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

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

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, 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.

Planned Impact

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.

Publications

10 25 50
 
Description Please see lead Organisation's key findings.

Our overall aim is to analyse the processes of selection that drive diversity in vertebrate immune system genes. We will achieve this aim using (i) next-generation sequencing methods that allow the rapid characterisation of diversity across hundreds of genes simultaneously, and (ii) detailed ecological datasets on pathogen susceptibility in natural populations.We just started this grant in August 2013, and so over the course of three years, we will address the following specific objectives:Objective 1: Analyse genetic variation and identify immune system genes subject to selection in natural populations. Thus far we have created a genome sequence for two wild rodents (wood mouse and bank vole) and combined with the sequence Mus musculus and field vole, were able to identify >800 genes across the 4 genomes that are identified with the immune response. This list will contribute to further analyses. Objective 2: Identify phenotypic consequences of genetic variation in immune system genes for parasite resistance in natural populations of wild rodents.Meeting these objectives will allow us to answer 4 key questions:How many genes are under selection and what pathways are these genes in?There are hundreds of immune genes, each with different roles in innate, cellular and humoural immune responses and with a variety of functions within, on the surface of, or secreted from a variety of different cell types. A key challenge is to discover which genes are subject to directional or balancing selection and whether they tend to be found in specific pathways of the immune response. For example, one might predict rapid evolution in cell-surface molecules interacting directly with pathogens.Are the same genes, or the same types of genes, repeatably subject to selection in different taxa?Different host species are infected by different pathogen species and may exhibit different pathologies for even closely related pathogens. This sets up alternate hypotheses that either unique host-parasite interactions will drive selection at a unique set of host genes for each species or that there are hot-spots in the genome repeatably targeted by selection.Do genes that are rapidly diverging between species exhibit reduced or elevated levels of diversity within species?One may predict that repeated selective sweeps within species would both drive divergence between species and reduce genetic diversity within populations. However, if different selective sweeps occur in different populations (i.e. local adaptation), diversity among populations within a species could also increase. Alternatively, balancing selection within species may maintain diversity within populations but reduce divergence among populations and species. The extent to which selective sweeps versus balancing selection shape diversity of immune system genes in natural populations is currently unknown.Do immune system genes identified as subject to selection also exhibit phenotypic variation in parasite resistance or immune function?From the perspective of evolutionary biology, demonstrating that genetic diversity has a phenotypic consequence for pathogen resistance is crucial to support the hypothesis that pathogens are the selective agent maintaining diversity at immune system genes1. But additionally, from a conservation or health perspective, linking genotype to phenotype is critical to use genetics to help identify individuals, populations or species most vulnerable to infectious disease.
Exploitation Route Please see lead organisation's key findings.
Sectors Environment,Healthcare

URL http://www.biology.ed.ac.uk/research/groups/apedersen/
 
Description Standard Discovery Grant
Amount £789,000 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2018 
End 05/2021
 
Description Wellcome Trust Institutional Strategic Support Fund (WT ISSF)
Amount £24,810 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2014
 
Description Wellcome Trust Institutional Strategic Support Fund Grant
Amount £30,400 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 06/2018
 
Description Wellcome Trust Institutional Strategic Support Fund Grant
Amount £29,640 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 02/2017
 
Title Wild small rodent parasite and pathogen database 
Description We have accumulated a spatially explicitly database from two consecutive NERC grants, totally 6-years of captures of individually marked individuals caught throughout their life, were at each capture significant demographic, physiological and infection histories are recorded. We monitor >30 species of parasites and pathogens. This data base currently involves wood mice and bank voles, captured 1- 20 times, and totally >8000 individually-tagged mice captured >12,000 times. We have spatially-explicit information of reach capture location on our sampling grids (rangingin size from 50x50m-70mx70m; with 6x6 -8x8 trap locations at 10m intervals with 2 traps/location,spanning 4 different woodlands, 2-8 grids/woodland, each grid replicated across 2-4 years). In addition to this data, we also have extracted DNA samples for the vast majority of captures, and immune gene polymorphism data for around 1000 mice. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact We are just building these external collaboration now. 
 
Description Popular Press and science communication: I actively engage in communicating science to the public and my career and research have featured in the following: Bioscience, Nature, Lab Times, The Daily Telegraph, The Santa Barbara Independent, The Metro, Google News, Herald Scotland, Science Daily, Science, Newsline, News about Planet Earth, and Forth Radio and the South African Broadcast Company Radio. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Popular Press and science communication: I actively engage in communicating science to the public and my career and research have featured in the following: Bioscience, Nature, Lab Times, The Daily Telegraph, The Santa Barbara Independent, The Metro, Google News, Herald Scotland, Science Daily, Science, Newsline, News about Planet Earth, and Forth Radio and the South African Broadcast Company Radio.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
 
Description Popular science lecture at the Edinburgh International Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Edinburgh International Science Festival (2018): I presented and participated in a panel discussion that was aimed at the general public, titled 'Bad Ways to Die'; where I was introducing the audience to the diversity and biology of human animal parasites.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/events/festivals/highlights/all-events/2018/science-festival-interview-with-dr-...