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Scripps Research scientists and their collaborators have created microorganisms that can summarize the main features of organisms thought to have lived billions of years ago, allowing them to explore questions about how life has evolved from inanimate molecules to monocellular organisms into complex and multicellular life forms. see today.
By studying one of these modified organisms – a bacterium whose genome is composed of both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) -, scientists hope to shed light on the early evolution of genetic material, including the theorized transition from a world where life depended solely on the genetic RNA molecule, with DNA constituting the main storehouse of genetic information.
By using a second organism, a genetically modified yeast containing an endosymbiotic bacterium, they hope to better understand the origin of the cell called mitochondria. Mitochondria provide essential energy for eukaryotic cells, a large group of organisms – including humans – with complex cells containing nuclei.
The researchers reported the engineering of microbes in two articles, one published on October 29, 2018 in Proceedings of the National Academy of Sciences (PNAS) and another one published on August 30, 2018 in Journal of the American Chemical Society (JACS).
"These modified organisms will allow us to probe two key theories on the major stages of the evolution of living organisms: the transition from the world of RNA to the world of DNA and the transition from prokaryotes to eukaryotes with mitochondria", said Peter Schultz, senior author papers and president of Scripps Research. "Access to easily manipulated laboratory models allows us to search for answers to questions about early, previously insoluble evolutions."
The origins of life on Earth have fascinated humans for millennia. Scientists have traced the arc of life for billions of years and concluded that the simplest forms of life emerged from the Earth's primordial chemical soup and then evolved over the centuries into more and more organisms. more complex.
The emergence of DNA, a molecule that stores all the information necessary for the replication of life, encourages cellular machines to meet their needs by producing mainly RNA, which in turn directs protein synthesis, the molecular parents of the cells.
In the 1960s, Carl Woese and Leslie Orgel, as well as the pioneer of DNA, Francis Crick, proposed that before, organisms depended on RNA for transmitting genetic information, a molecule similar but much less stable than DNA, which can also catalyze chemical reactions such as proteins. .
"In science class, students learn that DNA leads to RNA, which in turn leads to proteins – it's a central dogma of biology – but the hypothesis of RNA world reverses this idea, "said Angad Mehta, first author of the Postdoctoral Research Associate at Scripps Research. "In order for the RNA world hypothesis to be true, one has to go from RNA to a DNA genome, but the way it could have happened is still a very strong one. big question for scientists. "
One possibility is that the transition goes through some kind of microbial missing link, an organism being replicated that stores genetic information in the form of RNA.
For the JACS study, the team led by Scripps Research created Escherichia coli bacteria that partially build their DNA with ribonucleotides, the molecular building blocks typically used to build RNA. These modified genomes contained up to 50% RNA, thus simultaneously representing a new type of synthetic organism and perhaps a backtracking back billions of years ago.
Mehta warns that their work so far has focused on the characterization of this chimeric DNA-RNA genome and its effect on bacterial growth and replication, but have not explicitly explored transitional issues. from the world of RNA to the world of DNA. But the fact that E. coli with half of its genome consisting of RNA can survive and replicate is remarkable and seems to support the possibility of the existence of organisms in evolutionary transition possessing RNA-DNA hybrid genomes.
The Scripps research team is currently studying how the mixed genomes of their E. coli function and plans to use bacteria to explore a number of evolutionary issues.
For example, one question is whether the presence of RNA leads to rapid genetic drift – large changes in the gene sequence in a population over time. Scientists assume that massive genetic drift occurred early in the evolutionary stage and that the presence of RNA in the genome may help explain how quickly genetic change occurs. 39 is produced.
In the paper published in PNAS, researchers report engineering another laboratory model for an evolutionary milestone that would have occurred more than 1.5 billion years ago. They have created a yeast whose energy depends on the bacteria that live there and which constitutes a beneficial parasite or "endosymbionte". This composite organism will allow them to study the ancient origins of mitochondria – tiny organelles similar to bacteria that produce chemical energy in higher organism cells.
Mitochondria are generally thought to have evolved from ordinary bacteria captured by larger unicellular organisms. They fulfill several key functions in the cells. Most importantly, they serve as oxygen reactors, using O2 to make the basic unit of the chemical energy of cells, the molecule ATP.
As crucial as mitochondria are to cells, their origins remain somewhat mysterious, although there is clear allusion to the offspring of a more independent organism, widely regarded as a bacterium.
Mitochondria have a double membrane structure like some bacteria and, again like bacteria, contain their own DNA. The mitochondrial genome analyzes suggest that it shares an old ancestor with the rickettsia bacteria, which can live in the cells of their hosts and cause disease. Stronger support for the bacterial origin of the mitochondrial theory would come from experiments showing that independent bacteria could actually be transformed, in a progression similar to that of evolution, into symbiots analogous to those mitochondria.
To this end, scientists at Scripps Research have developed E. coli bacteria that could live in, depend on and provide essential assistance to the cells of Saccharomyces cerevisiae, also known as baker's yeast.
The researchers began by modifying E. coli lack of the gene encoding thiamine, making bacteria dependent on yeast cells for this essential vitamin. At the same time, they added to the bacterium a gene for ADP / ATP translocase, a transporter protein, so that ATP produced in bacterial cells would be delivered to their yeast cell hosts, mimicking central function real mitochondria.
The team also modified the yeast so that their own mitochondria do not provide enough ATP. Thus, the yeast depends on the bacterium for a normal production of mitochondrial ATP.
The team discovered that some of the modified bacteria, after being modified with surface proteins to protect them from yeast, lived and proliferated in harmony with their hosts for over 40 generations and appeared to be viable indefinitely.
"The modified bacteria seem to accumulate new mutations within the yeast to better adapt to their new environment," said Lubica Supekova, co-first author of the publication. PNAS paper and a scientist at Scripps Research.
With this system in place, the team will try to evolve the E. coli become organelles resembling the mitochondria. For the new E. coli endosymbionte, adapting to life inside the yeast could allow him to lose weight radically his genome. A typical E. coli The bacterium, for example, has several thousand genes, while the mitochondrion has only changed to 37.
The Scripps research team completed the study with further gene subtraction experiments. The results were promising: they discovered that they could eliminate not only the E. coli the thiamine gene, but also the genes underlying the production of the metabolic molecule NAD and serine, an amino acid, and still obtain a viable symbiosis.
"We are now on the right track to show that we can remove the genes for making the 20 amino acids, which are an important part of the E. coli genome, "said Schultz." Once we reach this goal, we will remove genes for cofactor and nucleotide synthesis, and we hope to have a truly minimal endosymbiotic genome in a few years. "
The researchers also hope to use similar endosymbionte-host systems to study other important episodes of evolution, such as the origin of chloroplasts, light-absorbing organelles playing a role similar to that of mitochondria in the supply of energy to plants.
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