At the broadest level my research interests focus on the genetics of natural and sexual selection. My current research efforts focus on the genes of the major histocompatibility complex (MHC). MHC genes play a central role in immune recognition, but they have also been shown to influence individual odors and reproductive traits such as mating preferences and spontaneous abortion. MHC genes are also the most polymorphic loci known for vertebrates. This extreme genetic diversity has the following relatively unique features:
What is the nature of the selection acting on MHC genes? Answering this question is a central focus of my laboratory and leads to at least four major levels of inquiry involving host-parasite interactions, inbreeding, sexual selection and kin recognition systems. Our current understanding suggests the following relationships. Parasite-driven selection favors MHC genetic diversity through both heterozygote advantage (McClelland et al., 2003 , Penn et al.,2002)] and frequency dependent selection (McClelland et al., 2004. This in turn favors the evolution of MHC-based disassortative mating preferences (Potts et al., 1991). because such matings preferentially produce high fitness MHC heterozygous progeny. Such mating preferences would further increase MHC genetic diversity, making these loci increasingly useful as a kin recognition marker (Manning et al. 1992, Penn and Potts, 1998). Consequently, the avoidance of matings with kin (i.e. inbreeding) is an additional factor favoring MHC-based mating preferences( Meagher et al. 2000 , Ilmonen, et al. 2008) None of these hypothesized interactions enjoy definitive support and we are testing aspects of each.
The hypothesis that pathogens drive MHC genetic diversity predicts that pathogen variants that escape MHC-dependent immune recognition will be favored by natural selection. This in effect leads to a "molecular arms race" where variant MHC genes are in turn favored in the host. We are testing this prediction by conducting experimental evolution experiments involving serial passage of various pathogens through strains of mice that differ only at MHC genes. We know pathogens adapt during such passages as reflected in increased virulence. These experiments will determine if some of the increased virulence is MHC-dependent.
We tested the heterozygote advantage hypothesis and demonstrated that MHC heterozygotes have an advantage when coinfected with Salmonella and Theilerís virus. Heterozygotes have no advantage when infected individually with either pathogen. This is the first experimental confirmation that MHC heterozygote advantage may emerge because heterozygotes have greater overall resistance during coinfections (McClelland et al., 2003 , Slev and Potts, 2006).
We are investigating the adaptive significance and mechanisms of MHC-based mating preferences. We are using olfaction assays ( Carroll et al. 2002) and cross-fostering experiments (Penn and Potts, 1998) designed to reveal the development of perceived odor profiles that individuals subsequently avoid during mate choice. We have demonstrated that fitness consequences of full-sib inbreeding is an order of magnitude greater than previous estimates ( Meagher et al. 2000 ) and that cousin-level inbreeding reduces fitness by 34%. This fitness cost rises to 57% during Salmonella infections. Thus, the inbreeding avoidance function would be a powerful selective force favoring the evolution MHC-based mating preferences.
These dramatic inbreeding results suggest that fitness measures in seminatural populations of mice will be a powerful and sensitive way to measure genetic defects (Carroll et al., 2004, Carroll and Potts, 2006), potentially toxic substances and any treatment that might compromise health. For example, reintroduction of natural and sexual selection to wild mice bred in captivity for some generations increases fitness substantially.
MHC studies have been largely restricted to humans and laboratory rodents. To expand the breadth of questions that can be addressed, we are cloning and sequencing MHC genes in other vertebrate species. The laboratory also utilizes molecular genetic tools to address a variety of other problems in molecular evolution and population biology.