Scientists develop tRNA Neochromosome for synthetic yeast genome

They've already combined six and a half synthetic chromosomes into a functioning yeast cell, which is a significant achievement. This marks the first time researchers have completely written a yeast's genetic code, with more than 50% of its DNA made in the lab.

Cutting-edge technology in genetic engineering

This project lays the groundwork for designing genomes for specific purposes, like creating new medicines or biofuels.

“We decided that it was important to produce something that was very heavily modified from nature’s design,” says senior author and Sc2.0 leader Jef Boeke, a synthetic biologist at NYU Langone Health. “Our overarching aim was to build a yeast that can teach us new biology.”

Yeast is important in various industries, and redesigning its genome could lead to more robust, faster, and more productive yeast strains. 

This is a big deal because, in the past, scientists have created synthetic genomes for simpler organisms like bacteria and viruses. But now, they've achieved this with a more complex type of cell called a eukaryote, which has multiple chromosomes. The synthetic yeast's genome is like a customized and unique version, distinct from the yeast used in brewing or baking.

The tRNA neochromosome is a unique addition and will house and organize specific genes from the yeast. It was created using artificial intelligence and computer-assisted design. 

Fundamental building blocks of life

The research is a result of a 10-year-long international collaboration led by Professor Patrick Cai at the University of Manchester. 

“Our motivation is to understand the first principles of genome fundamentals by building synthetic genomes,” says co-author and synthetic biologist Patrick Yizhi Cai of the University of Manchester, who is also senior author of two other papers in the collection. 

“The team has now re-written the operating system of the budding yeast, which opens up a new era of engineering biology—moving from tinkering a handful of genes to de novo design and construction of entire genomes,” added Cai.

Synthetic designer genomes are like flexible tools that can help us answer tricky questions in biology.

The researchers have published their findings acrossCell, Molecular Cell, andCell Genomicsthat showcase the Synthetic Yeast Genome Project (Sc2.0).

Study abstract:

The Sc2.0 project is building a eukaryotic synthetic genome from scratch. A major milestone has been achieved with all individual Sc2.0 chromosomes assembled. Here, we describe the consolidation of multiple synthetic chromosomes using advanced endoreduplication intercrossing with tRNA expression cassettes to generate a strain with 6.5 synthetic chromosomes. The 3D chromosome organization and transcript isoform profiles were evaluated using Hi-C and long-read direct RNA sequencing. We developed CRISPR Directed Biallelic URA3-assisted Genome Scan, or ‘‘CRISPR D-BUGS,’’ to map phenotypic variants caused by specific designer modifications, known as ‘‘bugs.’’ We first fine-mapped a bug in synthetic chromosome II (synII) and then discovered a combinatorial interaction associated with synIII and synX, revealing an unexpected genetic interaction that links transcriptional regulation, inositol metabolism, and tRNASerCGA abundance. Finally, to expedite consolidation, we employed chromosome substitution to incorporate the largest chromosome (synIV), thereby consolidating >50% of the Sc2.0 genome in one strain.