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Critical Reviews™ in Immunology

Impact factor: 3.857

ISSN Print: 1040-8401
ISSN Online: 2162-6472

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v17.i2.40
pages 179-224

The Nature of Selection on the Major Histocompatibility Complex

Victor Apanius
Institute of Parasitology, McGill University-Macdonald College, 21,111 Lakeshore Rd., Ste-Anne-de-Bellevue, Quebec, Canada,Department of Biological Sciences, Florida International University, University Park, Miami, FL 33199
Dustin Penn
Department of Zoology, University of Florida, Gainesville, FL 32611; Department of Biology, University of Utah, Salt Lake City, UT 84112
Patricia R. Slev
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
L. Ramelle Ruff
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
Wayne K. Potts
Department of Biology, University of Utah, Salt Lake City, UT 84112; Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610

ABSTRACT

Only natural selection can account for the extreme genetic diversity of genes of the major histocompatibility complex (MHC). Although the structure and function of classic MHC genes is well understood at the molecular and cellular levels, there is controversy about how MHC diversity is selectively maintained. The diversifying selection can be driven by pathogen interactions and inbreeding avoidance mechanisms. Pathogen-driven selection can maintain MHC polymorphism based on heterozygote advantage or frequency-dependent selection due to pathogen evasion of MHC-dependent immune recognition. Empirical evidence demonstrates that specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both heterozygote advantage and frequency-dependent models. Additional research is needed to discriminate between these mechanisms. Infectious agents can precipitate autoimmunity and can potentially contribute to MHC diversity through molecular mimicry and by favoring immunodominance. MHC-dependent abortion and mate choice, based on olfaction, can also maintain MHC diversity and probably functions both to avoid genome-wide inbreeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often treated as competing alternatives, we believe that they all fit into a coherent, internally consistent thesis. It is likely that at least in some species, all of these mechanisms operate, leading to the extreme diversification found in MHC genes.