Debunking myths on genetics and DNA

Monday, March 5, 2012

It takes all the running you can do to keep in the same place

"Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"
~Lewis Carroll, Through the Looking Glass
The Red Queen Effect is a genetic effect named after Lewis Carroll's famous quote, "It takes all the running you can do to keep in the same place." As it turns out, Carroll's witty and paradoxical thinking fits viral host evolution: out of the whole viral population, only a few manage to infect new hosts -- these are the viruses that are fit enough to overcome the first hurdle (bottleneck) of "jumping" into a new host. Once there, though, these viral particles are not necessarily fit to survive the new host's environment because the defenses they have developed have been selected for in the previous host (this in genetics is called "fitness cost"). Therefore, they must mutate rapidly in order to acquire new defenses that will allow them to escape the new immune system.

Do you see why Carroll's Red Queen applies? A virus has to do all the running (mutating) it takes in order to keep (survive) in the same place (host).

Variety in hosts' immune responses is ensured by the MHC genes, the major histocompatibility complex genes in vertebrates. These genes, which are the most polymorphic among vertebrates, encode molecules found on all cell surfaces that mediate antigen presentation: when an antigen (any object, either a molecule or another organism, that is recognized as a "non-self" by the body) enters a cell, it is broken up and the bits of proteins are transported to the cell surface for "presentation" to the immune system. High variability in this class of molecules ensures that a wide range of antigens can be recognized and hence trigger the immune response. The high variability found in the MHC genes is the reason for the high variation in disease susceptibility in the population, for example, why a particular flu strain can keep one person in bed for a whole week, while another only gets a mild cold for a couple of days.

Just like the virus needs to do a lot of running in order to overcome the immune system, the immune system itself is at an advantage the more antigens it is able to recognize. So, you see, the Red Queen Effect, applies to both the host and the pathogen, leading to an antagonistic coevolution that ensures diversity in the MHC genes in the population.

A recent PNAS paper [1] investigates how this mechanism is maintained:
"One leading explanation, antagonistic coevolution (also known as the Red Queen), postulates a never-ending molecular arms race where pathogens evolve to evade immune recognition by common MHC alleles, which in turn provides a selective advantage to hosts carrying rare MHC alleles. This cyclical process leads to negative frequency-dependent selection and promotes MHC diversity if two conditions are met: (i) pathogen adaptation must produce trade-offs that result in pathogen fitness being higher in familiar (i.e., host MHC genotype adapted to) vs. unfamiliar host MHC genotypes; and (ii) this adaptation must produce correlated patterns of virulence (i.e., disease severity)."
In [1], Kubinak et al. describe how they repeatedly transmitted the same pathogen through different hosts (groups of genetically identical mice, each group carrying a different MHC family) and observed patterns of pathogen adaptation.
"Results from our experiments demonstrate that pathogen adaptation is host MHC genotype-specific. We conclude that pathogen adaptation to the familiar host MHC genotype produces trade-offs in pathogen fitness by reducing the reproductive output of adapted viruses when infecting hosts carrying unfamiliar MHC genotypes. Although previous work has shown that interactions between host and pathogen genotypes are important for determining patterns of pathogen fitness and virulence associated with infection, our dataset is unique in that it provides direct experimental support for fitness trade-offs associated with a pathogen’s adaptation to specific host MHC genotypes, thus confirming the first major assumption of the antagonistic coevolution model of MHC evolution."
With their experiment, Kubinak and colleagues proved that diversity in the MCH gene complex is maintained through the antagonistic coevolution between pathogen and host. This does not exclude other factors such as the heterozygote advantage and mating preferences, which have also been considered as likely explanations of the high variability in this gene family. As it often happens in genetics, the likely explanation is an interaction between all these phenomena and the hardest thing is to disentangle each contribution.

The authors conclude with one final thought, as their results suggest that populations with low MHC genetic diversity are likely to select for more virulent pathogens.
"If this suggestion is true, many livestock breeds and endangered species that exhibit reduced genetic diversity may be particularly sensitive to the consequences of rapid pathogen adaptation. Additionally, the prophylactic use of antibiotics on domesticated livestock places a selective pressure on pathogen populations to evolve antibiotic resistance, and as a consequence has been implicated in the emergence of antibiotic-resistant strains of human pathogens."

[1] Kubinak, J., Ruff, J., Hyzer, C., Slev, P., & Potts, W. (2012). From the Cover: Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types Proceedings of the National Academy of Sciences, 109 (9), 3422-3427 DOI: 10.1073/pnas.1112633109

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