Collaborative Research: EDGE CMT: Predicting the evolution of disease resistance across heterogeneous landscapes

野生动物传染病会导致动物灭绝和种群减少，通常也会影响公众健康。森林鼠疫（更广为人知的是黑死病）于1900年传入北美，现在在美国西部的本土哺乳动物中维持，周期性地引发疾病爆发。虽然有些物种似乎具有天然的抵抗力，但其他物种——比如草原土拨鼠——却非常容易受到影响。尽管在少数草原土拨鼠中发现了鼠疫抗性，但这种疾病仍然在其活动范围内大量灭绝。草原土拨鼠的持续易感性表明，有一些限制因素抑制了对鼠疫的抵抗力的广泛进化。该项目使用耐药和易感草原土拨鼠的全基因组和转录组测序来确定最近进化的鼠疫抗性的基因组基础。然后将在自然种群和实验中绘制与抗性相关的突变，以确定抗性等位基因的空间分布并预测潜在抗性热点的位置。博物馆的草原土拨鼠标本也将进行基因分型，以确定鼠疫抗性的进化速度。鉴于全球新型病原体出现的速度越来越快，这项研究将对了解naïve宿主的适应可能持续的时间和地点具有广泛的意义。该项目将利用研究成果，通过在为美洲原住民和西班牙裔学生提供服务的大学中建立能力来加强教育。旅行基因组学研讨会将提供给学生和教师，学生将在他们自己的机构接受指导，因为他们在系统中进行独立研究。对病原体的适应应该在很大程度上得益于选择：一旦免疫力进化，它应该在整个物种范围内形成固定。矛盾的是，一种更常见的观察模式是可变免疫。由于对不完全耐药有多种解释，对新病原体维持耐药性的生态和进化条件仍然知之甚少。例如，通过基因稀释等过程，生境基质在多大程度上影响了抗性的维持？种群间独立的耐药性从头进化是否会导致上位性相互作用，从而阻止耐药性的广泛传播？在西部6个州的草原土拨鼠（草原土拨鼠属）中已观察到对森林鼠疫（由鼠疫耶尔森氏菌引起）的抗性，但抗性仍然罕见。该项目将基因组学和转录组学分析与大范围的时空采样相结合，以阐明抗性是如何、何时、何地进化的，以及是什么阻止了这种适应性特征从蔓延到固定。以前的实验感染和自然动物流行病将用于确定两个物种的耐药性的基因组基础。与抗性相关的等位基因，以及作为零模型的中性等位基因，将在跨越不同鼠疫传入时间的种群的纬度样带中，以及在至少三个不同时间范围的博物馆标本中进行基因分型。这些数据将有助于估计抗性等位基因的进化速度，并推断促进抗性的景观空间结构和基因组特征。了解适应是如何跨越空间和时间持续下去的，可以促进濒危系统的适应。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。

Wildlife infectious diseases can cause extinctions and populations declines in animals, often also impacting public health. Sylvatic (better known as bubonic) plague was introduced to North America in 1900 and is now maintained in native mammals in the western U.S., periodically eliciting disease outbreaks. Although some species seem to have natural resistance, others—such as prairie dogs—are highly susceptible. Despite the detection of plague resistance in a small number of prairie dogs, the disease still decimates populations throughout their range. The continued susceptibility of prairie dogs suggests there is some constraint inhibiting the widespread evolution of resistance to plague. This project uses whole-genome and transcriptome sequencing of resistant and susceptible prairie dogs to determine the genomic basis of recently evolved plague resistance. Mutations associated with resistance in natural populations and experiments will then be mapped in nature to determine the spatial distribution of resistance alleles and predict the location of potential resistance hotspots. Museum specimens of prairie dogs will also be genotyped to determine the rate of evolution of plague resistance. Given the increasing rate of novel pathogens emerging around the globe, this research will have broad implications for understanding when and where adaptation in naïve hosts is likely to persist. This project will use research to enhance education by building capacity in universities serving Native American and Hispanic students. Traveling genomics workshops will be delivered to students and faculty, and students will be mentored at their own institutions as they conduct independent research in the system.Adaptation to pathogens should be heavily favored by selection: Once immunity evolves, it should sweep to fixation across a species’ range. Paradoxically, a more commonly observed pattern is variable immunity. Because there are multiple explanations for incomplete resistance, the ecological and evolutionary conditions under which resistance to novel pathogens is maintained are still poorly understood. For instance, to what extent does the habitat matrix influence the maintenance of resistance through processes such as gene dilution? Does the de novo evolution of resistance independently across populations lead to epistatic interactions preventing widespread resistance? Resistance to sylvatic plague (caused by the bacterium Yersinia pestis) has been observed in prairie dogs (genus Cynomys) in six western states, but resistance is still rare. This project integrates genomic and transcriptomic analysis of experimentally infected animals with rangewide spatiotemporal sampling to elucidate how, when and where resistance evolves, and what prevents this adaptive trait from sweeping to fixation. Previous experimental infections and a natural epizootic will be used to determine the genomic basis of resistance in two species. Alleles associated with resistance, along with neutral alleles serving as a null model, will be genotyped in latitudinal transects spanning populations with different plague introduction times, and in museum specimens from at least three distinct time ranges. These data will enable estimates of the rate of evolution of resistance alleles and inferences of the landscape spatial structure and genomic characteristics facilitating resistance. Understanding how adaptation persists across space and time can enable facilitated adaptation in imperiled systems.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.