The immunologically critical MHC gene cluster plays by its own rules through the arms race of life.
Last week, I discussed the very general landscape of variation in the human genome, specifically the tradeoff between prevalence in the population and effect size. Given that the vast majority of variants are deleterious, those that affect our phenotypic traits are more heavily selected against the greater effect they have. The result is that at a gross level, most genes and most traits share the same general distribution of lots of variants (alleles) with minor effects, and far fewer with large effects. And those with minor effects also turn out to be tangential for biologists, rarely informative about the nature of the traits they (sort-of) affect.
This week, another paper and another view of evolution, though the eyes of one the more critical genes of the immune system, the major histocompatibility complex, or MHC group of genes. While our adaptive immune system has developed the extraordinary and powerful ability (though semi-controlled DNA recombination of the antibody and TCR genes) to recognize practically any antigen, foreign or domestic, that system requires stringent controls. One of those controls on T cells, which carry the antigen-recognizing TCR receptor, is that it can only see antigens that are "presented" on MHC molecules. MHC proteins have a surface cleft that gets loaded with and holds small peptides (8 to 12 amino acids long) that are cleaved from other proteins, either from pathogens or from the cell itself. The MHC+peptide complex then sits on the surface of the cell, announcing either that 1) I am healthy, full of normal cell proteins, going about their business, nevermind, or 2) I have some other proteins inside, either from a viral infection (class I MHC) or from some bacterium I have just phagocytosed to deal with an infection (class II MHC). In the second case, T cells carrying the TCR receptor lock onto the MHC+peptide complex, and start up the process of killing that cell.
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| MHC proteins (beige, pink) present an antigen (red) from one cell, and dock to a T-cell which recognizes the antigen+MHC complex by shape, using the TCR receptor. The additional CD8 or CD4 receptors help to verify the proper binding. While class I MHC are present on all cells, class II MHC are on phagocytosing cells like dendritic cells and macrophages that commonly ingest, reprocess, and re-display bits of encountered pathogens. |
Given that the TCR gene recombination process is unbiassed and produces a galaxy of random binding specificities, how do these cells distinguish self from non-self antigens? This is a deep question that is not fully resolved. But one major mechanism is thymic selection, which is what gives T cells their name. Special cells in the thymus display a wide range of self-antigens, and T cells, which are obliged to pass through the thymus during their maturation, are induced to commit suicide if they react to any of them. A paper from 2018 fascinatingly discussed how it is possible to create a T cell population that knows the "language" of foreign vs domestic after what is known to be a rather haphazard selection process, which displays only a partial range of self-antigens, and leaves quite a few self-reactive T cells around.
At any rate, the MHC proteins do not benefit from hyper-variation provided by genetic recombination. Yet it turns out that variation is beneficial here as well. The way foreign antigen peptides nestle in the MHC groove can be varied by mutations in the MHC molecule, providing a rich field of variation in antigen recognition and thus disease resistance. So, our MHC genes have not just a few alleles in the population, not just a few dozen, but over six thousand alleles. For each individual MHC protein, each person has only two, but over the population, there myriads with different properties. MHC was first recognized for its role in self vs non-self recognition and transplant rejection, (thus the "compatibility" in its name), and it quickly became evident that people vary tremendously in their MHC complement. And this variation plays a big role in keeping us (and all other animals) going as populations, in the face of pathogens that evolve a lot faster than we do.
A recent paper provided a phylogenetic history of MHC molecules in monkeys, covering the last sixty million years of evolution in our lineage. It is a festival of gene birth, death, and duplication, quite apart from the smaller mutations that are constantly accumulating and cycling through the population. The MHC region carries about 200 related genes, most of which have minor roles, and only six of which (three MHC class I, and three MHC class II) follow the high-mutation pattern because they encode the main antigen presenting proteins. These genes are subject to, quite obviously, unique selective forces.
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| How the MHC gene cluster looks, when aligned and identified by gene, over the primates. Note the deep divergence between the new- and old-world primates. Genes A, B, and C are the major MHC class I genes, which vary the most over this time. Note also how some of these genes have gone through extensive duplication in some old-world monkey lineages. |
The first force is balancing selection. As soon as one allele becomes common, pathogens evolve to evade its presentation skills, rendering it less effective and less desirable. This results in a population full of minor variants. Indeed, for any individual person, having two MHC molecules that are the same would be bad. Being heterozygous at these genes is highly advantageous, thus enforcing both the retention of minor alleles, and an observed behavior in mating to favor partners with different MHC complements. Apparently, our MHC makeup is reflected in our personal aroma!
A second force, conversely, is the retention of ancient alleles. It turns out that, across the old-world monkeys, many MHC alleles are preserved and cluster more closely in sequence comparisons with each other than they do with other alleles in the same species. That is, despite the general speed of MHC evolution and constant accumulation of new alleles, old alleles are preserved in all monkey populations as well, due to their distinct capabilities, under balancing selection. This is part of what makes population bottlenecks so damaging to near-extinction species. They lose critically valuable genetic resources (in the form of rare MHC alleles) that represent millions of years of accumulated variation.
Incidentally, the trees shown here again reinforce the history of primate evolution, with new world monkeys splitting off from the old-world monkeys quite early on and developing a very distinct set of MHC molecules.
So, while virtually every other gene in the genome is being relentlessly optimized, sticking to its knitting, doing one thing and being beaten down whenever any mutation steers it from its optimized path, the MHC genes follow quite a different path, at least in portions of their sequence that provide variation in antigen binding and presentation. These genes revel in endless diversity, throw off pseudogenes at a high rate, wink out of existence and come back in other forms. Natural selection is the motor in each case, but meets the challenge of survival in different ways.
- We are still OK.
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- Outstanding overview of China and Xi Jinping thought.
- A total empathy deficit.
