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RESEARCH INTERESTS
Evolutionary and ecological genetics; host-parasite coevolution; behavioral ecology
PUBLICATIONS
At the broadcast 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: (1) There are a large number
of alleles per locus, often over 100. (2) The sequence diversification
between alleles is extreme, with some alleles differing by as much as
30%, a degree of divergence normally found between homologous
gene sequences taken from taxa as distant as birds and mammals. (3) This
allelic sequence diversification results because MHC allelic lineages are
ancient, more ancient than recent speciation events. So, for example, any
given human MHC allele is more related to alleles from chimpanzees and
gorillas than it is to most other human alleles. (4) Antigen binding site
codons show a high rate of substitutions that change the amino acid,
indicationg that new antigenic profiles are being favored. It can be
demonstrated that to account for each of the above features some form of
natural selection acting on the antigen binding site is required.
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 and frequency dependent
selection. This in turn favors the evolution of MHC-based disassortative
mating preferences 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. Consequently, the avoidance of
matings with kin (inbreeding) becomes an additional selective force
favoring MHC-based mating preferences. 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 evaluating the evolution of MHC-dependent
virulence during serial passage of a number of pathogens, including
influenza, Theileršs virus, mouse hepatitis virus and Salmonella.
An alternative way that pathogens may favor MHC diversity is if MHC
heterozygotes have an advantage over homozygotes at resisting infections.
We are testing this hypothesis by determining with experimental
infections involving Theileršs virus, Toxoplasma, Plasmodium,
and Salmonella.
We are also testing predictions from the pathogen hypothesis by
determining if MHC genotype effects fitness in seminatural populations of
house mice containing both normal parasite loads and experimental
parasite infections. Among the genotypes being tested are mice that do
not express MHC class I genes (involved in recognizing intracellular
parasites).
We are investigating the adaptive significance and mechanisms of MHC-
based mating preferences. We are using olfaction assays and cross-
fostering experiments designed to reveal the development of perceived
odor profiles that individuals subsequently avoid during mate choice. We
are evaluating the importance of inbreeding avoidance in the evolution of
MHC-based mating preferences by measuring the fitness consequences of
inbreeding in house mice.
Until recently MHC studies have been 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
problems in evolution and population biology.
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