RESEARCH INTERESTS

My research interests focus on the genetics of host-pathogen coevolution.  Our current studies focus on the genes of the major histocompatibility complex (MHC), which play a central role in vertebrate immune recognition. MHC genes are also the most polymorphic loci known for vertebrates and many MHC alleles confer susceptibility to autoimmune and infectious diseases. What evolutionary mechanisms account for the extreme diversity of MHC genes? Why are these demonstrably “bad” alleles not eliminated by natural selection? These questions currently form the central focus of my laboratory and lead 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 and relentless pathogen adaptation to common host genotypes, leading to rare MHC allele advantage. This in turn favors the evolution of MHC-based disassortative mating preferences because they preferentially produce high-fitness (disease-resistant) progeny. Such mating preferences would further increase MHC genetic diversity, making these loci increasingly useful as a kin recognition marker. Consequently, the avoidance of matings with kin (i.e. inbreeding) is an additional factor favoring MHC-based mating preferences. None of these hypothesized interactions enjoy definitive support and we are testing predictions from each. To test these hypotheses we use a varied set of approaches including laboratory experiments involving host-parasite interactions and sexual selection. We also use population and behavioral studies on natural and semi-natural populations of vertebrate species, primarily house mice. Molecular genetic techniques are utilized extensively to characterize the genotypes of both hosts and parasites in these studies. Below I briefly describe three major projects that are either underway or proposed.

MHC heterozygote superiority

If MHC heterozygotes were superior to both homozygotes in resisting infectious agents, this would contribute to MHC genetic diversity. However, this is seldom seen for single infectious agents. MHC heterozygotes would be superior over the course of multiple infections if resistance is generally dominant. We are testing this hypothesis with multiple pathogen combinations. The first test using Salmonella and Theiler's virus did reveal MHC heterozygote superiority (McClelland et al., 2003, Infection and Immunity).

Experimental pathogen evolution studies to characterize how pathogens adapt to hosts

As a pathogen is passaged through a series of genetically similar host individuals, virulence increases in the passage host, but decreases in previous hosts. This nearly universal result has profound implications for understanding host-pathogen interactions because it provides a powerful experimental method for identifying and characterizing the complex interactions between hosts and pathogens. We are using this approach to characterize pathogen escape of MHC-dependent immunity (McClelland et al., 2004, Proc. Royal Society B) and have recently published rapid.

Ecological functional genomics: using ecology to reveal gene function

A major problem in determining gene function is that many genes when disrupted reveal no phenotype. We have argued that many such genes function to solve ecological problems and as such, will fall into a category where expression of their phenotype will be ecology dependent. A particularly important aspect of Mus ecology that will help reveal phenotypes that have subtle health and vigor declines is male-male competition over territory ownership. Direct support for this hypothesis comes from our recent demonstration that the deleterious fitness effects of inbreeding in Mus are barely detectable using lab assays (10% effect), but are amplified 50-fold (in males) when analyzed under semi-natural population conditions (Meagher et. al. 2000). We are using this population ecology approach on a number of the developmentally important Hox genes that show no-phenotype when disrupted. We believe this will be a powerful general approach for determining the function of many genes.

Toxicity assessment using OPA assays

All too often, substances once considered safe at a particular dose are later found to have adverse consequences, usually through years or decades of epidemiological or experimental research. As a result, humanity often becomes the guinea pig of its mastery of applied chemistry. To prevent such experimentation on ourselves, there is a great need for broad, sensitive assays able to detect toxicity of many agents. We have discovered such an assay, which we call OPA (Organismal Performance Assays). This assay uses house mice in seminatural populations (phenotrons) where experimental mice treated with the toxin compete directly with sham treated controls. This animal model achieves its breadth and sensitivity because high performance from most physiological systems is required for individual success, as determined by survival, social dominance, reproduction and a variety of other components of fitness. Consequently, any potentially toxic substance that reduces performance of any physiological system is likely to be detected in this assay. The first potential toxin tested using this assay, high fructose corn syrup, revealed substantial reductions in survival and competitive ability at doses considered safe and experienced by 20% of Americans. We are currently testing three pharmaceuticals (Vioxx, Paxil and Baycol) that failed in final clinical testing or after being released to the public. Two of the three show major fitness and health consequences during OPAs that were missed in preclinical and clinical screening. We envision OPAs as a major new tool to detect toxicities of a variety of treatments relevant to public health.

2018  Cornwall D.H., Kubinak J.L., Zachary E., Stark D.L., Seipel D., Potts W.K. Experimental manipulation of population-level MHC diversity controls pathogen virulence evolution in Mus musculus. J Evol Biol. 31:314-322. doi: 10.1111/jeb.13225. Epub 2018 Jan 12. PMID: 29266576

2017  Ruff J.S., Saffarini R.B., Ramoz L.L., Morrison L.C., Baker S., Laverty S.M., Tvrdik P., Capecchi M.R., Potts W.K. Mouse fitness measures reveal incomplete functional redundancy of Hox paralogous group 1 proteins. PLoS One. 12(4):e0174975. doi: 10.1371/journal.pone.0174975. eCollection 2017. PMID: 28380068.

2017  Morris J.S., Ruff J.S., Potts W.K., Carrier D.R. A disparity between locomotor economy and territory-holding ability in male house mice. J. Exp. Biol. 220:2521-2528. doi: 10.1242/jeb.154823. Epub 2017 May 3. PMID: 28468871.

2017    Ruff, J.S., Cornwall, D.H, Morrison, L.C., Cauceglia, J.W., Nelson, A.C., Gaukler, S.M, Meagher, S.M., Carroll, L.S., and Potts, W.K. Sexual selection constrains the body mass of male but not female mice. Ecol. Evol. 7:1271-1275. doi: 10.1002/ece3.2753. PMID: 28303195 (cover photo article, Jan. 27 issue)