Doctoral Dissertation Research: Investigating Genomic and Expression-level Adaptations for Detoxification in Primates

氰化物是一种常见于植物中的毒物，对大多数动物有毒。尽管如此，三种竹狐猴的大部分进食时间都集中在马达加斯加巨竹的各个部分，这使狐猴每天暴露在估计致死剂量的12-50倍氰化物中。本计画将探讨竹狐猴氰化物解毒的生理学与基因组学。除了解决这些狐猴如何能够消耗高水平氰化物的数十年之久的难题外，这项研究还可以为人类氰化物暴露的治疗，解毒剂或解毒剂的开发提供信息。在这项工作的过程中，PI和co-PI将邀请和招募来自肯特州立大学麦克奈尔学者计划的本科生，该计划的使命是帮助第一代低收入本科生进入博士学位课程。合作PI还将利用与东北俄亥俄州的公共图书馆和学校的密切联系，目前这个项目的学生和广大公众。本研究的中心问题集中在已知的哺乳动物之间的氰化物解毒途径。低剂量的毒素可以通过多种保守机制代谢，其中最重要的是使用硫转移酶的途径。这种机制的限制因素似乎是这些酶的相对表达水平和硫供体分子的可用性（例如，硫代硫酸盐）。因此，本研究的第一个工作假设是H。金黄色葡萄球菌已经适应了通过对参与硫或含硫氨基酸代谢的基因的正选择来解毒其高氰饮食。这一假设将通过组装和挖掘H.金黄色葡萄球菌，并将其与来自狐猴基因组组装的数据进行比较，狐猴是最接近的饮食通才物种。进一步假设H.金黄色葡萄球菌通过适应性地改变血流的成分来解毒其高水平的循环氰化物。第二个假设将通过转录组学和代谢组学方法进行检验，以分别比较自由放养的H. aureus和captive L.卡塔。总之，这些方法将检查适应性变化的H。金黄色葡萄球菌基因组，以及全血转录组和代谢组，这些与该物种异常的氰化物耐受性有关。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的评估被认为值得支持影响审查标准。

Cyanide is a poison that is common among plants and toxic to most animals. Nonetheless, three species of bamboo lemur focus most of their feeding time on various parts of Malagasy giant bamboo, which exposes the lemurs to 12-50 times their estimated lethal dose of cyanide on a daily basis. This project will examine the underlying physiology and genomics of cyanide detoxification in bamboo lemurs. In addition to addressing the decades-old puzzle of how these lemurs are able to consume high levels of cyanide, this study may inform the development of therapies, antidotes, or prophylactics to cyanide exposure in humans. During the course of this work, the PI and co-PI will invite and recruit undergraduates from Kent State University's McNair Scholars Program, whose mission is to help first-generation, low-income undergraduates matriculate to a doctoral degree program. The co-PI will also utilize close ties with Northeast Ohio's public libraries and schools to present this project to students and the general public.The central questions of this study focus on known routes of cyanide detoxification among mammals. Low doses of the poison can be metabolized by a variety of conserved mechanisms, foremost among which is a pathway that uses sulfurtransferase enzymes. The limiting factors for this mechanism appear to be relative expression levels for these enzymes and the availability of sulfur-donor molecules (e.g., thiosulfate). Therefore, the first working hypothesis of this study is that H. aureus has adapted to detoxify its highly cyanogenic diet through positive selection on genes involved in the metabolism of sulfur or sulfur-containing amino acids. This hypothesis will be tested by assembling and mining a reference-quality genome for H. aureus and comparing it to data taken from a proposed genome assembly for Lemur catta, the most closely related species of dietary generalist. It is further hypothesized that H. aureus detoxifies its high levels of circulating cyanide through adaptive changes to the composition of the bloodstream. This second hypothesis will be tested by transcriptomic and metabolomic methods in order to compare the expression profiles and thiosulfate levels, respectively, of free-ranging H. aureus and captive L. catta. Together, these methods will examine adaptive changes in the H. aureus genome, as well as the whole-blood transcriptome and metabolome, which are related to the exceptional cyanide tolerance of this species.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.