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

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

Despite advances in genome-editing and functional genomics tecDespite advances in genome-editing and functional genomics
technologies enhancing our ability to characterise genetic loci, systematic functional studies of genomic features have thus far been
limited 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 be
revolutionised 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 genetic
elements. Harnessing this new resource and technology, the work described in this proposal aims to elucidate important aspects of
tRNA and rRNA biology through an engineering biology approach. Our motivation is to explore three fundamental aspects of ncRNA
biology: ncRNA organisation, regulation, and evolution. Our vision for this proposal is to unravel genomic fundamentals, remove
biological complexity and redundancies, and ultimately couple evolution with engineering to optimise translation processes. Our
approach will radically reorganise the genome, providing a unique opportunity to carry out three inter-linked work packages to
systematically study the organisation, regulation, and evolution of tRNAs and rRNAs. The steps towards the overarching goal are each
significant 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 limitations
associated with directly assaying currently intractable biological questions regarding ncRNA biology and molecular evolution. In the
long-term, since yeast is a safe and tractable model organism, this project will shed new light on genome fundamentals, but also
potentially have profound impacts on medicine and biotechnologies.

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