CSUN Team Finds ‘Blips’ that Scientists need to Keep in Mind as They Study DNA

Scientists have been studying DNA – the molecules that carry the genetic instructions used in growth, development, function and reproduction of all living organisms and many viruses – for decades.

Hendrik Postma

Henk Postma

California State University, Northridge associate professor of physics Henk Postma and team of researchers at CSUN have been studying the way scientists examine DNA molecules — by passing a strand of DNA through microscopic gaps in a material called graphene — and these new CSUN findings could have implications on future research. Postma and his team found that serrated edges in the graphene gaps could change the way DNA passes through those holes.

“As we try to get closer in identifying how to treat ailments and identify their origins, this is important,” Postma said.  “Knowing what we now know can open doors to better understanding what we are looking at when we are studying DNA sequences.”

Postma headed a team of researchers that included Mark Raul, a mechanical engineering professor at Virginia Polytechnic Institute and CSUN graduate students Hiral N. Patel, Ian Carroll, Rodolfo Lopez, Jr., and Sandeep Sanakararaman, undergraduate Charles Etienne and Subba Ramaiah Kodigala, a former laboratory technition for Postma who is now a researcher at the University of Nevada. They published their results earlier this month in the Public Library of Science (PLoS) ONE journal,  a peer-reviewed open access scientific journal.

Postma explained that when scientists study a DNA sequence — or a strand of DNA — they are trying to understand the order of the chemical building blocks that make up a DNA molecule. During the process, an assumption is made that DNA molecules taken from the same specimen are all alike.

“But that can be tricky,” Postma said, “because not all DNA molecules may be alike in the same sample. Further, you may not have enough material to do a reliable statistical study.”

Postma and his team tried to come up with a way to help scientists notice the differences between molecule by focusing on single-molecule sequencing, and in the process improve the way DNA molecules are examined.

When scientists worked on the DNA of the human genome in the 1990s, Postma said, the DNA molecules were chopped up in little pieces with a size called the “read length,” and they were distributed to researchers around the world to analyze.

“At the time, an assumption was made that there would be some overlap in their sequencing work,” Postma said. “So, they [the researchers] just lined [the results] up using computer software, figuring it out like with a jigsaw puzzle.”

The problem with that, he said, is that it only works “if your sequence is varying on a scale of the read length. You can’t have stuff that is repeating.”

Referring back to his jigsaw analogy, Postma explained that “imagine you’re putting together a jigsaw puzzle and the image is a mountain against a clear blue sky.”

“Now, you will have a really hard time putting together the sky because you cannot figure out how the pieces fit together because they are all featureless blue,” he said. “If the pieces were bigger, you would see the mountain’s edge on it, and you could put it together easily. Moreover, most of the time, you will find more pieces than you need to put the puzzle together, so you also do not know how large the entire puzzle is.”

The answers, for example, to some health questions cannot be found if you never look at the parts of the genome that have may repeats in them, Postma said.

“It’s like blue sky part of the puzzle,” he explained. “It may not appear so, but it is biologically relevant.”

The way to get to the problematic parts is to give scientists access to longer read lengths of DNA, he said.

Scientists would like to use graphene — a material made from honeycomb sheets of carbon just one atom thick — to examine DNA. As a DNA molecule passes through a tiny hole in the graphene, it interrupts currents of electrically charged particles — ions.  The data collected from these “blips,” as Postma called them, is registered as electronic waves on a computer, providing scientists with valuable information about the DNA molecule.

Postma and his team saw these signals looked different than what was expected. They wondered if this could be because the graphene holes, which are microscopic in size, were not cleanly cut — but serrated.

“The length of these events [passing through the holes of the graphene], then varies depending on where the molecule has to squeeze through the gap,” Postma said.

In some instances — when the holes were particularly small — the molecule would pull the edges with it as it passed through. Once the molecule was clear, the graphene edge would retract to its original position, but at an unusually slow rate.

“It took us a long time to figure this out because the recovery [of the graphene from the molecule passing through the hole ] is very slow, and not what you would expect,” Postma said.  “We realized that these molecules interact quite a lot with the edge of the graphene.”

What they discovered could have implications as equipment is developed to take DNA research becomes more precise.

“If you are going to build a super device to do DNA sequencing, you have to take this into account — the fact that the edges of the graphene may slow the molecule down or speed them up or may be deformed by the passing DNA molecule,” Postma said. “That is something that scientists are going to have to keep in mind when they do experiments.”

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