The Causes of Genetic Variation in Susceptibility to Infectious Disease in Natural Populations

这个项目的目的是了解为什么人群中的一些人比其他人更容易感染传染病。这种变异不仅决定了疾病对人类健康、作物产量和农场动物的影响，而且也是当种群进化出对感染的抵抗力时自然选择发挥作用的原材料。尽管它很重要，但我们对这种变异背后的基因了解甚少，对它在种群中维持的进化原因也知之甚少。我们要问的第一个问题是，自然选择是否增加了感染易感性的遗传变异。为了做到这一点，我们将测试自然遇到病原体的宿主种群是否在对该病原体的易感性方面表现出更多的遗传变异。为此，我们将用六种不同的病毒感染六种果蝇，观察病毒感染自然宿主后是否会产生更多的变异。我们要问的第二个问题是，自然选择是否意味着感染的易感性有一个简单的遗传基础，只有少数几个基因对个体被感染的几率有很大的影响。使用一些相同的苍蝇物种和病毒，我们将对抗性和易感苍蝇的基因组进行测序，并利用这些信息来识别引起抗性的基因。这样，我们就可以知道，是否只有在病毒感染其自然宿主时才有简单的遗传基础来产生抗药性，而在病毒感染其他物种时则没有。然后我们可以继续使用统计方法来了解自然选择是如何作用于这些基因的。我们要问的最后一个问题是，宿主是否通过提高自身的防御能力而变得有抵抗力，或者防止寄生虫为了寄生虫的利益而劫持宿主自己的分子机制。我们将通过遗传操纵苍蝇来回答这个问题，看看易感形式是否是病毒所需的（“劫持”假说），或者抗性形式是否正在伤害病毒（“改善防御”假说）。

The aim of this project is to understand why some individuals in populations are more susceptible to infectious disease than others. This variation not only determines the impact of disease on human health, crop yields and farm animals, but it is also the raw material on which natural selection acts when populations evolve resistance to infection. Despite its importance, we have a poor understanding of the genes that underlie this variation and the evolutionary reasons why it is maintained in populations are poorly understood. The first question we will ask is simply whether natural selection is increasing genetic variation in susceptibility to infection. To do this we will test whether host populations that naturally encounter a pathogen show more genetic variation in susceptibility to that pathogen. To do this we will infect six species of fruit flies with six different viruses, and see whether there is more variation when a virus infects its natural host.The second question we will ask is whether natural selection means that susceptibility to infection has a simple genetic basis, with just a few genes having large effects on the chances of an individual being infected. Using some of the same fly species and viruses, we will sequence the genomes of resistant and susceptible flies, and use this information to identify genes causing resistance. We will then be able to see whether there is a simple genetic basis to resistance only when a virus infects its natural host but not when it infects a different species. We can then go on to use statistical methods to understand how natural selection has acted on these genes.The final question we will ask is whether hosts become resistant by improving their defences, or preventing parasites from hijacking the host's own molecular machinery for the parasite's benefit. We will answer this by genetically manipulating flies to see if the susceptible form is required for by the virus (the 'hijacking' hypothesis) or the resistant form is harming the virus (the 'improving defences' hypothesis).