Study reveals how the most common DNA mutation happens

February 1, 2018, The Ohio State University
DNA
DNA double helix. Credit: public domain

Shape-shifters aren't just the stuff of fiction, they're real—and they're inside our DNA.

In the Feb. 1 issue of the journal Nature, researchers describe how two normally mismatched bases in human DNA, guanine and thymine, are able to change shape in order to form an inconspicuous rung on the helical DNA "ladder." This allows them to survive by avoiding the body's natural defenses against genetic mutations.

"When these two bases form a hydrogen bond by accident, at first, they don't fit quite right," explained Zucai Suo, professor of chemistry and biochemistry at The Ohio State University and co-corresponding author of the study. "They stick out along the DNA helix, so normally it's easy for the enzymes that replicate DNA to detect them and fix them. But once in a while, before they can be detected, they change shape. It's almost as if the two bases are able to 'fix' each other, so they can fit like a normal base pair and escape DNA repair mechanisms.

"They're bad guys, but they pretend to be good guys to survive," Suo said.

The discovery provides a foundation for work on other types of DNA mutations, which are responsible for diseases as well as normal aging and even evolution.

The four bases of DNA each have their own size and shape, and are supposed to fit together in just the right way. Adenine (A) is always supposed to pair with thymine (T), and cytosine (C) is always supposed to pair with guanine (G). The two "Watson-Crick" base pairs, A-T and C-G, form the DNA sequences of all life as we know it. However, if G were to somehow mispair with T, for example, that would be a mutation.

In fact, the G-T mutation is the single most common mutation in human DNA. It occurs about once in every 10,000 to 100,000 base pairs—which doesn't sound like a lot, until you consider that the human genome contains 3 billion base pairs.

Researchers would like to understand how happen in order to better understand a myriad of diseases, including cancer, that are caused by them. This work provides an important piece of information that researchers can use moving forward in this effort.

Though scientists had long speculated that the G-T mispair shape-shifted in order to resemble a normal G-C or A-T pair, this phenomenon had not been directly observed until Duke University biochemists, led by Hashim M. Al-Hashimi, used a form of nuclear magnetic resonance imaging to reveal that these Watson-Crick-like G-T mispairs form in so-called "naked" DNA.

Still, the question remained of just how G-T mispairs come to exist. That's why Al-Hashimi contacted Suo at Ohio State, and asked him to help pin down the biochemical mechanism that was responsible.

"An interesting question is: What determines the mutation rate in a living organism," Al-Hashimi said. "From there, we can begin to understand the specific conditions or environmental stressors that can elevate errors."

Suo and doctoral student Walter Zahurancik used a DNA polymerase, an enzyme that replicates DNA, to insert a G-T mispair into a DNA strand. By stopping the chemical reaction at different times and analyzing the resulting DNA molecules, they were able to measure how efficiently the polymerase could form the G-T mispair.

Together, Al-Hashimi and Suo determined that the G and T bases would pair, but in a misshapen way that stuck out from the DNA helix. Then, in a fraction of a second, the bases would re-arrange their chemical bonds so that they could "snap" into the shape of a normal base pair and fool the polymerase into completing the chemical reaction.

In short, they perform a masquerade that enzymes are less likely to detect during DNA replication and repair.

The mutation's survival is a real feat, since it has to overcome a good bit of basic physics. Bases pair in a certain way because of how the protons and electrons in their atoms are arranged. Base pairing requires some amount of energy, and the easiest, most energy-efficient pairs to form are the "right" ones—A-T and C-G.

In effect, the G-T pair has to overcome an energy barrier to form and maintain itself. It turns out that when the G and T bases change shape, they make themselves more energy efficient—still less efficient than a normal base pair, but efficient enough.

Next, the researchers will try to replicate the experiments with another, somewhat less common mutation, the A-C mispair.

More information: Isaac J. Kimsey et al, Dynamic basis for dG•dT misincorporation via tautomerization and ionization, Nature (2018). DOI: 10.1038/nature25487

Related Stories

Recommended for you

Identifying Crohn's disease risk factors in the Ashkenazi Jewish population

May 25, 2018
It is estimated that one in three individuals of Ashkenazi Jewish (AJ) descent carry mutations that increase their risk for certain genetic diseases. For instance, Crohn's, a highly heritable inflammatory bowel disease, is ...

How do insects survive on a sugary diet?

May 25, 2018
There's a reason parents tell their kids to lay off the sugar: too much isn't good for you.

Regulatory mutations missed in standard genetic screening lead to congenital diseases

May 25, 2018
Researchers have identified a type of genetic aberration to be the cause of certain neurodevelopmental disorders and congenital diseases, such as autism and congenital heart disease, which are undetectable by conventional ...

New chromosome study can lead to personalised counselling of pregnant women

May 25, 2018
Foetuses with a so-called new balanced chromosomal aberration have a higher risk of developing brain disorders such as autism and mental retardation than previously anticipated. The risk is 20 per cent for foetuses with these ...

New findings on autism-related disorder

May 24, 2018
In a study published today in Nature, Marc Bühler and his group at the Friedrich Miescher Institute for Biomedical Research (FMI) have taken a major step forward in elucidating the mechanisms underlying a disorder known ...

Genome study presents new way to track historical demographics of US populations

May 24, 2018
Sharon Browning of the University of Washington and colleagues developed a method to estimate historical effective population size, which is the number of individuals who pass on their genes to the next generation, to reveal ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

katesisco
1 / 5 (2) Feb 01, 2018
But isn't our history one of successful mutations instead of the ballyhooed 'evolution.?'

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.