We know from decades of biological study that all living
beings share many similar genes. We also know that these genes are subject to
evolution, from mutations that change the DNA sequence of an organism’s
offspring, or through horizontal gene transfer (HGT), the acquisition of DNA
from a creature other than a parent, and even of a different species.
This got a team of bioengineers at UC San Diego wondering:
could a human gene function in other organisms? And if it does function, what
evolutionary changes are happening to the DNA to allow it to work properly in a
new host species?
Bioengineers in Professor Bernhard Palsson’s Systems BiologyResearch Group used genetic engineering and laboratory evolution to test the
functionality of DNA placed into a new species and study how it can mutate to
become functional if given sufficient evolutionary time. They published their
results on August 10 in Nature Ecology and Evolution.
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| Schematic of the experimental workflow. Native E. coli glycolytic isomerases pgi and tpiA were replaced with the coding sequence of foreign orthologues and subjected to laboratory evolution for improved exponential phase growth rate. Ma, million years ago. |
The two genes used—pgi and tpiA-- cripple E. coli when
removed, causing the bacteria to grow about 5 times slower. Initially,
following the gene swap, E. coli’s growth rate did drop, signaling that the
genes weren’t functioning properly. But then, the researchers subjected the
transformed E. coli strain to a laboratory “evolution machine”—a robotic system
used to study how engineered bacteria adapt to changes. After thousands of
generations of evolution, the new genes started to function properly. The human
genes could serve just the same function in the bacterium as its own genes.
The automated evolution system enabled a large-scale study,
generating hundreds of mutant strains evolved for more than 50,000 cumulative
generations, something that would take decades rather than months if performed
manually.
How was it possible that the human genes were fulfilling the
same role in E.coli? The researchers
sequenced the genomes of the evolved strains to find out.
For every strain that successfully evolved, the critical
factor was one or more mutations increasing gene expression level. Most of
these mutations did not occur within the foreign gene, but rather in regions of
E. coli’s DNA controlling regulation of the gene, with their nature depending
sensitively on the gene’s specific DNA sequence and location in the chromosome.
Some of these mutations occurred with shocking regularity, including one
observed independently more than 20 times, demonstrating that evolutionary
outcomes can be (probabilistically) predicted to the single DNA basepair.
“This result shows the importance of systems biology,” said
Professor Bernhard Palsson, principal investigator of the study. “Namely, biological
function, in this case, is not so much about the parts of the cell, but how
they come together to function as a system.”
The original motivation for the study was to determine
’self’ versus ’non-self’ at the molecular biology level. The surprising answer
is that even if human enzymes are foreign entities to the E. coli bacterium,
they are not recognized as such, and the bacterium adopts their function by
simply adjusting their abundance to achieve balanced phenotypic state.
This study establishes the influence of various DNA and
protein features on cross-species genetic interchangeability and evolutionary
outcomes, with implications for both natural horizontal gene transfer and
strain design via genetic engineering.
