Yeast cells are being rebuilt from scratch to strip away millions of years of evolutionary clutter and reveal how hidden RNA molecules control the production of proteins. The problem is that natural genomes are messy. Every organism carries vast amounts of background genetic variation that obscures the roles of specific elements, particularly non-coding RNAs (ncRNAs) such as transfer RNAs and ribosomal RNAs. These molecules are essential for translation—the process that turns genetic code into proteins—but their organisation, regulation, and evolution remain poorly understood because conventional genome-editing tools cannot isolate them from surrounding noise. This project uses the synthetic yeast genome Sc2.0, a completely redesigned chromosome set, to systematically reorganise and simplify the genetic landscape. By removing redundancies and controlling where ncRNA genes are placed, the researchers can test cause and effect with unprecedented clarity. If successful, the work will reveal fundamental principles of genome organisation that apply across all life. In the long term, understanding how translation is optimised could improve biotechnologies that rely on protein production—such as manufacturing enzymes, vaccines, or therapeutic antibodies—and may offer insights into human diseases where translation goes wrong. For now, this is fundamental science: building a simpler genome to ask questions that natural genomes cannot answer.
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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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