THE NATURE OF SELECTION ON THE MAJOR HISTOCOMPATIBILITY COMPLEX

Only natural selection can account for the extreme genetic diversity o f genes of the major histocompatibility complex (MHC). Although the st ructure and function of classic MHC genes is well understood at the mo lecular and cellular levels, there is controversy about how MHC divers ity is selectively maintained. The diversifying selection can be drive n by pathogen interactions and inbreeding avoidance mechanisms. Pathog en-driven selection can maintain MHC polymorphism based on heterozygot e advantage or frequency-dependent selection due to pathogen evasion o f MHC-dependent immune recognition. Empirical evidence demonstrates th at specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both hete rozygote 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 di versity through molecular mimicry and by favoring immunodominance. MHC -dependent abortion and mate choice, based on olfaction, can also main tain MHC diversity and probably functions both to avoid genome-wide in breeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often trea ted as competing alternatives, we believe that they all fit into a coh erent, internally consistent thesis. It is likely that at least in som e species, all of these mechanisms operate, leading to the extreme div ersification found in MHC genes.