Diversity and evolution of vertebrate immune system genes in the natural environment.

A major part of biodiversity research is to understand the consequences of genetic differences between individuals. Such differences may mean that some individuals are more resistant to infectious diseases than others. Indeed, genes involved in the immune system often exhibit evidence that evolution has driven their genetic diversity. However, such evidence has so far been relatively piecemeal: either studies of a very limited number of genes in the natural environment; or studies of entire genomes, but divorced from any ecological information. Here we propose a more comprehensive approach that exploits (i) the latest sequencing technology to rapidly assay genetic diversity across hundreds of genes, and (ii) detailed ecological datasets relating individual genotype to pathogen resistance and immune phenotype.

Our study is based on a pair of wild rodent species, wood mice and field voles, that are common in the UK and are host to a variety of pathogens in the natural environment and which have been characterised for large numbers of samples in previous studies. Thus we have a replicated study in which we will ask:

How many genes are under selection and what do these genes do?
Does evolution target the same genes in different species?
Are genes that are diverse within a species also divergent between species?
Do differences between individuals at these genes cause differences in resistance to pathogens?

This proposal is fundamental, blue-skies research with broad implications:

In conservation, there has been a long-standing interest in conserving genetic biodiversity, particularly to protect populations from epidemics of infectious disease. But it has not been clear what genes are important for such diversity and this proposal will help us understand what to conserve.

In biomedicine, much of our understanding of immunology derives from the laboratory mouse, but only in animals with a very limited genetic diversity and with no interaction with the natural environment. Studies of wild rodents, such as we propose, should help to place results from the laboratory mouse into a more ecological context. In so doing, our results may help to inform immunological studies of humans, particularly in the developing world, where there is considerable interest in understanding why some individuals are resistant and some susceptible to common and fatal diseases such as malaria and TB.

In evolutionary biology, there is a wealth of theory on the role of pathogens to drive the evolution of hosts and vice versa. But data with which to test the theory, and to drive the field forward, is mostly lacking. We now have the tools to provide such data and to examine the role of pathogens for the evolution of host genomes in the natural environment. The proposed work may highlight novel genes that are highly diverse, or evolving rapidly, that will provide exciting avenues of future research.

Who will benefit from this research and how will they benefit?

Primarily this proposal represents fundamental, blue-skies research, and so is not targeted directly at specific users. Nevertheless, we identify the following two general groups of users that are likely to benefit from our results in the longer term.

Researchers and policy makers in conservation, both within government departments and the charitable sector.
Genomics can help to decide what to conserve. Often conserving species is more than conserving their habitat, it is also about conserving their genetic diversity, since inbred populations tend to be more vulnerable to pathogens. The work proposed in this project will determine which genes within the immune system are most variable and what the consequences of this variation are. Our research may therefore inform captive breeding or translocation strategies to preserve or promote genetic variation at key genes.

Researchers in human and animal health in the public and private commercial sector.
Identifying which individuals are most vulnerable to infection, or who are likely to respond poorly to vaccination is a major question in human and animal health. Wild rodents provide a novel model to answer this question and can act as a bridge between laboratory mice and human epidemiological studies. In the longer term, therefore, our research will help to identify genes, or mechanisms, that help to enhance natural immune responses to infectious disease or to vaccination. Such knowledge may be used, for example, to develop novel vaccine adjuvants.