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

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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.