CAREER: The genetic and developmental basis of body size evolution in nematodes

动物体型(至少从蚂蚁到大象)的差异是巨大的，需要解释。然而，导致体型进化的遗传和发育变化仍然未知。拟议的工作旨在解决这一问题，方法是利用长期确立的和尖端的遗传技术，在体型截然不同的密切相关蛔虫物种中寻找体型差异的原因。这项工作很重要，因为我们知道较大的蛔虫物种比较小的蛔虫物种拥有更大的细胞，当调节细胞大小的过程出错时，就会出现癌症等疾病。这项工作有可能发现控制细胞大小的新基因，从而成为癌症治疗的潜在新靶点。除此之外，上述研究工作将与俄克拉荷马州多项既定的教育举措相结合，包括：1)俄克拉荷马大学的四年制本科生研究体验计划；2)为美国印第安人本科生提供的多年暑期研究计划；3)为高中生提供的研究体验暑期计划；以及4)研究生主导的夏季编码研讨会。此外，还将开发一门本科发育生物学实验室课程，学生将参与上述原始研究活动。这项拟议的工作不仅旨在在理解身体大小的进化和细胞大小变化的基因方面取得重大进展，而且这项工作还旨在将多项教育努力与这些研究努力联系起来，以同时促进科学知识和社会公益。理解发育系统如何进化以促进表型多样性是生物学的一个基本目标。这些系统包括并调节多细胞生物体构建和最终形成所必需的形态发生场、信号因子和分化决定。尽管如此，尽管基因调控网络在少数几个模型系统中被煞费苦心地描述，但网络结构的变化很少与物种之间的形态差异联系在一起。基因变异如何改变发育过程，从而导致表型差异？四十多年的线虫遗传学揭示了规范的转化生长因子-β信号网络的发育细节，该网络调节该物种的身体大小。Inopinata是秀丽线虫的姐妹物种，它的体型几乎是其高度研究的近亲的两倍长。在这里，一个长期存在的模型系统的广泛背景知识将与比较方法相结合，以理解网络修改如何导致表型差异。这项工作将包括：1)两个物种中转化生长因子-β途径活性的扰动，以确定祖先身体大小基因是如何进化以促进细胞大小分化的；2)产生和定位大效应身体大小突变，以发现驱动细胞大小调节的新基因；以及3)表征两个物种中不同发育阶段突变体的组织特异性细胞大小差异。这项工作不仅将基因类型映射到生物表型，如身体大小，而且还将展示基因如何影响细胞表型，从而导致这些生物表型的出现。上述研究工作将与俄克拉荷马州多项既定的教育举措相结合，以扩大各级学生参与科学研究的范围。该项目由BIO-IOS发展系统计划和既定的激励竞争研究计划(EPSCoR)联合资助。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。

The diversity among animal body sizes (from at least ants to elephants) is immense and demands explanation. Yet, the genetic and developmental changes that cause body size evolution remain unknown. The proposed work aims to address this problem by harnessing both long-established and cutting-edge genetic techniques in closely-related roundworm species with drastically different body sizes to identify the causes of body size variation. This work is important because we know larger roundworm species have larger cells than those of smaller species, and when the processes regulating cell size go awry, diseases such as cancer emerge. This work then has the potential to discover novel genes that control cell size and thus potential novel targets for cancer therapeutics. Beyond this, the research work described above will be integrated with multiple, established educational initiatives in the state of Oklahoma including: 1) The University of Oklahoma’s four-year undergraduate research experience program; 2) A multi-year summer research program for American Indian undergraduates; 3) A research experience for high school students summer program; and 4) A graduate-student led summer coding workshop. Additionally, an undergraduate developmental biology laboratory course will be developed where students will participate in the original research activities described above. The proposed work not only aims to make significant advances in understanding the evolution of body size and the genes underlying cell size variation, but this work also aims to connect multiple educational efforts with these research efforts to simultaneously advance both scientific knowledge and societal good.Understanding how developmental systems evolve to promote phenotypic diversity is a fundamental goal of biology. These systems include and regulate the morphogenetic fields, signaling factors, and differentiation decisions essential for the construction and ultimate form of a multicellular organism. Despite this, while gene regulatory networks have been painstakingly described in a handful of model systems, network architecture change is rarely connected to morphological divergence among species. How does genetic variation change developmental processes to cause divergent phenotypes? Over forty years of C. elegans genetics has revealed the developmental details of a canonical TGF-β signaling network that regulates body size in this species. C. inopinata is the sister species of C. elegans, and it is nearly twice as long in size as its highly-studied close relative. Here, the vast background knowledge of a long-standing model system will be integrated with a comparative approach to understand how network modification causes phenotypic divergence. This work will include: 1) The perturbation of TGF-β pathway activity in two species to determine how ancestral body size genes evolve to promote cell size divergence; 2) The generation and mapping of large-effect body size mutations in C. inopinata to discover novel genes driving cell size regulation; and 3) The characterization of tissue-specific cell size variation in mutants across development in two species. Not only will this work map genotypes to organismal phenotypes such as body size, but it will also show how genotypes influence cellular phenotypes to cause the emergence of such organismal phenotypes. The research work described above will be integrated with multiple, established educational initiatives in the state of Oklahoma to broaden the participation of students at all levels in scientific research.This project is jointly funded by the BIO-IOS-Developmental Systems Program and the Established Program to Stimulate Competitive Research (EPSCoR).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.