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Designer chromosome

17 Jun, 2014

In a world first, an international research team has successfully synthesised a functional chromosome and implanted it into brewer’s yeast (Saccharomyces cerevisiae). The research could help in developing synthetic strains of yeast that could be used in the manufacture of medicines or production of vaccines.

The research is believed to be the most significant advance in yeast genetics since 1996, when scientists initially mapped out yeast's entire DNA code.

The emerging field of synthetic biology – designing microorganisms to produce novel medicines, biofuels and food materials – has taken off, with the last 5 years having seen the synthesis of bacterial chromosomes and viral DNA. However, this is the first report of building from scratch an entire eukaryotic chromosome – the threadlike structure that carries genes in the nucleus of all plant and animal cells.

In a press release from the New York University Langone Medical Center, lead scientist Dr Jef Boeke said, “Our research moves the needle in synthetic biology from theory to reality. This work represents the biggest step yet in an international effort to construct the full genome of synthetic yeast. It is the most extensively altered chromosome ever built. But the milestone that really counts is integrating it into a living yeast cell. We have shown that yeast cells carrying this synthetic chromosome are remarkably normal. They behave almost identically to wild yeast cells, only they now possess new capabilities and can do things that wild yeast cannot.”

The team reported in their published paper how, using computer-aided design, they built a fully functioning chromosome, called synIII. The job took some 7 years and involved hooking together 272 871 base pairs of DNA (adenine paired with thymine, cysteine paired with guanine – when stacked, these base pairs form the helical structure of DNA).

The fully functional synIII is 14% smaller than its native version of the chromosome (chromosome III), which has 316 617 base pairs. Some of the changes made to the synthesised version involved removing repeating sections of base pairs and junk DNA (including base pairs known not to encode for any particular proteins and ‘jumping gene’ segments known to randomly move around and introduce mutations). Other sets of base pairs were added or altered to enable researchers to ‘tag’ DNA as synthetic or native and to easily delete or move genes on the synIII chromosome.

“When you change the genome, you're gambling. One wrong change can kill the cell. We have made over 50 000 changes to the DNA code in the chromosome and our yeast is still live. That is remarkable. It shows that our synthetic chromosome is hardy, and it endows the yeast with new properties.”

Chromosome III (and now synIII) controls how yeast cells mate and undergo genetic change.

Yeast shares about a third of its 6000 genes with humans and has a total of 16 chromosomes, compared to 23 pairs in humans.

“Now that we can shuffle the genomic deck, it will allow us to ask, can we make a deck of cards with a better hand for making yeast survive under any of a multitude of conditions, such as tolerating higher alcohol levels?” says Dr Boeke.

Using a ‘scrambling’ technique, researchers say they will be able to more quickly develop synthetic strains of yeast that could be used in the manufacture of medicines, such as artemisinin for malaria, or in the production of certain vaccines, including the vaccine for hepatitis B, which is derived from yeast. Synthetic yeast, they say, could also be used to bolster development of more efficient biofuels, such as alcohol, butanol and biodiesel.

Other researchers from the 80-strong team involved in creating the chromosome came from Johns Hopkins University, Loyola University and the Carnegie Institution of Washington in the US, Sorbonne University in France and the University of Edinburgh in Scotland.

They were also aided by some 60 undergraduate students enrolled in the Build a Genome project at Johns Hopkins University. The students pieced together short snippets of the synthetic DNA into stretches of 750–1000 base pairs or more, an effort led by co-author Professor Srinivasan Chandrasegaran.

Dr Boeke says the international team's next steps involve synthesising other larger yeast chromosomes, faster and cheaper. His team, with further support from Build a Genome students, is already working on assembling base pairs in chunks of more than 10 000.

The research was published in the 4 April edition of the journal Science.

References

Annaluru, N., Boeke, J.D., Chandrasegaran, S.et al. (2014). Total synthesis of a functional designer eukaryotic chromosome. Science, 44(6179), 55–58. doi:10.1126/science. 1249252. Available from www.sciencemag.org/content/344/6179/55.

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