What are the effects of switching off the proofreading function in the reproduction of genetic information?

New study by the Institute of Virology published in "Nature Microbiology"

No 249/2019 from Sep 03, 2019

Researchers from the Institute of Virology at Freie Universität Berlin have studied the effects of switching off the proofreading function of what are known as DNA polymerases - enzymes involved in reproducing genetic information. The research team headed by Professor Klaus Osterrieder pursued this question as part of their work on the genetic variability of herpesviruses. In viruses without a proofreading function, more errors initially occurred during copying of genetic information, as the research team expected, and the viruses were significantly weaker. Under certain conditions, however, error-prone viruses were able to establish highly diverse virus populations that were able to multiply without restrictions in cell cultures in a lab setting. These populations also showed increased ability to trigger disease. The researchers hope that their DNA virus model will yield new findings on the applicability of the disputed quasispecies theory and thus contribute to answering key questions surrounding virus evolution.

Ever since Charles Darwin’s discoveries concerning how species arise through natural selection, it has been taken as a certainty that over the course of evolution, the "fittest" individuals are selected from within populations and the standard phenotype for a given species forms around that of the fittest individuals over time. But for any kind of selection to occur, there must be a certain diversity among individuals.

These differences, in turn, stem from genetic variability, which is the basis for all evolutionary activity. Genetic variability arises due to copying errors in genome replication. Without errors, there is no variability, and without variability, there is no change. At the same time, the genetic information stored in nucleic acids is the most valuable information in any organism, and changes that are too dramatic can jeopardize it.

Over the course of evolution, organisms have developed enzymes for reproducing genetic information, known as DNA polymerases. These enzymes perform a proofreading function, which allows them to sharply reduce the number of copying errors (mutations) that occur during genome replication. The few errors that arise despite this guarantee a certain level of variability, and they form the necessary basis for later selection; the fact that there are only a few of them guarantees the necessary stability in the information, even over generations.

After observing that switching off the proofreading function of DNA polymerases in herpesviruses can lead to highly diverse virus populations under certain conditions, the research team analyzed the genes of these populations. "The genetic analyses indicate that this behavior is probably not triggered by individual, especially fit viruses within the diverse population. Instead, it may trace back to cooperative behavior by the population as a whole," explains Klaus Osterrieder, a professor of virology. "This kind of behavior in which diverse populations consisting of individuals that are not especially fit can be superior to uniform populations of highly fit individuals has been postulated for RNA viruses for a long time, and it is described in what is known as quasispecies theory."

RNA viruses are the only known organisms that naturally replicate their genetic material without a proofreading function, producing very high error rates as a result. "The quasispecies theory is disputed among virologists and geneticists," Osterrieder says. "This theory requires that we overthrow a central dogma in evolutionary theory: If it isn’t possible to select fit individuals, the selection has to occur differently, in this case at the level of the population, or the ’ensemble,’ with the result that ultimately, successful cooperatives can win out over successful individuals." The researchers from the Institute of Virology at Freie Universität Berlin hope that their DNA virus model will help clear up this key question surrounding the evolution of viruses in the future.