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有些人比其他人更能抵抗传染病。事实上，与免疫系统有关的基因经常显示出进化驱动了它们的遗传多样性的证据。然而，到目前为止，这样的证据相对零散：要么是对自然环境中数量非常有限的基因的研究；或者是对整个基因组的研究，但与任何生态信息分离。在这里，我们提出了一种更全面的方法，利用(i)最新的测序技术快速测定数百个基因的遗传多样性，以及（ii）将个体基因型与病原体抗性和免疫表型相关的详细生态数据集。我们的研究是基于一对野生啮齿动物物种，木鼠和田鼠，它们在英国很常见，是自然环境中各种病原体的宿主，并且在以前的研究中已经对大量样本进行了表征。因此，我们有一个重复的研究，我们会问：有多少基因在选择中，这些基因做什么？进化是否针对不同物种的相同基因？同一物种内的不同基因在不同物种之间是否也存在差异？这些基因的个体差异会导致对病原体的抗性差异吗？这是一项具有广泛意义的基础性研究：在生物保护领域，人们一直对保护遗传生物多样性感兴趣，特别是保护种群免受传染病的流行。但目前还不清楚哪些基因对这种多样性很重要，这一建议将帮助我们了解应该保护哪些基因。在生物医学中，我们对免疫学的理解大部分来自实验室小鼠，但仅限于遗传多样性非常有限的动物，而且与自然环境没有相互作用。对野生啮齿动物的研究，如我们所建议的，应该有助于将实验室小鼠的结果置于更生态的背景下。这样做，我们的结果可能有助于为人类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耐药性，而有些人则容易感染。在进化生物学中，关于病原体驱动宿主进化和宿主驱动病原体进化的理论非常丰富。但是，用来检验这一理论并推动这一领域向前发展的数据在很大程度上是缺乏的。我们现在有工具来提供这些数据，并检查病原体在自然环境中宿主基因组进化中的作用。这项工作可能会突出高度多样化或快速进化的新基因，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 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.