Human Genetics

, Volume 131, Issue 7, pp 1205–1216

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 Lee
Original Investigation

DOI: 10.1007/s00439-012-1147-5

Cite this article as:
Perry, G.H., Xue, Y., Smith, R.S. et al. Hum Genet (2012) 131: 1205. doi:10.1007/s00439-012-1147-5

Abstract

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 FST 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.

Supplementary material

439_2012_1147_MOESM1_ESM.pdf (68 kb)
Supplementary material 1 (PDF 69 kb)
439_2012_1147_MOESM2_ESM.xls (67 kb)
Supplementary material 1 (XLS 67 kb)
439_2012_1147_MOESM3_ESM.doc (82 kb)
Supplementary material 1 (DOC 83 kb)
439_2012_1147_MOESM4_ESM.xlsx (89 kb)
Supplementary material 1 (XLSX 90 kb)

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
  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