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

动物身体大小的差异（至少从蚂蚁到大象）是巨大的，需要解释。然而，导致体型进化的基因和发育变化仍然未知。提出的工作旨在通过利用长期建立的和尖端的遗传技术来解决这一问题，这些技术用于密切相关的体型差异巨大的蛔虫物种，以确定体型变化的原因。这项工作很重要，因为我们知道较大的蛔虫物种比较小的物种拥有更大的细胞，当调节细胞大小的过程出错时，癌症等疾病就会出现。这项工作有可能发现控制细胞大小的新基因，从而发现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何马州的多个已建立的教育计划相结合，包括：1)俄克拉何马大学的四年本科研究经验计划；2)针对美国印第安本科生的多年夏季研究项目；3)高中生暑期项目的研究经历；4)研究生主持的暑期编程工作坊。此外，将开设本科发育生物学实验课程，学生将参与上述原始研究活动。拟议的工作不仅旨在在理解体型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种教育工作与这些研究工作联系起来，同时推进科学知识和社会利益。了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的形成和最终形态所必需的形态发生场、信号因子和分化决定。尽管如此，尽管基因调控网络已经在少数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有关。遗传变异如何改变发育过程从而导致不同的表型？四十多年的秀丽隐杆线虫遗传学研究揭示了该物种调节体型的典型TGF-β信号网络的发育细节。C. inopinata是秀丽隐杆线虫的姐妹种，它的长度几乎是其高度研究的近亲的两倍。在这里，长期模型系统的大量背景知识将与比较方法相结合，以了解网络修饰如何导致表型差异。这项工作将包括：1)对两种物种中TGF-β通路活性的扰动，以确定祖先体型基因如何进化以促进细胞大小分化；2)利用大效应体大小突变的产生和定位，发现驱动细胞大小调控的新基因；3)两种突变体发育过程中组织特异性细胞大小的变化特征。这项工作不仅将基因型映射到生物体表型（如体型），而且还将显示基因型如何影响细胞表型，从而导致这种生物体表型的出现。上述研究工作将与俄克拉何马州的多个已建立的教育计划相结合，以扩大各级学生对科学研究的参与。该项目由bio - ios -发展系统计划和促进竞争研究的既定计划（EPSCoR）共同资助。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。

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.