|Evolutionary Antagonism Between Genes and Germs|
|SciMed - Genetics & Genome|
|TS-Si News Service|
|Monday, 13 February 2012 09:00|
Salt Lake City, UT, USA. Biologists have found new evidence of why mice, people and other vertebrate animals carry thousands of varieties of genes to make immune-system proteins even though some of those genes make vertebrate animals susceptible to infections and to autoimmune diseases.
"Major histocompatibility complex" (MHC) proteins recognize invading germs, reject or accept transplanted organs and play a role in helping vertebrates smell compatible mates.
MHCs are found on the surfaces of most cells in vertebrate animals. They distinguish proteins like themselves from foreign proteins, and trigger an immune response against these foreign invaders. "Results of this study explain why there are so many versions of the MHC genes, and why the ones that cause susceptibility to diseases are being maintained and not eliminated," says biologist Wayne Potts of the University of Utah. "They are involved in a never-ending arms race that causes them, at any point in time, to be good against some infections but bad against other infections and autoimmune diseases."
Photo courtesy of Elizabeth Fischer and Kim Hasenkrug, the National Institutes of Health (NIH).
This is a friend mouse leukemia virus (yellow) budding from infected T-lymphocyte (blue).By allowing a disease virus to evolve rapidly in mice, Wayne Potts, Jason Kubinak and other scientists from the University of Utah produced new experimental evidence for the continuing arms race between genes and germs known technically as "antagonistic co- evolution." Their findings appear in the Proceedings of the National Academy of Sciences (PNAS).
"The genetic diversity of the MHC complex is critical for vertebrates, including humans, to mount a defense against novel pathogens," says George Gilchrist, acting deputy director of the Division of Environmental Biology at the National Science Foundation (NSF).
"This study demonstrates that trade-offs between MHC genotypes and the severity of pathogen effects are key factors maintaining that diversity. The work has important implications for agricultural practice and conservation genetics, as well as human health."
Most genes in humans and other vertebrates have only one or two alleles, varieties or variants of a single gene. Although any given person carries no more than 12 varieties of the six human MHC genes, the human population has anywhere from hundreds to 2,300 varieties of each of the six human genes that produce MHC proteins.
"The mystery is why there are so many different versions of the same [MHC] genes in the human population," Kubinak says, especially because many people carry MHCs that make them susceptible to pathogens (including the AIDS virus, malaria and hepatitis B and C) and autoimmune diseases (type I diabetes, rheumatoid arthritis, lupus, multiple sclerosis, irritable bowel disease and ankylosing spondylitis).
Theory One. Scientists have proposed three theories for why so many MHC gene variants exist in vertebrate animal populations (invertebrates don't have MHCs), and say all three likely are involved in maintaining the tremendous diversity of MHCs. An organism with more MHC varieties has a better immune response than organisms with fewer varieties, so over time, organisms with more MHCs are more likely to survive. However, this theory cannot explain the full extent of MHC diversity.
Theory Two. Previous research indicates that people and other animals are attracted to the smell of potential mates with MHCs that are "foreign" rather than "self." Parents with different MHC variants produce children with more MHCs and thus stronger immune systems. Antagonistic co-evolution between an organism and its pathogens: "we have an organism and the microbes that infect it," Kubinak says. "Microbes evolve to better exploit the organism, and the organism evolves better defenses to fight off the infection."
One theory to explain this great diversity in MHC genes is that those competing interests over time favor retaining more diversity. "You naturally keep genes that fight disease," says Kubinak. "They help you survive, so those MHC genes become more common in the population over time because the people who carry them live to have offspring."
Theory Three. Pathogens disease-causing viruses, bacteria or parasites infect animals, which defend themselves with MHCs that recognize the invader and trigger an immune response to destroy the invading pathogen. But over time, some pathogens mutate and evolve to become less recognizable by the MHCs and thus evade an immune response. As a result, the pathogens thrive.
What about disease-susceptibility?
MHCs that lose the battle to germs become less common because they now predispose people who carry them to become ill. It was thought that such disease-susceptibility MHC genes eventually should vanish from the population, but they usually don't. Why? While some of those MHCs do go extinct, others can persist, for two reasons.
The researchers studied 60 mice that were genetically identical, except that the mice were divided into three groups, each with a different variety of MHC genes known as b, d and k, respectively.
In this first experiment, the biologists showed that they could get the Friend virus to adapt to and thus evade the MHC variants (b, d or k) in the mouse cells it attacked.
Next, the researchers showed that the virus adapted only to specific MHC proteins. For example, viruses that adapted to and sickened mice with the MHC type b protein still were attacked effectively in mice that had the type d and k MHCs.
In the third experiment, the researchers showed that pathogen fitness (measured by the number of virus particles in the spleen) correlated with pathogen virulence (as measured by spleen enlargement and thus weight). So the virus that evaded the MHC type b made mice with that MHC sicker.
The findings have important implications, say the scientists. "The experiments demonstrate the first step in the antagonistic co-evolutionary dance between a virus and MHC genes," Potts says. The use of antibiotics to boost productivity in dairy herds and other livestock is a major reason human diseases increasingly resist antibiotics. Selective breeding for more milk and beef has reduced genetic diversity in livestock, including their MHCs. So breeding more MHCs back into herds could enhance their resistance to disease and thus reduce the need for antibiotics.
Because their populations are diminished, endangered species have less genetic diversity, making them an easier target for germs. Potts says it would be desirable to breed protective MHCs back into endangered species to bolster their disease defenses.
Genetic variation of MHCs in people and other organisms is important for limiting the evolution and spread of emerging infectious diseases. In effect, the researchers created emerging diseases by making a virus evolve in mice. "It's a model to identify what things change in viruses to make them more virulent," says Potts, "and thus emerging diseases."
ParticipationIn addition to Potts and Kubinak, the paper's lead author, the paper's co-authors are James Ruff, Cornelius Whitney Hyzer, and Patricia Slev, all of the University of Utah.
FundingThe research was funded by the National Science Foundation (NSF) and the National Institute of Allergy and Infectious Diseases (NIAID).
CitationExperimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types. Jason L. Kubinak, James S. Ruff, Cornelius Whitney Hyzer, Patricia R. Slev, and Wayne K. Potts. Proceedings of the National Academy of Sciences 2012. doi:10.1073/pnas.1112633109
The unprecedented genetic diversity found at vertebrate MHC (major histocompatibility complex) loci influences susceptibility to most infectious and autoimmune diseases. The evolutionary explanation for how these polymorphisms are maintained has been controversial. 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). Here we test these fundamental assumptions using an experimental evolutionary approach (serial passage). We demonstrate rapid adaptation and virulence evolution of a mouse-specific retrovirus to its mammalian host across multiple MHC genotypes. Critically, this adaptive response results in trade-offs (i.e., antagonistic pleiotropy) between host MHC genotypes; both viral fitness and virulence is substantially higher in familiar versus unfamiliar MHC genotypes. These data are unique in experimentally confirming the requisite conditions of the antagonistic coevolution model of MHC evolution and providing quantification of fitness effects for pathogen and host. These data help explain the unprecedented diversity of MHC genes, including how disease-causing alleles are maintained.
Keywords: host-pathogen, antibiotic resistance, endangered species, pathogen escape of adaptive immunity.
|Last Updated on Monday, 13 February 2012 09:04|