Around 5,000-10,000 years ago, dairy farming changed some people’s DNA. As they began to drink milk, human adults’ genes began to accumulate mutations that would help them digest it.
Such mutations help an organism evolve. Complex organisms like humans contain thousands of genes, most of which are not essential for survival. Mutations in these genes are not lethal. As a result, evolutionary forces can act on these genes, and any beneficial mutation becomes more abundant over time.
But what if a simple organism contained only those genes essential for its survival? Any mutation in such an organism could lethally disrupt its cellular functions. How will evolutionary forces act on the genome of such an organism when it contains so few targets on which selection can act?
Through 2,000 generations
Researchers from Indiana University, Bloomington, used a synthetically designed minimal cell containing only genes essential for survival to answer this question. Their findings, published recently in the journal Nature, showed that even such a cell can evolve as fast as a normal cell.
This “demonstrates the capacity for organisms to adapt, even with an unnatural genome that would seemingly provide little flexibility,” said Jay Lennon, a professor at Indiana University, whose team made the discovery.
Dr. Lennon’s team used a synthetic version of Mycoplasma mycoides, a microbe commonly found in the guts of goats and cattle. They created a stripped-down minimal cell (JCVI-syn3.B) with only 493 genes, down from the 901 genes in the non-minimal strain (JCVI-syn1.0). Although the minimal cells were alive and could reproduce, genome minimisation also made them sick, reducing their fitness by over 50%.
To test whether these minimal cells responded differently to the forces of evolution compared to non-minimal cells, the team grew them separately in a liquid medium, transferring a small, fixed amount of the population into fresh medium every day. They did this for 300 days, allowing the bacterial lineage to pass through 2,000 generations (equivalent to about 40,000 years of human evolution).
‘This is unavoidable’
In this time, they found that the minimal cells exhibited a mutation rate comparable to that exhibited by non-minimal cells. (Indeed, Mycoplasma mycoides has the highest recorded mutation rate for any cellular organism.)
“It’s not surprising the mutations arose in the minimal cell. This is unavoidable,” Dr. Lennon said. “What’s more important is that the rate of adaptation was not hampered by having a synthetically reduced genome.”
Over 300 days, they found that the minimal cell also effectively regained all of the fitness it had lost due to genome minimisation and could perform as well as the non-minimised cell – suggesting that a ‘reduced’ genome is not a permanent curse.
This said, the minimal cell grew to be smaller than the non-minimal cell: the size of the non-minimal cell increased by 80% over 300 days whereas the minimal cell remained the same size. When the team examined the genomes of the adapted cells, they found that the minimal and non-minimal cells improved their fitness and evolved via distinct genetic pathways.
Surprising fitness
“It is an interesting question to ask – in what ways is a minimal cell going to behave differently during evolution compared to a non-minimal cell? But the fact that a minimal cell evolved is not surprising,” Deepa Agashe, an associate professor at the National Centre for Biological Sciences (NCBS), Bengaluru, who studies evolutionary biology, said.
“Anything that is able to survive and reproduce can evolve.”
Dr. Agashe added that enough genetic variation will be generated, to help the cell to evolve, thanks to the high mutation rate, the large population size used in the experiment, and the sufficient growth material provided in the nutrient-rich liquid medium.
“Mutations are inevitable,” said Samay Pande, an assistant professor at the Indian Institute for Science, Bengaluru, who studies the evolutionary dynamics of bacterial predators. He noted that a high mutation rate wasn’t surprising – given that the mechanisms responsible for correcting these mutations were compromised in minimal cells. Instead, he added, “I am more surprised by the extent of the fitness gain than the fact that such cells can evolve.”
An interesting step would be to see whether an organism with a lower inherent mutation rate adapts as well, according to Dr. Agashe – something the authors have also noted. She also observed that using more independent cell populations (the experiments have four) or using media that didn’t encourage microbial growth as much could also shine light on the ways in which minimal cells evolve differently.
Dr. Lennon agreed, saying that they may want to see whether “a minimal cell adapts as easily when maintained in different, perhaps more stressful environments.”
‘Something fundamental about evolution’
Nonetheless, the finding that the evolutionary potential of organisms remains very high despite their distinct evolutionary trajectories is a “very significant contribution to our understanding of microbial evolution,” according to Dr. Pande.
“Scientists learn from simple-case scenarios. We were able to learn something fundamental about evolution and its limits (or lack thereof) by studying a minimal cell,” Dr. Lennon added.
He said that his team’s findings were relevant to synthetic biology, where researchers apply engineering principles to design organisms for applications in medicine and fuel production. “Engineered cells are not static. They evolve. Our study sheds some light on how synthetic organisms might change when confronted by the inevitable forces of evolution,” he said.
Dr Agashe agreed. She noted the importance of minimal cells in synthetic biology since the large genomes of normal bacterial cells can interfere with the cell’s ability to do what it was designed for. From that perspective, “it is good to understand the minimal cell more, and to know that you can evolve those synthetic cells in interesting ways,” she said.
“I do feel that it is going to lead to a lot of interesting work in future.”
Sneha Khedkar is a biologist-turned freelance science journalist based out of Bengaluru.
