Synthetic yeast project unveils cells with 50% artificial DNA
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Synthetic
yeast project unveils cells with 50% artificial DNA
Designer
chromosomes enable new studies of genome organization
and evolution
- 8
Nov. 2023
- 11:00
a.m. ET
- ByMitch
Leslie
A
yeast cell with roughly 31% synthetic DNA.Zhao et
al./Cell “It’s
a very impressive body of work,” says synthetic
biologist Sanjay Vashee of the J. Craig Venter
Institute, who wasn’t connected to any of the studies.
Researchers
have tinkered with the genomes of yeast and many other
organisms using editing technologies such as CRISPR. But
building a new version from the ground up opens the way
to making bigger changes to an organism’s genome and
delving deeper into its organization, function, and
evolution.
Developing
synthetic genomes may also make it easier to upgrade
the many organisms that are crucial for industry,
agriculture, and medicine. Yeast, for example, not
only keeps breweries and wineries in business, but
also churns out a variety of chemicals and drugs,
including insulin. With a synthetic genome, “we can
more rapidly improve strains and find the genes that
are important for increasing production,” Boeke says.
So
far, scientists have generated artificial genomes for
several viruses and bacteria, but yeast would be the
first eukaryote—the group of organisms, such as flies,
snakes, and humans, whose cells have a nucleus. The
yeast species the researchers used, Saccharomyces
cerevisiae, carries 16 chromosomes and is a much
bigger challenge than bacteria, which typically have a
single chromosome and a fraction as much DNA. Launched
in 2006, the Synthetic Yeast Genome Project enlisted
scientists at more than a dozen institutions worldwide
to tackle the problem, along with hundreds of
undergraduates who helped synthesize bits of the
genome.
The
researchers didn’t attempt to redesign the genome one
nucleotide at a time. Instead, they revised the native
yeast genome, adding thousands of modifications that
simplify its structure, boost its stability, and make
it easier to study. For instance, they carved out the
transposons, itinerant stretches of DNA that can leap
from location to location in the genome, disrupting
DNA sequences.
They
also pruned the genome by excising many of the
introns, segments of DNA that don’t code for portions
of proteins. And to make the new yeast genome easier
to manipulate in future experiments, the team included
several hundred short DNA sequences that can prompt
sections of chromosomes to rearrange.
In
most cases, the researchers left genes on their
original chromosomes. But a team led by synthetic
biologist Yizhi “Patrick” Cai of the University of
Manchester, international director of the project,
created a new, 17th chromosome to house yeast’s 275
tRNA genes. They code for RNA molecules that transport
amino acids, the building blocks of proteins.
Although
tRNAs are essential for protein synthesis, their genes
“are a lot of trouble for the genome,” Cai says,
because “they are DNA damage hotspots” that can cause
breaks. By isolating these disruptive genes on one
chromosome, the researchers hoped to tame them. They
found that yeast
cells could survive and grow—albeit more slowly than
unmodified cells—with this newfangled
chromosome, they report in Cell.
Synthetic biologist Paul Freemont of Imperial College
London calls this work “a tour de force.”
Separate
teams assembled each synthetic chromosome in a
different strain of yeast. “We show all chromosomes
can be successfully constructed under the same design
principles from scratch,” says biologist Yue Shen of
BGI Research, who heads one team. But the researchers
needed to incorporate the chromosomes into the same
yeast cell and determine whether it was healthy. Boeke
and colleagues repeatedly mated cells harboring
different synthetic chromosomes, eventually producing
yeast that contained six full-size synthetic
chromosomes and a fragment of another, but not the
extra tRNA chromosome.
This
yeast grew slower than normal because of some harmful
genomic glitches, but after the researchers identified
and corrected them, the
strain grew about as fast as unaltered cells,
the team reported in a second Cell paper.
They then used a similar mating approach to add
another synthetic chromosome, bringing the total to
7.5. In these cells, more than 50% of the DNA is
synthetic. “We are more than halfway there,” Boeke
says.
In
other papers published this week, scientists with the
project used cells with the remade chromosomes to test
the effects of specific structural changes. For
example, moving the centromere, the junction between
chromosome arms that is essential for cell division,
revealed that a
small stretch of DNA adjacent to the centromere
helps keep chromosomes stable, Boeke and
colleagues reported in Cell
Genomics. And repositioning chromosomes
within the nucleus showed that confining
them near its boundary led to gene silencing, he
and his co-workers revealed in Molecular
Cell.
Synthetic
genomicist Ian Ehrenreich of the University of
Southern California says the results offer “a cool
system for discovering rules for how DNA elements
combine to produce a functional genome.” Researchers
are now “moving past a descriptive form of biology, to
one where we understand life by building it,” he says.
The
team is now working to integrate the remaining
chromosomes into a yeast cell and correct any genomic
problems that arise. Boeke expects a yeast with a
fully synthetic genome to debut in about a year.
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About
the author
Mitch Leslie writes about cell biology and immunology.