The breadth of genomic diversity endows organisms with rich biosynthetic capabilities and allows them to adapt to diverse environments. This species diversity in biological systems has tremendous potential to solve global challenges, such as the remediation of hazardous waste, producing new drugs and designer cells to alleviate human diseases, and the synthesis of novel chemicals and materials to ensure environmental sustainability. These challenges motivate the need to develop entirely new functional genomic tools, and enabling technologies to modify genomes on a large scale. Specifically, methods are needed for parallel and continuous directed evolution of gene networks or genomes to enhance understanding and expedite the design and evolution of organisms with prescribed functions. In this project, the investigators address these challenges through the development of multiplex genome engineering technologies in non-conventional yeast species. This project also promotes interdisciplinary education, including the specific expansion of STEM education and career opportunities for underrepresented minorities and women. Further, the investigators create experiential learning modules that bring genome engineering research to K-12 and undergraduate classrooms and connect students to the science in the laboratory. This new outreach program ensures that advances made in this project benefit a broader community and contribute to motivating and training young scientists and engineers.

In this project, we seek to develop cross-species multiplex genome engineering technologies to enable gene function discovery in non-conventional yeast (NCY) species. By integrating state-of-the-art molecular biology, laboratory evolution, and synthetic biology technologies, this project creates a new framework for studying and generating genetic variation. This framework is focused on establishing cross-species genome editing capabilities in nonconventional yeast with improved capabilities of delivering synthetic DNA in cells. The ability to introduce many targeted genome modifications at base-pair level precision establishes a general strategy for multiplex combinatorial genome engineering in NCYs and more broadly for eukaryotes. These advances enable the construction of targeted sets of genetic variants that can be functionally studied to elucidate causal links between genotype and phenotype and reprogram cellular behavior. In the long-term, the present work will transform the way scientists perform large-scale genetic modifications in non-conventional yeast species and usher in an era wherein globally reprogramming cellular behavior will become simple, inexpensive, and empower researchers to uncover new biological phenomena, elucidate causal links between genotype and phenotype, and design and reprogram organisms. In sum, this project provides new directions for academic and industrial efforts related to genome engineering, while simultaneously training the next generation of scientists and engineers to be full participants in the work force.

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.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Edda Thiels
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Yale University
New Haven
United States
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