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

生物多样性研究的一个主要部分是了解个体之间遗传差异的后果。这种差异可能意味着一些人比其他人对传染病更有抵抗力。事实上，参与免疫系统的基因经常显示出进化推动了它们的遗传多样性。然而，到目前为止，这样的证据相对零碎：要么是对自然环境中数量非常有限的基因的研究；要么是对整个基因组的研究，但与任何生态信息脱节。在这里，我们提出了一种更全面的方法，它利用(I)最新的测序技术来快速分析数百个基因的遗传多样性，以及(Ii)详细的生态数据集，将单个基因型与病原体抗性和免疫表型联系起来。我们的研究基于一对野生啮齿动物物种，木鼠和田鼠，这些物种在英国很常见，在自然环境中是各种病原体的宿主，在以前的研究中，这些物种的特征是大量样本。因此，我们有一个重复的研究，在这个研究中，我们将问：有多少基因处于选择之中，这些基因有什么作用？进化是否针对不同物种中的相同基因？一个物种内具有多样性的基因是否也在不同物种之间存在差异？个体之间在这些基因上的差异是否会导致对病原体抵抗力的差异？这一提议是一项具有广泛影响的基础性蓝天研究：在保护方面，人们长期以来一直对保护遗传生物多样性感兴趣，特别是为了保护人们免受传染病流行的影响。但目前还不清楚哪些基因对这种多样性很重要，这一提议将帮助我们了解应该保护哪些基因。在生物医学中，我们对免疫学的大部分了解来自于实验室的小鼠，但仅限于遗传多样性非常有限的动物，并且与自然环境没有相互作用。对野生啮齿动物的研究，如我们提出的，应该有助于将实验室老鼠的结果放在更生态的背景下。通过这样做，我们的结果可能有助于为人类的免疫学研究提供信息，特别是在发展中国家，那里有相当大的兴趣了解为什么有些人对疟疾和结核病等常见和致命的疾病具有抵抗力，而有些人容易患上这些疾病。在进化生物学中，有丰富的理论关于病原体驱动宿主进化的作用，反之亦然。但用来检验这一理论并推动该领域向前发展的数据大多是缺乏的。我们现在有了工具来提供这样的数据，并检查病原体在自然环境中宿主基因组进化中的作用。这项拟议的工作可能会突出高度多样化或进化迅速的新基因，这将为未来的研究提供令人兴奋的途径。

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.