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First synthetic yeast chromosome revealed
US-based project recruited dozens of undergraduates to stitch DNA fragments together.
Ewen Callaway
27 March 2014
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It took geneticist Craig Venter 15 years and US$40 million to synthesize the genome of a
bacterial parasite. Today, an academic team made up mostly of undergraduate students
reports the next leap in synthetic life: the redesign and production of a fully functional
chromosome from the bakers yeast Saccharomyces cerevisiae.

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As a eukaryote, a category that includes humans and other animals, S. cerevisiae has a more
complex genome than Venter's parasite. The synthetic yeast chromosome which has been
stripped of some DNA sequences and other elements is 272,871 base pairs long,
representing about 2.5% of the 12-million-base-pair S. cerevisiae genome.The researchers,
who report their accomplishment in Science
1
, have formed an international consortium to
create a synthetic version of the full S. cerevisiae genome within 5 years.
This is a pretty impressive demonstration of not just DNA synthesis, but redesign of an
entire eukaryotic chromosome, says Farren Isaacs, a bioengineer at Yale University in New
Haven, Connecticut, who was not involved in the work. You can see that they are
systematically paving the way for a new era of biology based on the redesign of genomes.
The project began a few years ago, when Jef Boeke, a yeast geneticist at New York
University, set out to synthesize the bakers yeast genome with much more drastic alterations
than those demonstrated by Venter and his team in 2010.
The group at the J. Craig Venter Institute in Rockville, Maryland, had chemically synthesized
short strands of DNA and stitched them together to create a version of the 1.1-million-base-
pair DNA genome of the bacterium Mycoplasma mycoides, which was then inserted into a
recipient cell
2
. Venters team wrote a few coded 'watermarks' into the genome sequence,
which spelled out the names of the team members, as well as several famous quotes. But
besides these tweaks and a few other changes, the synthetic M. mycoides genome was
identical to its blueprint.
By contrast, Boeke and his team thought that by stripping the genome of certain features to
test their importance, they could justify the enormous cost and effort of synthesizing whole
yeast chromosomes.
I wasnt sceptical about whether it could be done, Boeke says. The question, he explains,
was: How can we make this different from a normal chromosome and put something into it
thats really going to make it worthwhile?

'Build-a-genome'
The scientists decided to omit certain DNA sequences from their synthetic chromosome, such
as elements with the ability to move around the genome, known as transposons, and sections
within genes that do not encode proteins, called introns. They also inserted a 'scrambling'
system which shuffles and removes genes to provide a way of testing whether a given
gene is essential to survival.
The initial plan was to contract commercial DNA-synthesis companies to create large chunks
of the yeast genome to Boekes specifications. But the first order, a 90,000-base-pair chunk
of DNA corresponding to a portion of the S. cerevisiae chromosome IX
3
, cost roughly
US$50,000 and took a year to arrive.
Ill be dead long before this project will ever be finished, Boeke remembers thinking. So he
turned his mind to thinking up other ways of assembling chromosome-length stretches of
DNA.
He realized that university campuses were full of undergraduate students interested in
dabbling in research. In the summer of 2007, he taught the first build-a-genome course at
Johns Hopkins University in Baltimore, Maryland, and the classes have been offered most
terms since.
Each student makes their own stretch of the yeast genome, which involves stitching together
very short lengths of DNA created by a DNA-synthesis machine into ever-larger chunks.
These chunks are then incorporated into the yeast chromosome, a few at a time, through a
process called homologous recombination. Eventually, this results in an entirely synthetic
chromosome. Many of the students are co-authors on Boeke's Science paper, which details
the synthesis of S. cerevisiae's chromosome III.
Despite all its alterations, yeast cells containing the synthetic chromosome grew just as well
as normal yeast. Whats amazing about it is that there are over 50,000 base pairs that were
either deleted, inserted or changed in that chromosome of 250,000 base pairs, and it works.
Thats kind of a remarkable effect, Boeke says.
Global push
The team has grander experiments in mind including many that depend on creating an
entirely synthetic yeast genome. Well really be able to explore the depth of what can be
done to a genome and still come out with viable cells that are recognizable as yeast, Boeke
says.
To make an entire yeast genome from scratch, Boeke has enlisted collaborators including
undergraduate students from around the world. A build-a-genome class at Tianjin
University in China is tackling one of S. cerevisiaes 16 chromosomes, as are teams at BGI-
Shenzhen in China, Imperial College London and a few US institutions. Boeke says that half
the DNA sequences have already been made.
This work is another remarkable example of how synthetic biology can be used to rewrite
chromosome sequences at a sizable scale, Venter and his colleagues say in a written
statement. This work is a prelude to and demonstrates the feasibility of extensive refactoring
or streamlining of the other chromosomes.
Tom Ellis, a synthetic biologist at Imperial College London who is leading the effort to
synthesize S. cerevisiae chromosome XI, sees the project as a riposte to factory-scale
synthetic biology. This shows that the academic, open-source reply to what Venter did is:
lets set up some labs with undergraduates, and they can do the same. They can make
chromosomes as well.
Journal name:
Nature
DOI:
doi:10.1038/nature.2014.14941
References
1. Annaluru, N. et al. Science http://dx.doi.org/10.1126/science.1249252 (2014).
2. Gibson, D. et al. Science 329, 5256 (2010).
3. Dymond, J. S. et al. Nature 477, 471476 (2011).
Related stories and links
From nature.com
Genomes edited to free up codons
14 July 2011
Death-row drug dilemma
27 January 2011
Genome-building from the bottom up
10 October 2010
Synthetic genome resets biotech goals
26 May 2010
Researchers start up cell with synthetic
genome
20 May 2010
Five hard truths for synthetic biology
20 January 2010
From elsewhere
Synthetic Yeast Project
Author information
Author details
Ewen Callaway
Ewen joined Nature in August 2010, after 2 years at New Scientist as Boston-based
biomedical reporter. He attended the science-writing programme at the University of
California, Santa Cruz, and earned a masters degree in microbiology at the
University of Washington. He spends his free time learning
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1.
Astilbe Martin 2014-03-27 07:18 PM
Samuel Adams Utopias 2013 is 56 proof by direct yeast fermentation. They
fermented until yeast poisoned themselves with alcohol, retrieved the last survivors,
and repeated. Given raw material, the potential for gene-gineering to create the world
is gobsmacking. Successful genetic selection and reconstruction must be banned -
with the most heinous possible penalties - lest we make progress and live better lives.
The risk of one failure must always counterbalance the promises of a thousand
victories. Eat teosinte not corn.
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