Farmar J, Russo D, Redman C (1999) Proteolytic processing of big endothelin-3 by the Kell blood group protein. Blood 94:1440–1450PubMedGoogle Scholar
  37. Lee HJ, Barry CH, Borisova SN, Seto NO, Zheng RB, Blancher A, Evans SV, Palcic MM (2005) Structural basis for the inactivity of human blood group O2 glycosyltransferase. J Biol Chem 280:525–529PubMedGoogle Scholar
  38. Lentsch AB (2002) The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white? FASEB J 16:1093–1095CrossRefPubMedGoogle Scholar
  39. Lo YMD, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CWG (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–487CrossRefPubMedGoogle Scholar
  40. Lögdberg L, Reid ME, Lamont RE, Zelinski T (2005) Human blood group genes 2004: chromosomal locations and cloning strategies. Transfus Med Rev 19:45–57CrossRefPubMedGoogle Scholar
  41. Loscertales M-P, Owens S, O’Donnell J, Bunn J, Bosch-Capblanch X, Brabin BJ (2007) ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism. Adv Parasitol 65:1–50CrossRefPubMedGoogle Scholar
  42. Mayer DCG, Jiang L, Achur RN, Kakizaki I, Gowda DC, Miller LH (2006) The glycophorin C N-linked glycan is a critical component of the ligand for the Plasmodium falciparum erythrocyte receptor BAEBL. Proc Nat Acad Sci USA 103:2358–2362CrossRefPubMedGoogle Scholar
  43. Mayer DCG, Cofie J, Jiang L, Hartl DL, Tracey E, Kabat J, Mendoza LH, Miler LH (2009) Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1. Proc Natl Acad Sci USA 106:5348–5352CrossRefPubMedGoogle Scholar
  44. Mohandas N, Gallagher PG (2008) Red cell membrane: past, present, and future. Blood 112:3939–3948CrossRefPubMedGoogle Scholar
  45. Mohandas N, Narla A (2005) Blood group antigens in health and disease. Curr Opin Hematol 12:135–140CrossRefPubMedGoogle Scholar
  46. Mouro I, Colin Y, Chérif-Zahar B, Cartron J-P, Le Van Kim C (1993) Molecular genetic basis of the human Rhesus blood group system. Nat Genet 5:62–65CrossRefPubMedGoogle Scholar
  47. Oriol R (1995) ABO, Hh, Lewis, and secretion, serology, genetics, and tissue distribution. In: Cartron J-P, Rouger P (eds) Blood cell biochemistry, vol 6. Plenum Press, New York, pp 36–73Google Scholar
  48. Page-Christiaens GCML, Bossers B, van der Schoot CE, de Haas M (2006) Use of bi-allelic insertion/deletion polymorphisms as a positive control in maternal blood. First clinical experience. Acad Sci 1075:123–129CrossRefGoogle Scholar
  49. Pasvol G, Wainscoat JS, Weatherall DJ (1982) Erythrocytes deficient in glycophorin resist invasion by the malarial parasite Plasmodium falciparum. Nature 297:64–66CrossRefPubMedGoogle Scholar
  50. Perreault J, Lavoie J, Painchaud P, Côté R, Delage G, Dubuc S, Lemieux R, St-Louis M (2009) Set-up and routine use of a database of 10,555 genotyped blood donors to facilitate the screening of compatible blood components for alloimmunised patients. Vox Sang 97:61–68CrossRefPubMedGoogle Scholar
  51. Pham B-N, Peyrard T, Juszczak G, Dubeaux I, Gien D, Blancher A, Cartron J-P, Rouger P, Le Pennec P-Y (2009) Heterogeneous molecular background of the weak C, VS+, hrB−, HrB− phenotype in black persons. Transfusion 49:495–504CrossRefPubMedGoogle Scholar
  52. Poole J, Warke N, Hustinx H, Taleghani BM, Martin P, Finning K, Karamatic Crew V, Green C, Bromilow I, Daniels G (2006) A KEL gene encoding serine at position 193 of the Kell glycoprotein results in expression of KEL1 antigen. Transfusion 46:1879–1885CrossRefPubMedGoogle Scholar
  53. Poole J, Tilley L, Warke N, Spring FA, Overbeeke MAM, van der Mark-Zoet JACM, Ahrens N, Armstrong D, Williams M, Daniels G (2007) Two missense mutations in the CD44 gene encode two new antigens of the Indian blood group system. Transfusion 47:1306–1311CrossRefPubMedGoogle Scholar
  54. Pruenster M, Rot A (2006) Throwing light on DARC. Biochem Soc Trans 34:1005–1008CrossRefPubMedGoogle Scholar
  55. Reid ME, Mohandas N (2004) Red blood cell blood group antigens: structure and function. Semin Hematol 41:93–117CrossRefPubMedGoogle Scholar
  56. Ridgwell K, Eyers SAC, Mawby WJ, Anstee DJ, Tanner MJA (1994) Studies on the glycoprotein associated with Rh (Rhesus) blood group antigen expression in the human red blood cell membrane. J Biol Chem 269:6410–6416PubMedGoogle Scholar
  57. Rowe JA, Moulds JM, Newbold CI, Miller LH (1997) P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388:292–295CrossRefPubMedGoogle Scholar
  58. Seltsam A, Blasczyk R (2005) Missense mutations outside the catalytic domain of the ABO glycosyltransferase can cause weak blood group A and B phenotypes. Transfusion 45:1663–1669CrossRefPubMedGoogle Scholar
  59. Shen H, Schuster R, Stringer KF, Walthz SE, Lentsch AB (2006) The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. FASEB J 20:59–64CrossRefPubMedGoogle Scholar
  60. Sim BKL, 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
  61. Singleton BK, Green CA, Avent ND, Martin PG, Smart E, Daka A, Narter-Olaga EG, Hawthorne LM, Daniels G (2000) The presence of an RHD pseudogene containing a 37 base pair duplication and a nonsense mutation in most Africans with the Rh D-negative blood group phenotype. Blood 95:12–18PubMedGoogle Scholar
  62. Singleton BK, Burton NM, Green C, Brady RL, Anstee DJ (2008) Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype. Blood 112:2081–2088CrossRefPubMedGoogle Scholar
  63. Spring FA, Dalchau R, Daniels GL, Spring FA, Dalchau R (1988) The Ina and Inb blood group antigens are located on a glycoprotein of 80,000 MW (the CDw44 glycoprotein) whose expression is influenced by the In(Lu) gene. Immunology 64:37–43PubMedGoogle Scholar
  64. Telen MJ (2005) Erythrocyte adhesion receptors: blood group antigens and related molecules. Transfus Med Rev 19:32–44CrossRefPubMedGoogle Scholar
  65. Tilley L, Green C, Daniels G (2006) Sequence variation in the 5′ untranslated region of the human A4GALT gene is associated with, but does not define, the P1 blood group polymorphism. Vox Sang 90:198–203CrossRefPubMedGoogle Scholar
  66. Tilley L, Green C, Poole J, Gaskell A, Ridgwell K, Burton NM, Uchikawa M, Akkøk CA, Garvik LJ, Daniels G (2009) A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein. Vox Sang (in press)Google Scholar
  67. Tournamille C, Colin Y, Cartron JP, Le Van Kim C (1995) Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet 10:224–228CrossRefPubMedGoogle Scholar
  68. Uneke CJ (2007) Plasmodium falciparum malaria and ABO blood group: is there any relationship? Parasitol Res 100:759–765CrossRefPubMedGoogle Scholar
  69. van der Schoot CE, Ait Soussan A, Koelewijn J, Bonsel G, Paget-Christiaens LG, de Haas M (2006) Non-invasive antenatal RHD typing. Transfus Clin Biol 13:53–57CrossRefPubMedGoogle Scholar
  70. Wagner FF, Flegel WA (2000) RHD gene deletion occurred in the Rhesus box. Blood 95:3662–3668PubMedGoogle Scholar
  71. Yamamoto F, Clausen H, White T, Marken J, Hakomori S (1990) Molecular genetic basis of the histo-blood group ABO system. Nature 345:229–233CrossRefPubMedGoogle Scholar
  72. Yamamoto F, McNeill PD, Hakomori S (1992) Human histo-blood group A2 transferase coded by A2 allele, one of the A subtypes, is characterized by a single base deletion in the coding sequence, which results in an additional domain at the carboxyl terminal. Biochem Biophys Res Commun 187:366–374CrossRefPubMedGoogle Scholar
  73. Yazer MH (2005) What a difference 2 nucleotides make: a short review of ABO genetics. Transfus Med Rev 19:200–209CrossRefPubMedGoogle Scholar
  74. Yazer MH, Hosseini-Maaf B, Olsson ML (2008) Blood grouping discrepancies between ABO genotype and phenotype caused by O alleles. Curr Opin Hematol 15:618–624CrossRefPubMedGoogle Scholar
  75. Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT, Hazlett F, Mgone CS, Alpers MP, Genton B, Boatin BA, Kazura JW (1999) Emergence of FY*A null in a Plasmodium vivax-endemic region of Papua New Guinea. Proc Natl Acad Sci USA 96:13973–13977CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Bristol Institute for Transfusion SciencesNHS Blood and TransplantBristolUK

Personalised recommendations