Genetic Deviation Called ‘Extraordinary’ Discovery
Researchers have discovered an unprecedented and unsuspected deviation from one of the fundamental dogmas of molecular biology: that all genetic information is contained in deoxyribonucleic acid (DNA) and that this information is faithfully copied in the production of proteins and other cellular components.
The discovery may trigger a fundamental rethinking of mechanisms by which genetic information is converted into living organisms.
In a family of parasites called kinetoplastids that cause widespread tropical diseases, such as Chagas’ disease and sleeping sickness, the DNA blueprint for at least five proteins important in cellular activity is garbled and unusable, researchers from UCLA and the University of Washington report in the most recent issue of the journal Cell.
But some unknown mechanisms in the cell substantially alter copies of this genetic information, by as much as 60% in two cases, and produce functional proteins. “It’s like my sending out garbage in the mail and the post office straightening it out so that it is intelligible to the recipient,” UCLA molecular biologist Clifford Brunk said.
“The phenomenon they have identified is extraordinary . . . absolutely striking,” said molecular biologist Giuseppe Attardi of Caltech. “The excitement is that it could point to the existence of a more primitive method for transmitting information (within cells) and that may operate in other organisms.”
Even in the unlikely case that the new discovery should apply only to kinetoplastids, it will be important because it could lead to new methods to treat many parasitical diseases, said UCLA molecular biologist Larry Simpson, who performed the research, said in a telephone interview. Chagas’ disease alone, a chronic wasting disease, affects more than 30 million people, he noted, and there are no drugs to treat it.
But the implications may be much broader, said his co-author, microbiologist Kenneth Stuart of the University of Washington. Most living organisms, including humans, he said, have in their genetic complement what are known as “pseudogenes”--long strings of DNA that superficially resemble genes, but that are missing certain key segments that are necessary for a gene to function.
Unusual Manner
The pseudogenes, Stuart said, are very similar to the kinetoplastid genes he and Simpson have studied, and it is possible that genetic information in all species could sometimes be processed in this unusual manner.
“Now that we are aware of this (new mechanism), we can look at data in a different way and try to interpret it in terms of this phenomenon,” Simpson said. “This just might open up a new understanding of genetics that could apply to human genetic diseases in the future.”
The new discovery raises a number of intriguing mysteries, including what cellular components carry out the “editing” of the genetic messages and how the process is controlled. But “the big question now is: Where does the (added) genetic information come from?” Simpson said.
The flow of information in cells has always been thought to be unidirectional. DNA is the master blueprint of the cell; it contains all the information necessary to produce a cell and keep it operating.
Cell’s Working Blueprint
For the information in a given gene to be used, it must first be copied from DNA into what is known as messenger ribonucleic acid (mRNA), which serves as the cell’s working blueprints. The sequence of individual chemicals called bases in mRNA tell the cell’s protein-making machinery what amino acids to put in a protein and in what order. Other sequences of bases tell the protein-making machinery when to start or stop.
Geneticists have known for at least 10 years that mRNA can be edited by cellular machinery. Genes in most organisms, for example, contain long nonsense segments called “introns” that must be edited out of mRNA before a functional protein can be produced.
This type of editing is fairly well understood, and the information about which segments to delete is clearly contained in the gene itself. There is even one human gene in which the editing out of a single base in the mRNA causes a new protein to be produced.
But no previously known cases have involved the addition of genetic information to mRNA and never have such wholesale changes been observed, Simpson said. “It doesn’t agree with genetic theory, and this has to be explained,” Simpson said.
New Way to Control Genes
Stuart believes that the phenomenon they have observed may represent an entirely new way to control the expression of genes--that is, to determine when a protein should or should not be produced.
In Trypanosoma brucei, which causes sleeping sickness, he found that the mRNA is edited in the form of the parasite that is carried by the tsetse fly, but is not edited in the form that infects humans. And the proteins resulting from the edited mRNA are, in fact, not needed by the trypanosome in humans and are not present.
Whatever the role of the new phenomenon, both researchers are confident it will be found in other organisms. “I tend to believe in the generality of biological systems,” Simpson said. “Once something occurs in one system, it probably occurs somewhere else.”
