Human Genetics

, Volume 131, Issue 7, pp 1205–1216 | Cite as

Evolutionary genetics of the human Rh blood group system

  • George H. Perry
  • Yali Xue
  • Richard S. Smith
  • Wynn K. Meyer
  • Minal Çalışkan
  • Omar Yanez-Cuna
  • Arthur S. Lee
  • María Gutiérrez-Arcelus
  • Carole Ober
  • Edward J. Hollox
  • Chris Tyler-Smith
  • Charles LeeEmail author
Original Investigation


The evolutionary history of variation in the human Rh blood group system, determined by variants in the RHD and RHCE genes, has long been an unresolved puzzle in human genetics. Prior to medical treatments and interventions developed in the last century, the D-positive (RhD positive) children of D-negative (RhD negative) women were at risk for hemolytic disease of the newborn, if the mother produced anti-D antibodies following sensitization to the blood of a previous D-positive child. Given the deleterious fitness consequences of this disease, the appreciable frequencies in European populations of the responsible RHD gene deletion variant (for example, 0.43 in our study) seem surprising. In this study, we used new molecular and genomic data generated from four HapMap population samples to test the idea that positive selection for an as-of-yet unknown fitness benefit of the RHD deletion may have offset the otherwise negative fitness effects of hemolytic disease of the newborn. We found no evidence that positive natural selection affected the frequency of the RHD deletion. Thus, the initial rise to intermediate frequency of the RHD deletion in European populations may simply be explained by genetic drift/founder effect, or by an older or more complex sweep that we are insufficiently powered to detect. However, our simulations recapitulate previous findings that selection on the RHD deletion is frequency dependent and weak or absent near 0.5. Therefore, once such a frequency was achieved, it could have been maintained by a relatively small amount of genetic drift. We unexpectedly observed evidence for positive selection on the C allele of RHCE in non-African populations (on chromosomes with intact copies of the RHD gene) in the form of an unusually high F ST value and the high frequency of a single haplotype carrying the C allele. RhCE function is not well understood, but the C/c antigenic variant is clinically relevant and can result in hemolytic disease of the newborn, albeit much less commonly and severely than that related to the D-negative blood type. Therefore, the potential fitness benefits of the RHCE C allele are currently unknown but merit further exploration.


Segmental Duplication East Asian Population Gene Conversion Event Interbirth Interval Hemolytic Disease 
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.



We thank Rachael Cartlidge for assistance with initial development of the RHCE genotyping assays, David Hopkinson for DNA samples with known Rh serotype from the former MRC Blood Group Unit, Luis Barreiro for the HapMap Phase II F ST value database, Joe Pickrell for assistance with the iHS test, Richard Hudson for assistance with simulations, the Sanger Faculty Small Sequencing Projects Group for generating the sequence data, Steve McCarroll, Pardis Sabeti, and Molly Przeworski for helpful discussions, and two reviewers for insightful comments and suggestions on the manuscript. We acknowledge the participants who contributed samples for this study. This work was funded by National Institutes of Health Grant P41-HG004221 (to C.L.), The Wellcome Trust (WT098051, C.T.-S. and Y.X.), Medical Research Council New Investigator Award GO801123 (to E.J.H.), and National Institutes of Health Grant R01-HD21244 (to C.O.).

Supplementary material

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Supplementary material 1 (PDF 69 kb)
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Supplementary material 1 (DOC 83 kb)
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Supplementary material 1 (XLSX 90 kb)


  1. Abney M, McPeek MS, Ober C (2000) Estimation of variance components of quantitative traits in inbred populations. Am J Hum Genet 66:629–650PubMedCrossRefGoogle Scholar
  2. Allen SJ, O’Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ (1997) alpha+ -Thalassemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci USA 94:14736–14741PubMedCrossRefGoogle Scholar
  3. Allison AC (1954) The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Trans R Soc Trop Med Hyg 48:312–318PubMedCrossRefGoogle Scholar
  4. Avent ND, Reid ME (2000) The Rh blood group system: a review. Blood 95:375–387PubMedGoogle Scholar
  5. Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L (2008) Natural selection has driven population differentiation in modern humans. Nat Genet 40:340–345PubMedCrossRefGoogle Scholar
  6. Carritt B, Kemp TJ, Poulter M (1997) Evolution of the human RH (rhesus) blood group genes: a 50 year old prediction (partially) fulfilled. Hum Mol Genet 6:843–850PubMedCrossRefGoogle Scholar
  7. Chen JM, Cooper DN, Chuzhanova N, Ferec C, Patrinos GP (2007) Gene conversion: mechanisms, evolution and human disease. Nat Rev Genet 8:762–775PubMedCrossRefGoogle Scholar
  8. Colin Y, Cherif-Zahar B, Le Van Kim C, Raynal V, Van Huffel V, Cartron JP (1991) Genetic basis of the RhD-positive and RhD-negative blood group polymorphism as determined by Southern analysis. Blood 78:2747–2752PubMedGoogle Scholar
  9. Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, Absher D, Myers RM, Cavalli-Sforza LL, Feldman MW, Pritchard JK (2009) The role of geography in human adaptation. PLoS Genet 5:e1000500PubMedCrossRefGoogle Scholar
  10. Endeward V, Cartron JP, Ripoche P, Gros G (2008) RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane. FASEB J 22:64–73PubMedCrossRefGoogle Scholar
  11. Feldman MW, Nabholz M, Bodmer WF (1969) Evolution of the Rh polymorphism: a model for the interaction of incompatibility, reproductive compensation, and heterozygote advantage. Am J Hum Genet 21:171–193PubMedGoogle Scholar
  12. Fisher RA, Race RR (1946) Rh gene frequencies in Britain. Nature 157:48–49PubMedCrossRefGoogle Scholar
  13. Flegel WA (2011) Molecular genetics and clinical applications for RH. Transfus Apher Sci 44:81–91PubMedCrossRefGoogle Scholar
  14. Flint J, Hill AV, Bowden DK, Oppenheimer SJ, Sill PR, Serjeantson SW, Bana-Koiri J, Bhatia K, Alpers MP, Boyce AJ et al (1986) High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 321:744–750PubMedCrossRefGoogle Scholar
  15. Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709PubMedGoogle Scholar
  16. Haldane JBS (1942) Selection against heterozygosis in man. Ann Eugen 11:333–340CrossRefGoogle Scholar
  17. Hostetler J (1974) Hutterite society. Johns Hopkins University Press, BaltimoreGoogle Scholar
  18. Hudson RR (2002) Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics 18:337–338PubMedCrossRefGoogle Scholar
  19. International HapMap Project Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861CrossRefGoogle Scholar
  20. Knox G, Walker W (1957) Nature of the determinants of rhesus isoimmunization. Br J Prev Soc Med 11:126–130PubMedGoogle Scholar
  21. Kustu S, Inwood W (2006) Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels. Transfus Clin Biol 13:103–110PubMedCrossRefGoogle Scholar
  22. Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77:171–192PubMedCrossRefGoogle Scholar
  23. Levin BR (1967) The effect of reproductive compensation on the long term maintenance of the Rh polymorphism: the Rh crossroad revisited. Am J Hum Genet 19:288–302PubMedGoogle Scholar
  24. Levine P, Vogel P, Katzin EM, Burnham L (1941) Pathogenesis of erythroblastosis fetalis: statistical evidence. Science 94:371–372PubMedCrossRefGoogle Scholar
  25. Li CC (1953) Is Rh facing a crossroad? A critique of the compensation effect. Am Nat 87:257–261CrossRefGoogle Scholar
  26. Lo YM, Hjelm NM, Fidler C, Sargent IL, Murphy MF, Chamberlain PF, Poon PM, Redman CW, Wainscoat JS (1998) Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N Engl J Med 339:1734–1738PubMedCrossRefGoogle Scholar
  27. Luettringhaus TA, Cho D, Ryang DW, Flegel WA (2006) An easy RHD genotyping strategy for D− East Asian persons applied to Korean blood donors. Transfusion 46:2128–2137PubMedCrossRefGoogle Scholar
  28. Marini AM, Matassi G, Raynal V, Andre B, Cartron JP, Cherif-Zahar B (2000) The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast. Nat Genet 26:341–344PubMedCrossRefGoogle Scholar
  29. McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, Shapero MH, de Bakker PI, Maller JB, Kirby A, Elliott AL, Parkin M, Hubbell E, Webster T, Mei R, Veitch J, Collins PJ, Handsaker R, Lincoln S, Nizzari M, Blume J, Jones KW, Rava R, Daly MJ, Gabriel SB, Altshuler D (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166–1174PubMedCrossRefGoogle Scholar
  30. Moncharmont P, Juron Dupraz F, Vignal M, Rigal D, Meyer F, Debeaux P (1991) Haemolytic disease of the newborn infant. Long term efficiency of the screening and the prevention of alloimmunization in the mother: thirty years of experience. Arch Gynecol Obstet 248:175–180PubMedCrossRefGoogle Scholar
  31. Mouro I, Colin Y, Cherif-Zahar B, Cartron JP, Le Van Kim C (1993) Molecular genetic basis of the human Rhesus blood group system. Nat Genet 5:62–65PubMedCrossRefGoogle Scholar
  32. Ober C, Hyslop T, Hauck WW (1999) Inbreeding effects on fertility in humans: evidence for reproductive compensation. Am J Hum Genet 64:225–231PubMedCrossRefGoogle Scholar
  33. Pennings PS, Hermisson J (2006) Soft sweeps III: the signature of positive selection from recurrent mutation. PLoS Genet 2:e186PubMedCrossRefGoogle Scholar
  34. Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, Stone AC (2007) Diet and the evolution of human amylase gene copy number variation. Nat Genet 39:1256–1260PubMedCrossRefGoogle Scholar
  35. Potter EL (1947) Rh… Its relation to congenital hemolytic disease and to intragroup transfusion reactions. Year Book Publishers, ChicagoGoogle Scholar
  36. Reed TE (1971) Does reproductive compensation exist? An analysis of Rh data. Am J Hum Genet 23:215–224PubMedGoogle Scholar
  37. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837PubMedCrossRefGoogle Scholar
  38. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES (2006) Positive natural selection in the human lineage. Science 312:1614–1620PubMedCrossRefGoogle Scholar
  39. Schaffner SF, Foo C, Gabriel S, Reich D, Daly MJ, Altshuler D (2005) Calibrating a coalescent simulation of human genome sequence variation. Genome Res 15:1576–1583PubMedCrossRefGoogle Scholar
  40. 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 Africans with the Rh D-negative blood group phenotype. Blood 95:12–18PubMedGoogle Scholar
  41. Suto Y, Ishikawa Y, Hyodo H, Uchikawa M, Juji T (2000) Gene organization and rearrangements at the human Rhesus blood group locus revealed by fiber-FISH analysis. Hum Genet 106:164–171PubMedCrossRefGoogle Scholar
  42. Touinssi M, Chiaroni J, Degioanni A, De Micco P, Dutour O, Bauduer F (2004) Distribution of rhesus blood group system in the French basques: a reappraisal using the allele-specific primers PCR method. Hum Hered 58:69–72PubMedCrossRefGoogle Scholar
  43. Urbaniak SJ, Greiss MA (2000) RhD haemolytic disease of the fetus and the newborn. Blood Rev 14:44–61PubMedCrossRefGoogle Scholar
  44. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72PubMedCrossRefGoogle Scholar
  45. Wagner FF, Flegel WA (2000) RHD gene deletion occurred in the Rhesus box. Blood 95:3662–3668PubMedGoogle Scholar
  46. Wagner FF, Moulds JM, Tounkara A, Kouriba B, Flegel WA (2003) RHD allele distribution in Africans of Mali. BMC Genet 4:14PubMedCrossRefGoogle Scholar
  47. Westhoff CM (2004) The Rh blood group system in review: a new face for the next decade. Transfusion 44:1663–1673PubMedCrossRefGoogle Scholar
  48. Westhoff CM, Wylie DE (2006) Transport characteristics of mammalian Rh and Rh glycoproteins expressed in heterologous systems. Transfus Clin Biol 13:132–138PubMedCrossRefGoogle Scholar
  49. Xue Y, Daly A, Yngvadottir B, Liu M, Coop G, Kim Y, Sabeti P, Chen Y, Stalker J, Huckle E, Burton J, Leonard S, Rogers J, Tyler-Smith C (2006) Spread of an inactive form of caspase-12 in humans is due to recent positive selection. Am J Hum Genet 78:659–670PubMedCrossRefGoogle Scholar
  50. Xue Y, Sun D, Daly A, Yang F, Zhou X, Zhao M, Huang N, Zerjal T, Lee C, Carter NP, Hurles ME, Tyler-Smith C (2008) Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet 83:337–346PubMedCrossRefGoogle Scholar
  51. Xue Y, Zhang X, Huang N, Daly A, Gillson CJ, Macarthur DG, Yngvadottir B, Nica AC, Woodwark C, Chen Y, Conrad DF, Ayub Q, Mehdi SQ, Li P, Tyler-Smith C (2009) Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation. Genetics 183:1065–1077PubMedCrossRefGoogle Scholar
  52. Yokoyama S (1981) Family size and evolution of Rh polymorphism. J Theor Biol 92:119–125PubMedCrossRefGoogle Scholar
  53. Yu X, Wagner FF, Witter B, Flegel WA (2006) Outliers in RhD membrane integration are explained by variant RH haplotypes. Transfusion 46:1343–1351PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • George H. Perry
    • 1
    • 2
  • Yali Xue
    • 3
  • Richard S. Smith
    • 2
  • Wynn K. Meyer
    • 4
  • Minal Çalışkan
    • 4
  • Omar Yanez-Cuna
    • 2
    • 5
  • Arthur S. Lee
    • 2
  • María Gutiérrez-Arcelus
    • 2
    • 5
  • Carole Ober
    • 4
  • Edward J. Hollox
    • 6
  • Chris Tyler-Smith
    • 3
  • Charles Lee
    • 2
    Email author
  1. 1.Department of AnthropologyPennsylvania State UniversityUniversity ParkUSA
  2. 2.Department of PathologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Wellcome Trust Sanger InstituteCambridgeUK
  4. 4.Department of Human GeneticsUniversity of ChicagoChicagoUSA
  5. 5.Centro de Ciencias Genómicas, Universidad Nacional Autónoma de MéxicoCuernavacaMexico
  6. 6.Department of GeneticsUniversity of LeicesterLeicesterUK

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