title: Immunogenetics and polymorphism in a natural population of field voles (Microtus agrestis)
Creators: name: Turner, Andrew
Publisher: name: University of Liverpool Repository
Year: 2011

description: Most of our understanding of immunity has been gained through studies of humans or laboratory rodents. However, such studies do not allow the immune system to be studied in the ecological context in which it has evolved and, as such, they provide a poor model for studying the variation in infectious disease resistance and immune function observed in natural settings. Studies of natural populations have provided fresh insights into the evolution and phenotypic consequences of immunogenetic variation, but have thus far concentrated almost exclusively on genes of the major histocompatibility complex (MHC). As these genes form only a fraction of the vertebrate immune repertoire, there is a need to broaden research in natural populations to include non-MHC genes, in order to gain a more comprehensive understanding of natural selection and immunity. In this thesis, the genetic diversity of a range of non-MHC immune genes was examined in a natural population of field voles (Microtus agrestis L.) in Kielder Forest, UK, which are subject to infection by a range of pathogens. Cytokine genes were the primary focus of this study as they play a central role in regulating the immune response but have rarely been studied in wild species. I examined the hypothesis that, as cytokines are crucial to immunity, variation within these genes may be under selection within populations and between species, and may mediate phenotypic differences between individuals in parasite resistance and immune function. Coding regions from nine cytokine and three other non-MHC vole genes were sequenced, yielding 6.6 Kb of sequence data and 26 SNPs (1 per 255 bp). Three cytokine genes (Il1b, Il2, and Tnf) exhibited patterns of polymorphism consistent with balancing selection maintaining genetic diversity, including an excess of intermediate frequency mutations and more even allele frequencies than one would expect under neutrality. Polymorphism within Il1b and Il2 was also consistently associated with variation in parasite resistance, providing evidence that pathogens are the selective force driving the maintenance of genetic diversity at these loci. In addition, Il1b and Il2 exhibited repeated associations with variation in host immune phenotype, while the Il12b gene was associated both with variation in pathogen resistance and with altered expression levels of Il1b and Il2. Variation in immune function, mediated through the cytokine network, is therefore likely to contribute to parasite resistance in the field vole. This work is the first to show that variation in cytokine genes of a natural population can be maintained by selection, and that this variation can lead to phenotypic variation in parasite resistance and immune function. More broadly, this thesis demonstrates that wild rodents are an excellent model to help us bridge the gap in our understanding between the mechanistic insights gained through studies on laboratory rodents and the variation in infectious disease susceptibility and immune function observed in nature.