genetics, technology

Building a Genome: The First Synthetic Yeast Chromosome

When you were a kid, did you ever dream up fantastical creatures, like cats with wings or super-intelligent dogs that could speak? While we’re nowhere near making such animals, we’re definitely becoming increasingly better at genetically modifying the organisms around us. One amazing recent breakthrough is the creation of a synthetic yeast chromosome. This is the first time that anybody has made an entire chromosome in the lab for a eukaryote. (The eukaryocte group primarily includes plants, animals, and fungi, but not bacteria or archaea.) And what’s more, the group didn’t simply copy the chromosome – they made all kinds of changes to it. But, even with all the alterations, the yeast with the artificial chromosome still looked and acted just like the normal ones.

yeast artificial chromosome Saccharomyces cerevisiae
Saccharomyces cerevisiae, also known as baker’s yeast, as seen greatly magnified through a microscope. (Image credit: Masur)

So how exactly did the researchers make this artificial chromosome? They created the chromosome based on the yeast (Saccharomyces cerevisiae) chromosome III (S. cerevisiae has 16 chromosomes total). But the two chromosomes are different in a number of ways. The synthetic one, called synIII, is 272K DNA base pairs (bp) long, while the original chromosome III is 317K bp long. As shown by the difference in sizes, specific genetic material was deleted, mostly to prevent the chromosome from being unstable. Genetic elements were also added (including 98 loxP sites, which flank DNA that can be removed by choice using the Cre recombinase enzyme). These additions will allow other researchers to further manipulate the chromosome and create a series of yeast mutants to study. It’s a truly progressive, collaborative approach, and one that would be great to see more of. Genetic pieces were also replaced by keeping the function the same, but changing the genetic code to help researchers tell the original and synthetic chromosomes apart (like turning all TAG stop codons into TAA stop codons).

And as if making an entire chromosome from scratch weren’t enough, the group plans on having an artificial version of the entire yeast genome — all 16 chromosomes — completed in two years.

So why add the loxP sites so that chunks of DNA could be removed? It turns out that out of the approximately 6000 genes in the S. cerevisiae genome, most of them – some 5000 genes – are individually nonessential. This means that studies have been done where individual genes were knocked-out and the resultant yeast still functioned as usual. The question then arises – which genes are nonessential if you get rid of them along with other genes too? It’s not so difficult to get rid of two genes at once, but the more genes you try to knock-out (and match up in different knock-out combinations), the more labor intensive the process becomes. By creating an artificial chromosome with chunks that can be easily removed, it makes it much easier to generate many mutants and study them to answer these questions.

It’s also worth mentioning what a remarkable collaborative project this creation is based on. The lead researcher, Jef D. Boeke, while he was at Johns Hopkins University in Baltimore, Maryland, created a “Build a Genome” course where undergraduate students worked on making chunks of yeast chromosomes. Not only were their efforts essential for creating the artificial chromosome synIII, but the course also provided a valuable educational experience for the students. Additionally, over the six years of its existence, sequencing technology has improved so much that students’ goals have increased from assembling 1,500 to 30,000 bp per student. Boeke is now collaborating with multiple international groups to create the entire yeast genome in about two years.

So while we don’t have winged cats or chatty dogs yet, genetic sequencing technology is definitely taking off, and is allowing us to perform genetic manipulations at an ever-increasing rate. We’ll need to make sure that we don’t abuse these new abilities, but that’s a discussion for another time.

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