, Volume 55, Issue 11, pp 725–731

Heterozygote advantage fails to explain the high degree of polymorphism of the MHC

  • Rob J. De Boer
  • José A. M. Borghans
  • Michiel van Boven
  • Can Keşmir
  • Franz J. Weissing
Original Paper


Major histocompatibility (MHC) molecules are encoded by extremely polymorphic genes and play a crucial role in vertebrate immunity. Natural selection favors MHC heterozygous hosts because individuals heterozygous at the MHC can present a larger diversity of peptides from infectious pathogens than homozygous individuals. Whether or not heterozygote advantage is sufficient to account for a high degree of polymorphism is controversial, however. Using mathematical models we studied the degree of MHC polymorphism arising when heterozygote advantage is the only selection pressure. We argue that existing models are misleading in that the fitness of heterozygotes is not related to the MHC alleles they harbor. To correct for this, we have developed novel models in which the genotypic fitness of a host directly reflects the fitness contributions of its MHC alleles. The mathematical analysis suggests that a high degree of polymorphism can only be accounted for if the different MHC alleles confer unrealistically similar fitnesses. This conclusion was confirmed by stochastic simulations, including mutation, genetic drift, and a finite population size. Heterozygote advantage on its own is insufficient to explain the high population diversity of the MHC.


Heterozygote advantage MHC polymorphism 

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Rob J. De Boer
    • 1
  • José A. M. Borghans
    • 2
  • Michiel van Boven
    • 3
  • Can Keşmir
    • 1
  • Franz J. Weissing
    • 4
  1. 1.Theoretical BiologyUtrecht University UtrechtThe Netherlands
  2. 2.Biologie des Populations LymphocytairesInstitut Pasteur ParisFrance
  3. 3.Animal Sciences GroupWageningen University and Research Centre LelystadThe Netherlands
  4. 4.Theoretical BiologyUniversity of GroningenHarenThe Netherlands

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