The genetic basis of divergence in immune defense between species

所有的生物都会生病，但有些会比其他的更严重。这在一个物种内是正确的（有些人比其他人更容易受到某些感染），但在物种之间也是如此（类人猿不容易受到人类感染的感染）。这些差异很可能是遗传的。事实上，我们知道，与抗感染能力有关的基因在物种之间正在快速进化——有时是整个基因组中进化最快的基因。然而，我们最缺乏的是对使某些物种比其他物种更好地抵抗感染的基因的清晰理解。本研究旨在以果蝇为模型，研究近缘物种间免疫防御的差异。这项研究具有重要的基础科学意义和应用价值。由于免疫基因正在迅速进化，该方法允许在遗传和分子水平上研究物种之间的进化差异。在应用层面上，这种对抗新感染的快速进化可能会带来其他后果，例如增加自身免疫性疾病的风险。因此，了解不同物种如何进化以对抗感染将有助于阐明人类和其他生物体如何必须仔细调整他们的免疫反应来对抗感染，同时尽可能少地伤害自己。这项工作还将为高中生、本科生和研究生提供培训机会。该项目利用几种果蝇物种来研究不同物种之间的免疫防御是如何分化的。这些物种与黑腹果蝇（Drosophila melanogaster）密切相关，后者发现了许多先天免疫的基本租户。这让研究人员可以解决几个问题：一些物种是否比它们的相关物种更能抵抗感染？还是免疫防御更具有病原体特异性，是宿主暴露史的结果？哪些基因参与了对病原体的免疫防御的分化？这些基因是针对不同的病原体共享的还是针对特定的病原体？参与免疫分化的基因是否如基因组数据所预测的那样在正选择下进化？第一个目标是了解相关物种在对抗细菌、真菌和病毒感染的能力上有何不同。有了这些知识，研究人员将使用两种互补的遗传方法来剖析这些差异的遗传基础：数量性状位点定位和等位基因特异性基因表达分析。最后，研究人员将通过对不同物种进行基因操作来证实这些发现——使用CRISPR/Cas9编辑技术在物种之间移动基因，以确定这些基因是否能挽救一种强大的免疫反应。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

All organisms get sick, but some get sicker than others. This is true within a species (some humans are more susceptible to certain infections than other humans), but it is also true between species (apes are not susceptible to infections that humans suffer from). These differences are likely to be genetic. In fact, we know that genes involved in the ability to fight infection are fast evolving between species – sometimes the fastest evolving genes across the entire genome. What we mostly lack, however, is a clear understanding of the genes that allow some species to fight infection better than others. This research aims to study how immune defense differs among closely related species using Drosophila as a model. This research is important for both basic scientific and applied reasons. Since immune genes are rapidly evolving, the approach allows for the study of evolutionary divergence between species at the genetic and molecular level. At the applied level, such rapid evolution to fight new infections might have other consequences such as an increased risk of autoimmune disease. So, understanding how different species evolve to fight infection will help elucidate how humans and other organisms must carefully tune their immune responses to fight infection, but also do as little harm to themselves as possible. The work will also provide training opportunities for high school students, undergraduates and graduate students. The project utilizes several Drosophila species to study how immune defense diverges between species. These species are closely related to Drosophila melanogaster, where much of the basic tenants of innate immunity were discovered. This allows the researchers to address several questions: Are some species generally better at fighting infection than their related species? Or is immune defense more pathogen-specific and the result of the history of host exposure? What are the genes involved in the divergence in immune defense against pathogens? Are these genes shared for different pathogens or specific for specific pathogens? Are the genes involved in immune divergence evolving under positive selection as is predicted by the genomic data? The first goal is to understand how related species differ in their ability to fight bacterial, fungal and viral infections. With that knowledge, researchers will dissect the genetic underpinnings of those differences using two complementary genetic approaches: quantitative trait locus mapping and allele specific gene expression analysis. Finally, researchers will confirm findings by genetically manipulating the different species – using CRISPR/Cas9 editing to move genes between species to determine whether those genes rescue a robust immune response.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.