Scientists synthesise shortest-known genome

Chipping away at the genome of a tiny parasitic bacteria, genetic-sequencing trailblazer J. Craig Venter and colleagues say they’ve synthesised the shortest-known genome known to support life. This man-made set of genetic instructions contains only 473 genes, breaking the record held by the bacteria Mycoplasma genitalium, which with 525 genes contains the shortest-known genome found in nature.

Even with such a short list of genes, the researchers say the function of nearly a third of those genes remains a mystery — a hint that scientists still don’t fully understand the basic genetic requirements for life.

The so-called minimal genome, described in the journal Science, could help scientists better understand a cell’s essential instructions and shed light on the early evolution of life on Earth. The discovery could also pave the way towards creating designer microbes that could efficiently perform a host of functions useful for humans, from pumping out medicines to synthesising biofuels.

“As people start to think of industrial applications, de novo design using the repertoire of genetic pathways on this planet open up infinite numbers of new pathways that have never even been part of people’s imaginations before,” Venter said in a press briefing. “So I think it’s the start of a new era; it won’t happen overnight.”

Venter, who founded the La Jolla, California-based J. Craig Venter Institute and biotech company Synthetic Genomics, gained fame in 2007 for being the first human to have his entire genome sequenced. But long before that, he and his colleagues turned heads in 1995 when they reported that they had sequenced the first complete cellular genomes (one of which was M. genitalium) and showed four years later that many of those genes don’t seem to be necessary for growth.

In 2010, they announced that they had created the first synthetic organism by building a genome of M. mycoides from scratch and placing the finished product inside of a M. capricolum cell whose DNA they had removed.

But with a few exceptions, they had left M. mycoides’ genetic instructions mostly intact. This time the researchers wanted to create a living cell that had only the necessary genes for life.

This approach proved to be much harder, and to take much longer, than the team initially thought. Various estimates had put the number of essential genes anywhere from 256 to around 300, Venter said, and so the researchers took to designing with that in mind. They picked all of the genes that they thought were necessary in mycoides and put them together. Those directly designed cells did not work.

“No surprise to everybody now that has seen this paper, every one of our designs failed,” Venter said.

So the scientists began adding mycoides genes back to their designs until they got a functioning cell, and then divvied the genome up into eight overlapping chunks. They would delete genes in a given chunk and then add it back into the whole genome to see if the cell still functioned. If it didn’t work, they’d eliminated something essential. If it did work, they’d gotten rid of something that the cell hadn’t needed to survive.

They also found a number of quasi-essential genes, which, when deleted, would impair growth. Because the researchers needed to grow their bacteria fast enough to get their lab work done, some of these genes were kept in, even though there were not strictly necessary for life.

The scientists then synthesised their own version, consolidating the genes that worked together the way you might defrag your computer. This time, once they had inserted the man-made genome into an emptied cell of another species, it worked.

Although this is the shortest functioning genome now known, it is not the only minimal genome, the authors pointed out. First, they had to make concessions to include a few quasi-essential genes that sped up the growth time. Second, if they had started with a different critter — perhaps a photosynthetic or methanogenic bacteria, for example — they would have probably ended up with a different looking set of core genes.

But the research opens up a host of avenues to explore, the scientists said, pointing to the 149 genes in the minimal genomes whose exact function remained unknown.

“Knowing that we’re missing a third of our fundamental knowledge, I think, is a very key finding, even if there’s no other uses for this organism,” Venter said.

The next steps will include trying to nail down what those functions are; since some of those unknown genes seem to be shared by other species, they could point to basic required functions that scientists aren’t aware of yet.

And once they fully understand this genome, researchers can then start adding genes into the mix to see how they affect the cell, learning more about the additional gene in the process.

“One thing I’ve learned from this is the whole idea of the minimal genome is not quite as clear- cut as it seemed initially,” said project leader Clyde Hutchison of the J. Craig Venter Institute.