GREAT: Genome Refactoring and Engineering Approach to study non-coding genes driving Translation

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Despite advances in genome-editing and functional genomics tecDespite advances in genome-editing and functional genomicstechnologies enhancing our ability to characterise genetic loci, systematic functional studies of genomic features have thus far beenlimited to existing natural genomes. As such, vast background genomic variation introduces noise and clouds discovery.Subsequently, our understanding of the largely underexplored, yet integral, such as non-coding RNAs (ncRNAs), would berevolutionised by the radical approach of synthetic genomics.The synthetic yeast (Sc2.0) genome provides an invaluable technology and resource for probing the nuanced roles of these geneticelements. Harnessing this new resource and technology, the work described in this proposal aims to elucidate important aspects oftRNA and rRNA biology through an engineering biology approach. Our motivation is to explore three fundamental aspects of ncRNAbiology: ncRNA organisation, regulation, and evolution. Our vision for this proposal is to unravel genomic fundamentals, removebiological complexity and redundancies, and ultimately couple evolution with engineering to optimise translation processes. Ourapproach will radically reorganise the genome, providing a unique opportunity to carry out three inter-linked work packages tosystematically study the organisation, regulation, and evolution of tRNAs and rRNAs. The steps towards the overarching goal are eachsignificant and substantial, and most importantly, complementary to each other.This proposal will thereby expand state-of-the-art synthetic genomics approaches established in our lab, to overcome the limitationsassociated with directly assaying currently intractable biological questions regarding ncRNA biology and molecular evolution. In thelong-term, since yeast is a safe and tractable model organism, this project will shed new light on genome fundamentals, but alsopotentially have profound impacts on medicine and biotechnologies.