Scientists construct a synthetic yeast genome

Chromosomes are long DNA molecules that together form a genome containing all the genetic material of an organism. Advances in technology have allowed scientists to re-engineer and construct different chromosome sequences, making it easier to study the relationship between gene variation and traits.

It should be noted that yeast is an important model organism for understanding basic cellular processes, due to its similarity to plants and animals at the cellular level, while being significantly easier to manipulate and study. Therefore, redesigning and synthesizing a yeast genome can help scientists understand the impact of genetic variation on individual traits, potentially elucidating the mechanisms of genetic diseases.

With this goal in mind, scientists from the NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), the Synthetic Biology Translational Research Program (Syn Bio TRP) and the Department of Biochemistry at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have synthesized a modified yeast chromosome XV that consists of 1.05 million base pairs – the largest synthesized chromosome in Asia.

The work was published in Cellular genomics.

The research team, led by Associate Professor Matthew Chang, is part of the Yeast Synthetic Genome Project (Sc2.0), an international consortium involving laboratories around the world working together to redesign and construct from scratch all 16 yeast chromosomes. The work of A/Prof Chang’s team is seen as a major milestone in the field of synthetic biology.

In creating the synthetic chromosome XV (synXV), the NUS Medicine team extensively reworked the original DNA to incorporate various changes that resulted in a sequence that is distinctively unique and different from the natural one.

To streamline the synXV assembly process, the team developed a novel technology called CRISPR/Cas9-mediated mitotic recombination with endoreduplication (CRIMiRE). This innovative technology greatly accelerates the exchange of large chromosomal DNA segments at specific locations, thereby allowing multiple synthetic chromosome segments to be assembled simultaneously and stitched together into a complete synthetic chromosome XV.

When generating a synthetic yeast chromosome, CRIMiRE further allows for intentional mixing and matching of synXV with another yeast chromosome. This generates different genetic combinations for research, which illuminates the relationship between genetic variation and individual traits.

Given the challenges of working with extremely long DNA sequences, traditional approaches cannot modify the sequences efficiently. However, using CRIMiRE has simplified the process, shortening it tenfold, potentially revolutionizing the way larger synthetic chromosomes are constructed for more complex organisms.

“This achievement opens the door to understanding fundamental questions about biological processes,” said A/Prof Matthew Chang.

“Our journey to complete the construction of the synthetic yeast chromosome has been remarkable. Not only have we demonstrated our technical prowess in creating synthetic chromosomes, we are now able to rapidly reconfigure them into different designs for further research. These synthetic chromosomes are our key to unlocking answers to fundamental biological questions, offering the potential for groundbreaking advances that could ultimately be of great benefit to humanity,” he added.

“The achievements of this work promise to pave the way for future advances in synthetic genomics, especially with larger and more complex chromosomes.” This approach could be beneficial to decipher the mechanisms and understand genetic diseases better and potentially to develop treatments,” added Dr Foo Jee Loon, Research Assistant Professor from SynCTI, Syn Bio TRP and Department of Biochemistry, NUS Medicine, first author of the article.