In the last of this three part series (part I and part II), I'm going to be moving away from the distant past of the origins of this molecule and instead focusing on the current evolutionary factors that influence the high diversity of the MHC among humans. As mentioned in the first part of this series, the MHC is best characterised by its extreme diversity. The most common HMC types in humans, HLA-A (Or Human Leukocyte Antigen), HLA-B and HLA-DRB1 have 243, 499 and 321 different alleles respectively with more probably to find. As more genes in the MHC region are sequenced and compared from human populations world-wide, it turns out this is a typical characteristic of MHC loci. Although it would at first seem to be a relatively intuitive answer as to why the MHC has such a wide array of expression.
In its role in immunity, the ability to bind different peptides and recognise a wide range of different immunological insults would encourage diversity. In reality, the answer is not so obvious and the actual mechanisms that maintain MHC diversity are not properly understood. For example, although MHC regions between vertebrates have a similar structure being clustered together in single gene complexes, as comparisons between the gene regions that comprise the class I and class II MHCs in mammals and chickens reveal key differences. Mammalian MHCs have a lot more diversification among their loci while in chickens the B-complex codes for only two class I and two class II genes, of which only one of these genes is actually polymorphic.
Even with the different structures in other vertebrates, there is emerging support that MHC diversity is encouraged by an arms race against infectious parasites. Malaria in particular seems to be driving the diversification of different HLA class I and II haplotypes. Going back to chickens, there is strong evidence to associate the presence of certain class II MHC alleles with susceptibility to Mareks disease induced by a herpes virus, which causes a potentially lethal T-cell lymphoma. Similarly, studies conducted on mice indicate that mouse MHC haplotypes (H2 in this case) play important roles in determination of susceptibility to infection with Mycobacterium tuberculosis.
With this link in mind it leaves the question as to the mechanisms that caused the divergence in the first place. As Piertney and Oliver detail (see Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Nature, 96:7-21 for more information on this topic) there are two main hypotheses that propose to explain this high diversification. The first is negative frequency-dependant selection, where new or rare alleles may be selected when organisms are exposed to a novel pathogen. Essentially, picture a group of animals that have just been exposed to a debilitating new organism such as ebola. Some isolated members of the population may have a MHC allele that makes them more resistant than others in the population. As the pathogen spreads, those with the resistant MHC allele are able to breed more successfully than those without it and the frequency of their respective MHC increases.
Over time however, the original epidemic starts to wane due to the increased amount of resistance the original pathogen begins to hit a brick wall. As it can no longer spread as easily, due to the build of immunity combined with resistance, selection would favour pathogens that are not recognised by this allele or alternatively the emergence of a new pathogen. Corresponding to the original situation, if other members had a slightly different MHC allele that rendered them resistant to this new pathogen the frequency of their MHC type will increase. After repeated rounds of assaults from new microbial challenges and this rise and fall of different alleles being favoured, inevitably leads to the distribution of multiple MHC types.
Alternatively, another explanation called the overdominance hypothesis proposes that MHC diversity arises from heterozygosity at the MHC loci. Essentially, because humans have two different copies at their MHC alleles that can produce a wider array of different peptide chains. This allows for the recognition of a larger number of potential microbial structures than an individual who was homozygous (two of the same MHC allele). As a result, individuals with the least overlap between the peptides they produce would be favoured and be able to respond to a wider array of different pathogens.
It is worth noting that these two processes of negative frequency-dependant selection and overdominance are unlikely to be mutually exclusive processes (teach the controversy!). Determining how these processes affected selection in the past is also very difficult, as natural populations tend to be of relatively small sizes and may be challenged by several pathogens at once. Of course, selection and maintenance of new MHC alleles may not simply be just from selection from parasitic relationships. Evidence also suggests that sexual selection may be equally as important in maintaining diversity in both humans and in animals.
Recalling that in part I, a proposed original function for a proto-MHC like molecule was as a mechanism to ensure that organisms maintained a more diverse gene pool. It turns out that MHC in current vertebrates may play a role in sexual selection. This was first observed in studies with mice, where females preferentially mated with males who were MHC-dissimilar to themselves and vice-versa. How mice (and possibly other animals including humans) determine how similar a potential mates MHC alleles are is probably complicated, but is theorised to be heavily dependant upon olfactory (smell) senses. This is because the makeup of MHC genes can affect the concentration of violatile acids that make produce odour in sweat and urine.
One clear example where MHC molecules were found to profoundly affect mate choice appeared in the Proceedings of the National Academy of Sciences (PNAS) last year. The paper by Milinsky et al (referenced below) investigated if the peptides produced by MHC of the three spined sticklebacks (Gasterosteus aculeatus) could interact with the animals olfactory senses. Their results give strong evidence that MHC molecules can influence sexual selection, as fish preferentially moved into water with peptides produced from different MHC and not into water demonstrating similar peptides that their own MHC would produce.
Over this three part series I have detailed only a very narrow range of the total research that has gone into the evolution of this critical system. From beginnings as a simple mechanism to prevent asexually producing organisms from reducing the diversity of their gene pools to a critical component in immunity, the modern MHC is an example of a complex system built from simpler precursors over evolutionary time. Clearly important in this system was the original whole genome duplications that gave rise to modern jawed vertebrates some 766 and 528 million years ago. These allowed for the duplicated genes to be co-opted and diversified to form the required systems for the modern MHC function. Additionally, selection pressures from parasites and even sexual selection continue to ensure that MHC genes remain highly diverse.
In all, there are still a great deal of unanswered questions surrounding both the origins of this system and how such large gene diversity was derived. Unfortunately, there may never be definitive answers to these questions, as many of the organisms that developed the first immunological novelties have long since gone extinct or modified their original systems. It is important however, to realise that scientists working on this field have provided numerous important insights into the mechanisms of evolution and how systems such as the immune system arose. Even more importantly, that researchers continue to publish giving us even greater insight and furthering our understanding, even if it may never be truly complete.
Messaoudi I., J.A. Guevara Patino, R. Dyall, J. LeMaoult and J. Nikolich-Zugich (2002). Direct link between mhc polymorphism, T-cell avidity and diversity in immune defence. Science, 298:1797-1800.
Milinski M., Siân Griffiths, K.M. Wegner, T.B.H. Reusch, A. Haas-Assenbaum, and T. Boehm (2005). Mate choice decisions of stickleback females predictably modified by MHC peptide ligands. PNAS, 102:4414-4418.
Pichugin A.V., S.N. Petrovskaya and A.S. Apt (2006). H2 complex controls CD4/CD8 ratio, recurrent responsiveness to repeated stimulations, and resistance to activationinduced apoptosis during T cell response to mycobacterial antigens. The society for leukocyte biology, 79:1-8.
Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Nature, 96:7-21.
Hill A.V. (1999). The immunogenetics of resistance to malaria. Proceedings of the Association of American Physicians, 111:272-277.