RII Track-4: A Functional Genomics Approach to Explain the Evolution of Large Bodies and Long Life Spans

非技术摘要我们使用爬行动物，特别是巨型乌龟来研究衰老和癌症背后的过程。哺乳动物，包括人类，长期以来一直被用来研究这些话题，显然在改善健康方面有应用。然而，越来越明显的是，所有种类的动物--不仅仅是哺乳动物--都进化出了延缓衰老和避免癌症的方法。因此，对哺乳动物的关注限制了我们理解生物学如何解决这些主要生理挑战的武器库。在这个项目中，我们将调查哪些基因使巨型乌龟能够减轻癌症和其他生物过程，以便变得如此巨大和如此长寿。具体地说，我们将使用来自长寿的巨型乌龟及其小乌龟近亲的细胞来观察与衰老和癌症相关的某些基因在这两种类型的乌龟中的表现是否不同。这项工作不仅将扩大我们如何看待动物多样性对于应对人类健康挑战的重要性，而且还将揭示为什么我们在自然界中看到动物寿命和身体大小如此惊人的多样性。该项目还有一个很大的推广部分，包括开发高中学习模块，向学生传授遗传方面的尖端技术。技术摘要进化理论预测，自然选择应该会推动物种变得更大，活得更长，因为它提高了抵御捕食者、竞争资源和投资后代的能力。尽管有这样的优势，但随着身体尺寸和寿命的增加，进化的一个主要制约因素是：随着寿命的延长和细胞数量的增加，累积遗传毒性和细胞毒性损害的风险，这最终可能导致癌症。然而，一些物种已经克服了这些障碍，进化出了非常巨大的身体尺寸和很长的寿命，有时是在进化时间的狭窄窗口内。在这里，我们检查了与巨型乌龟的长寿和抗癌相关的关键基因的功能，并与它们较小、寿命较短的近亲进行了比较。这些候选基因是最近通过对加拉帕戈斯巨型陆龟和亚达布拉陆龟新测序的基因组进行分析而确定的。具体地说，我们将使用来自大乌龟和小乌龟的细胞系来评估这些候选基因对关键过程的影响，包括DNA修复、凋亡、坏死和细胞存活。我们独特的研究设计，将巨型乌龟与它们小得多的近亲配对，将解决生物学中的一个重大悖论，并展示进化如何克服了体型庞大和长寿的成本。该项目还有一个很大的推广部分，包括在大学之间进行先进的细胞培养和基因编辑技术的智力转让，开发高中学习模块，以及为动物园开发关于癌症和衰老生物学的教育小组和视频。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-Technical AbstractWe use reptiles, specifically giant tortoises, to study the processes behind aging and cancer. Mammals, including humans, have long been used to study these topics, with obvious applications for improving health. However, it is becoming clear that all kinds of animals -not just mammals- have evolved ways of delaying aging and avoiding cancer. Thus, focusing on mammals limits our arsenal for understanding how biology has solved these major physiological challenges. In this project, we will investigate which genes have allowed giant tortoises to mitigate cancer and other biological processes in order to grow so big and live so long. Specifically, we will use cells from long-lived, giant tortoises and their small tortoise relatives to see whether certain genes related to aging and cancer behave differently in these two types of tortoises. This work will not only expand how we look at the importance of animal diversity for meeting challenges in human health, but will also shed light on why we see such amazing diversity in animal life spans and body sizes in nature. The project also has a large outreach component including the development of high school learning modules to teach students cutting-edge technologies in genetics.Technical AbstractEvolutionary theory predicts that natural selection should drive species to grow bigger and live longer because of an improved ability to defend against predators, compete for resources, and invest in offspring. Despite such advantages, there is a major constraint to the evolution of increased body sizes and life spans: the risk of accumulating genotoxic and cytotoxic damage that comes with living longer and having more cells, which can ultimately lead to cancer. Yet, some species have overcome these barriers and have evolved remarkably large body sizes and long life spans, sometimes within a narrow window of evolutionary time. Here, we examine the function of key genes related to longevity and cancer resistance in giant tortoises as compared to their smaller, shorter-lived relatives. These candidate genes have recently been identified from analyzing the newly sequenced genomes of giant Galapagos and Aldabra tortoises. Specifically we will use cell lines from both giant and small tortoises to evaluate the influence of these candidate genes on critical processes including DNA repair, apoptosis, necrosis, and cell viability. Our unique study design, pairing gigantic tortoises with their much smaller relatives, will address a major paradox in biology, and show how evolution has overcome the costs of being large and long-lived. The project also has a large outreach component including the intellectual transfer of advanced cell culture and gene editing technology among universities, the development of high school learning modules, and the development of educational panels and videos for zoos on the biology of cancer and aging.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.