Frozen Evolution. Or, that’s not the way it is, Mr. Darwin. A Farewell to Selfish Gene.

An interesting example of the action of frequency-dependent selection is active in maintenance of polymorphism of the major histocompatibility complex antigens (MHC-antigens) (Klein & Ohuigin 1994). These proteins are of key importance in both cell and humoral immunity processes. They specifically bond, on their receptor region, some of the short peptides formed in the cells by enzymatic splicing of protein molecules and transport them to the cell surface.  In this way, they determine the sections of the aminoacid chain according to which the immune system of the given individual will recognize the foreignness of a particular protein. If all the individuals in the population were identical in their MHC-antigen alleles, they would recognize the foreignness of the individual antigens, e.g. proteins derived from viruses and bacteria, according to the same criteria, i.e. according to the same sections of the aminoacid chain.In typical cases, evolution occurs much more rapidly amongst parasitic organisms than in their hosts. Thus, a parasite would be capable of rapidly changing the relevant site of its proteins, which would remove it from the action of the immune system of the host and it would be capable of attacking all the individuals in the host population. However, MHC-antigens are extremely polymorphic in real populations. Each MHC gene (MHC is a complex consisting of several genes) has a number of alleles (frequently dozens) that occur with quite similar frequencies in the population. For most species, with the exception of identical twins, it is thus not possible to find two individuals that would have the same combination of alleles of the major histocompatibility complex.

This extreme polymorphism was not formed to teach transplantation surgeons humility (without MHC polymorphism, some organs could be transplanted on an extensive scale) but as a defensive strategy of organisms against parasites. The individual alleles of MHC antigens specifically bind different peptides (Fig. VIII.9). Because every individual in the population has different MHC alleles, it recognizes the foreignness of the parasite proteins according to different sections of their aminoacid chain. Thus, the parasite cannot mutate the sequence of its proteins in a manner that would allow it to successfully attack all the individuals in the host population. The evenness of the frequency of the individual alleles of the MHC genes is apparently ensured by a frequency-dependent selection mechanism. If the frequency of certain alleles increases in the population, the individuals in the parasite population that mutated in that area of their proteins that was originally specifically bonded to the MHC-antigen coded by the particular frequent allele begin to have a selection advantage in the parasite population. Thus, individuals that, through mutations, have removed, from their proteins, sites capable of binding to the commonest MHC-antigen and that can thus not be recognized by the immune system of the host begin, in time, to predominate in the parasite population. Consequently, the parasite will multiply most successfully in individuals bearing the commonest MHC-allele.As a result, these individuals will be affected most and their frequency and the frequency of the relevant allele will decrease.

In many species, including man, the maintenance of polymorphism in MHC genes is also strengthened with different mechanisms, by assortative reproduction.For example the fertility of partners with different MHC alleles is in average higher than that the partners with higher representation of same MHC alleles in genotype.It is partly caused by higher frequency of abortion of embryos homozygous in one or more genes of MHC [11567].

For a long time, immunologists discussed the question of whether the polymorphism of MHC-antigens is maintained in the population through the action of frequency-dependent selection or through the action of selection for heterozygotes. At the present time, it tends to be accepted that frequency-dependent selection plays the main role [10738].The usual argument is that, if selection for heterozygotes were the main factor, it would be much more advantageous for the organism to increase the number of loci for MHC-antigens and thus the number of various kinds of MHC-antigens located on the surface of one cell, than to increase the number of alleles in a constant, not very large number of loci.However, the problem is somewhat more complicated (Takahata 1995). The number of various molecules of MHC-antigens on a single cell may, in actual fact, be limited from above by the necessity of eliminating all the T-cells that recognize an organism’s own peptide capable of binding one of its own MHC-molecules, during development of the lymphocytes in the thymus.Individuals with a large number of variants of MHC-molecules on the surface of their cells could thus have a substantially reduced range of T-cells and thus much worse immunity.  Although it is more advantageous for the population as a whole to exhibit the greatest possible polymorphism of MHC molecules, there is a certain optimal number of MHC-alleles for individuals that, when exceeded, would lead to substantial reduction in the range of T-cells and thus to reduction in the ability to recognize the presence of foreign agents in the organism.It is apparently more advantageous for individuals to bear the less common variants of MHC-antigens than to bear the greatest number of these variants, i.e.  to be heterozygote in the greatest possible number of loci.However, this once again indicates that polymorphism in MHC-antigens will tend to be a consequence of the action of frequency-dependent selection rather than selection for heterozygotes.