The Major Histocompatibility Complex (MHC) plays a critical role in immune recognition. MHC molecules bind foreign antigens (e.g. small pieces of degraded viral and bacterial proteins) and present them on the cell surface to T-cell receptors. T cell recognition of a MHC-antigen complex initiates the cascade of immunologic events necessary to fight infection, including the destruction of the cells presenting the foreign antigen. An important feature of MHC is its ability to discriminate "self" peptides from "non self". T-cells that recognize (bind) MHC-presented "self" antigens are eliminated during development. As a result, an immune response is normally initiated only when foreign antigens are presented by MHC molecules.
In addition to its immunological importance, MHC plays a role in behavior. MHC appears to influence odors in an allele-specific fashion and animals can use olfactory cues to discriminate between MHC types. In mice this forms the basis of a MHC-mediated kin recognition and mate choice system. Mice are more likely to mate with individuals having different MHC haplotypes
( Nature 1991). They are more apt to participate in cooperative behavior, such as communal nesting, with MHC similar individuals ( Nature 1992).
Genetically, MHC is interesting for a number of reasons. There are multiple loci that code for MHC molecules. Certain loci, specifically those coding for the antigen-presenting site of the MHC molecule, have an extremely large number of alleles. While most genes are monomorphic or express only a few forms, MHC often has over 100 alleles per locus. It is this great diversity that gives each individual its unique immunological identity. This is the reason why organ donor matches are so difficult to find in unrelated individuals.
There is extreme sequence divergence between MHC alleles. This sequence divergence is ancient, meaning that MHC alleles evolved prior to the evolutionary split between primates. For example, a human is likely to share nucleotide sequence homology with a chimpanzee as well as with other humans. Nucleotide substitutions that define alleles are likely to alter the amino acid sequence of the antigen-presenting site, thus showing selection for functional changes. Understanding the selective mechanisms required to maintain MHC genetic diversity (Critical Reviews in Immunology 1997)is the organizing focus of our research program:
What is the nature of the selection maintaining the genetic diversity of MHC?
Some leading theories include:
- Heterozygote Advantage - If you are heterozygous at the MHC, you will produce a greater diversity of MHC molecules and might be better able to fight a greater repertoire of infectious agents then if you are homozygous.
- Pathogen adaptation or "Red Queen" - from Lewis Carrolls Through the Looking Glass: "Now, here, you see, it takes all the running you can do, to keep in the same place." If pathogens adapt to hosts by evading MHC-dependent immune recognition, this would favor new MHC molecules, this could favor diversification of MHC genes.
- Inbreeding avoidance/Kin recognition. A system that allows you to detect and avoid mating with close kin would allow you to avoid the detrimental effects of inbreeding, as well as increase the probability of being heterozygous at the MHC.
None of the aforementioned theories are mutually exclusive. In fact, it is entirely possible that several mechanisms contribute to the selective pressure resulting in the high genetic diversity of the MHC (see American Naturalist 1999 pdf for review).
How is our approach different?
To understand the interaction between genes, behavior and evolution it makes sense to study animals in the conditions under which they evolved. We therefore conduct many of our experiments on wild mice in semi-natural conditions. Selection favoring new mutations occurs when genetic changes arise increasing an individual's fitness. Fitness of course, is dependent on environmental factors. Animals raised in "cushy" laboratory settings where they are given ample resources may not respond in the same manner to a selective pressure (such as an infection) as a mouse that lives in an environment where he must compete for resources. Many of our experiments are performed in a facility we call "The Barn". The barn consists of large pens where populations of mice can live in semi-natural conditions. These mice compete for access to resources; territories, nest sites, mates etc., much as they would in the wild. The stresses encountered while living in the barn should help magnify the impact of infectious events or poor genetic backgrounds. The behavior of standard inbred laboratory mouse strains is not representative of their wild counterparts. Animals bred in the lab may have lost much of their "wild" behavior. For example, when bred in the lab, mice that are less "choosy" in regard to mates may produce more offspring, and therefore may be selected for by researchers. Because we are interested in natural behavior our lab uses wild or semi-wild mice when ever possible.
Our recent demonstration that when the fitness consequences of inbreeding is analyzed under semi-natural population conditions, it is 5 to 25 times stronger than previous estimates from lab studies( PNAS 2000). This approach has obvious utility in the new area of functional genomics. One great surprise is that numerous genes when knocked out appear to have no phenotype. A common interpretation has been "functional genomic redundancy", but it is more likely that these genes are not being assayed under the right ecological conditions. Analyzing such knockouts under natural ecology may reveal functions not present under lab conditions and/or amplify the effect due to extreme social competition.
Molecular genetic approaches are integral to our research program. Microsatellite markers, polymorphic simple sequence repeats that can be discriminated through gel electrophoresis, are often employed to genotype mice. Genotyping may be performed for a variety of reasons, including paternity studies of mice born in the barn, tracking of known genes while breeding our semi-wild mice, and assessing genetic diversity in wild mouse populations.