CAREER: Comparative genomics to reveal form, function and mechanism of splicing across eukaryotes

该项目将研究基因表达的一个关键而神秘的方面，即基因中的信息被解码以产生生命的分子和结构的过程。 与基因和产物之间具有简单的一对一关系的细菌不同，在复杂的生物体中，基因表达需要大规模的重排，增加、去除和联合收割机组合信息。 这种“RNA剪接”在所有复杂的生命中无处不在，而且非常多样化，但在极少数模式生物之外，它几乎仍然是完全神秘的。 该项目将开发生物信息学软件，利用来自数百个不同物种的可用生物序列数据：发现数百万个剪接案例;确定每个物种中剪接的一般形式和功能;并阐明剪接发生的分子过程。 通过推进对基因表达的输出和过程的理解，该项目将阐明生物体的功能，从我们自己到无数的作物，寄生虫，害虫和寄生生物。 此外，该项目将通过在我国最多样化的综合性大学之一培训生物和计算科学方面的研究生、本科生和社区学院学生，促进多样化和熟练劳动力的培训。 最后，拟议的工作将通过将前沿的生物信息学研究整合到多个本科课程的课堂教学中来支持课程创新。可以说，真核细胞核基因表达的最显著特征是剪接体对RNA加工的普遍性，在绝大多数特征性真核细胞谱系中，大多数蛋白质编码转录本都经历了剪接。 剪接体去除普遍存在的称为内含子的基因中断序列，可以通过选择性剪接促进来自同一基因的多个产物的产生，并且可以通过将来自基因组不同区域的转录物剪接在一起来产生新产物。 尽管剪接的重要性，几乎没有什么是已知的剪接以外的一小部分模式生物。 该项目将开发生物信息学管道，以利用来自300种不同真核生物物种的可用基因组和转录组数据来推进真核结构域剪接的知识。 具体而言，该项目将通过完成三个目标来促进对剪接形式、功能、机制和进化的理解：（i）首次全基因组范围内表征真核顺式和反式剪接事件;（ii）首次全基因组范围内多水平研究选择性剪接和反式剪接;以及（iii）第一个涉及剪接机制的顺式和反式因子的全域表征和比较。该奖项由分子和细胞生物科学部共同资助，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影响审查标准进行评估，被认为值得支持。

The project will investigate a crucial and mysterious aspect of gene expression, the process by which the information in genes is decoded to produce the molecules and structures of life. In contrast to bacteria, which have a simple one-to-one relationship between gene and product, in complex organisms, gene expression requires large-scale rearrangements that add, remove and combine information. Such "RNA splicing" is ubiquitous and remarkably diverse across all complex life, yet it remains almost completely mysterious outside of very few model organisms. The project will develop bioinformatic software to leverage available biological sequence data from hundreds of diverse species to: discover millions of cases of splicing; identify the general form and function of splicing in each species; and illuminate the molecular processes by which splicing occurs. By advancing understanding of the outputs and processes of gene expression, this project will elucidate how organisms function, from ourselves to countless crops, parasites, pests, and commensal organisms. In addition, the project will advance training of a diverse and skilled workforce by training graduate, undergraduate and community college students in biological and computational sciences at one of our nation's most diverse comprehensive universities. Finally, the proposed work will support curricular innovation by integrating cutting-edge bioinformatics research into classroom teaching in multiple undergraduate courses.Arguably the most striking feature of eukaryotic nuclear gene expression is the ubiquity of RNA processing by the spliceosome, with most protein-coding transcripts undergoing splicing in the vast majority of characterized eukaryotic lineages. Spliceosomes remove ubiquitous gene-interrupting sequences called introns, can facilitate the production of multiple products from the same gene by alternative splicing, and can produce novel products by splicing together of transcripts from different regions of the genome. Despite the importance of splicing, almost nothing is known about splicing outside of a small number of model organisms. This project will develop bioinformatic pipelines to leverage available genomic and transcriptomic data from 300 diverse eukaryotic species to advance knowledge of splicing across the eukaryotic domain. Specifically, this project will advance understanding of form, function, mechanism and evolution of splicing by accomplishing three objectives: (i) the first domain-wide genome-wide characterization of eukaryotic cis- and trans- splicing events; (ii) the first domain-wide multi-level study of alternative splicing and trans-splicing; and (iii) the first domain-wide characterization and comparison of cis- and trans- factors involved in the mechanism of splicing.This award was co-funded by the Division of Molecular and Cellular Biosciences , the Division of Evolutionary Biology, and the Rules of Life Venture fund.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.