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A recent issue of Nature (August 15th) contains a couple of papers on the 
evolution of genes in the major histocompatibility complex (MHC). It is
commonly assumed that class I genes show "astonishing polymorphism" 
(Howard, 1991) and this polymorphism requires an explanation.

In fact, it seems that the number of alleles of class I genes is not very 
unusual. There are many other examples of similar degrees of polymorphism in
genes that have been examined. For example, there are hundreds of hemoglobin
alleles so that it is not even correct to say that the MHC genes are "...the
most polymorphic known in man." (Hill et al., 1991).

Is there a general explanation for the large amount of polymorphism at 
some loci? I know that Lewontin et al. (1977) have addressed this question
and they point out that heterosis is not a satisfactory explanation. 
Lewontin seems to favor multiple niche selection or variable selection in
space and time although random drift cannot be ruled out.

Nei and Hughes (1991) on the other hand, strongly favor heterozygous advantage
or overdominance and their simulations suggest that the polymorphism at
the MHC loci (and other loci) can be explained this way. Are the Nei and
Hughes simulations reliable or are their assumptions too unrealistic?
(I am assuming that heterozygous advantage, overdominance, and heterosis are
equivalent terms for the same phenomenon.)

Back to the two recent Nature papers. One of the papers shows that specific
HLA antigens are associated with protection from severe malaria (Hill et al.
1991). The authors assume that the connection between this fact and the
presence of a large, stable number of alleles in a population is obvious. It
is not obvious to me - can someone explain it? Is this supposed to be evidence
in favor of multiple niche selection?

The second paper seems to support overdominance because it confirms a mating
preference in mice that could increase heterozygosity (Potts et al. 1991).
I also have trouble understanding this mechanism - particularly since it
seems to require that all heterozygotes are more fit than all homozygotes.
The authors show the results of computer simulations which are supposed to
convince us that "The above results suggest that MHC-based mating preferences
are a major force responsible for the maintenance of MHC genetic diversity in
Mus". Can anyone explain how this might work?

Is there any reason to believe that polymorphism at the mammalian MHC locus
requires a different explanation than that at any other locus? (I suspect 
that immunologists are biased towards an explanation that reflects their
belief in the importance, and uniqueness, of these genes.)

Laurence A. Moran (Larry)
Dept. of Biochemistry

Hill, A.V.S. and nine others (1991) Common West African HLA antigens are
   associated with protection from severe malaria. Nature 352, 595-600.
Howard, J.C. (1991) Disease and evolution. 
   Nature (News and Views) 352, 565-567.
Lewontin, R.C., Ginzburg, L.R., Tuljapurkar, S.D. (1978) Heterosis as an
   explanation for large amopunts of genic polymorphism. Genet. 88, 149-170.
Nei, M. and Hughes, A.L. (1991) Polymorphism and the evolution of the major
   histocompatibility complex loci in mammals. in EVOLUTION AT THE MOLECULAR
   LEVEL R.K. Selander et al. eds. Sinauer Associates Inc. pp. 222-247.
Potts, W.K., Manning, C.J. and Wakeland, E.K. (1991) Mating patterns in
   seminatural populations of mice influenced by MHC genotype.
   Nature 352, 619-621.