Evolution of cancer transmission

新发传染病日益威胁人类、野生动物和牲畜的健康。魔鬼面部肿瘤病（DFTD）是一种传染性癌症，是EID的一个显著例子，它导致了标志性的塔斯马尼亚魔鬼的急剧下降。自发现以来的20年里，DFTD已经在塔斯马尼亚州传播了95%，导致受影响最长的种群数量下降了90%以上，总种群数量减少了80%。值得注意的是，魔鬼对这种感染性细胞系表现出高度易感性，这几乎总是致命的。由于传播的频率依赖性，流行病学模型预测灭绝。然而，魔鬼在所有人群中持续存在，即使是在最长的患病地点。模型预测和经验观察之间的差异可能是由塔斯马尼亚魔鬼和DFTD的进化反应驱动的。魔鬼在负责癌症和免疫反应的候选基因上迅速进化，最初的迹象是抗体产生，甚至完全缓解肿瘤。贝叶斯状态空间模型和积分投影模型相结合，提出了研究的演变，通过整合个人层面的魔鬼角色接触网络，以及魔鬼和肿瘤基因组属性的变化，传输。这些模型将利用对魔鬼的长期标记重捕获研究，其中包括超过14，000个陷阱记录，以及在DFTD出现之前，期间和之后采集的1，000个肿瘤分离株和10，000个魔鬼DNA样本的档案。基于疾病的可预测传播，DFTD-devil系统提供了前所未有的机会，可以测试新感染人群以及感染不同代数人群的疾病传播演变模型预测。以下三个具体目标推动了拟议的研究：1）宿主（魔鬼）进化如何影响疾病传播？2)病原体（DFTD）进化如何影响传播？3)我们能预测塔斯马尼亚魔鬼DFTD系统的进化动力学吗？

Emerging infectious diseases (EIDs) increasingly threaten human, wildlife and livestock health. Devil facial tumor disease (DFTD), a transmissible cancer, is a marquee example of an EID that has caused dramatic declines of the iconic Tasmanian devil. In 20 years since its discovery, DFTD has spread 95% of the way across Tasmania, causing greater than 90% declines in populations affected the longest, and reducing the total population size by 80%. Remarkably, devils show high susceptibility to this infectious cell line, which is nearly always fatal. Due to the frequency-dependent nature of transmission, epidemiological models predict extinction. However, devils persist in all populations, even in the longest diseased sites. The discrepancy between model predictions empirical observations is likely driven by evolutionary responses in Tasmanian devils and DFTD. Devils have rapidly evolved at candidate genes responsible for cancer and immune response, with first signs of antibody production and even complete tumor remission. A combination of Bayesian state-space models and integral projection models are proposed to study the evolution of transmission by integrating individual-level devil roles in contact networks, as well as variation in devil and tumor genomic properties. These models will capitalize on long-term mark-recapture studies of devils with over 14,000 trap records, as well as an archive of 1,000 tumor isolates and 10,000 devil DNA samples taken before, during and after DFTD emergence. Based on the predictable spread of the disease, the DFTD-devil system affords the unprecedented opportunity to test model predictions regarding evolution of disease transmission in newly infected populations, as well as those infected for varying numbers of generations. The following three specific aims drive the proposed research: 1) How does host (devil) evolution influence disease transmission? 2) How does pathogen (DFTD) evolution influence transmission? 3) Can we predict evolutionary dynamics in the Tasmanian devil-DFTD system?