The field of synthetic biology aims to make discoveries about life via a bottom-up approach, piecing together genes to understand how they work together. A huge initiative in this field is the Synthetic Yeast Project (Sc2.0). Their goal is to advance synthetic biology by creating a fully synthetic genome for Saccharomyces Cerevisiae, i.e. baker’s yeast, one of the best studied single-celled organisms. This synthetic yeast would have entirely lab-generated DNA, with each gene modified to be easily manipulable and with unnecessary information removed from the genome. In a recent collection of articles, Sc2.0 detailed their success in making a yeast with 9 of its 16 chromosomes fully human generated.

In one article, they outlined the problems with having multiple synthetic chromosomes in one cell. They found that yeast with combinations of synthetic chromosomes didn’t grow normally, but it wasn’t obvious what the exact problems in the synthetic chromosomes were. To investigate, the researchers designed a large-scale experiment using CRISPR to swap out different parts of the natural vs synthetic chromosomes. Using this method, they were able to hone in on a couple defects, like a complex mutation that affected the yeast’s ability to create a specific sugar called inositol. Once the researchers fixed the defects, they were able to group the synthetic chromosomes into one cell, creating a yeast with more than half synthetic DNA.

This debugging process was described in just one of the ten recently published studies from Sc2.0. The others detail deep insights gleaned from synthetic chromosomes and how these chromosomes are tools to rapidly manipulate the way DNA organizes itself in the nucleus. Such insights and experiments would not be possible without reconstructing the yeast genome.

This study was led by Yu Zhao, a postdoctoral fellow in the lab of Jef Boeke in the Institute for Systems Genetics at NYU Langone Health. The Sc2.0 consortium comprises 11 research teams across the world. More information can be found at https://syntheticyeast.github.io/.

Managing Correspondent: Alex Yenkin

Original Journal Article: “Debugging and consolidating multiple synthetic chromosomes reveals combinatorial genetic interactions,” Cell

Press Article: “Researchers Assemble Nine Synthetic Yeast Chromosomes,” NYU Langone News

Image Credit: Wikimedia Commons/Rosser1954

Other Sc2.0 Research Articles:

• “Design, construction, and functional characterization of a tRNA neochromosome in yeast,” Cell
• “Synthetic chromosome fusion: Effects on mitotic and meiotic genome structure and function,” Cell Genomics
• “Manipulating the 3D organization of the largest synthetic yeast chromosome,” Molecular Cell
• “Consequences of a telomerase-related fitness defect and chromosome substitution technology in yeast synIX strains,” Cell Genomics
• “Dissecting aneuploidy phenotypes by constructing Sc2.0 chromosome VII and SCRaMbLEing synthetic disomic yeast,” Cell Genomics
• “Parallel laboratory evolution and rational debugging reveal genomic plasticity to S. cerevisiae synthetic chromosome XIV defects,” Cell Genomics
• “Synthetic yeast chromosome XI design provides a testbed for the study of extrachromosomal circular DNA dynamics,” Cell Genomics
• “Establishing chromosomal design-build-test-learn through a synthetic chromosome and its combinatorial reconfiguration,” Cell Genomics
• “Context-dependent neocentromere activity in synthetic yeast chromosome VIII,” Cell Genomics