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University of Utah chemists are refining a method for combing a person's genome in search of DNA damage that leads to mutations and disease. Professors Henry White and Cythnia Burrows are building on the so-called nanopore technique of sequencing DNA in which strands of genetic material are passed through a molecule-sized path, a protein known as a "nanopore."
"My interest in not just sequencing the A, T, C and G [letters corresponding to the basic molecules of DNA] but changes that happen on those bases from mutations," said Burrows. "A certain amount is OK because it gets fixed. That damage is ultimately where disease is caused, especially age-related diseases like cancer."
White, who chairs the U. chemistry department, and Burrows describe their method in a string of recent studies, including one published this week in the prestigious Proceedings of the National Academy of Sciences.
Strands of DNA are made of "nucleotide bases," the building blocks of nucleic acids. Some stretches of DNA strands are genes, which serve as codes that are translated into proteins.
The new mutation-hunting method looks for places where a base is missing — known as an "abasic site" — one of the most frequent lesions in the 3 billion-letter human genome. Such DNA damage happens 18,000 times a day in a typical human cell from exposure to countless irritants, such as sunlight, car exhaust and fast food.
"Over the course of a lifetime not every piece of damage gets repaired. You accumulate those over a lifetime. At some point you have a higher likelihood of one of these disease-causing mutations cropping up," Burrows said. Besides various cancers, other diseases arising from DNA damage include Huntington's and atherosclerosis.
The cost of sequencing a person's genome will soon drop to less than $1,000 and become commonplace, allowing patients greater access to their genetic predisposition to disease and responsiveness to particular treatments. It currently costs about $10,000 and takes at least a week.
Burrow and White's team adapted the nanopore sequencing technique so that it locates damage with the help of electrically charged saline-like liquids. Their method measures changes in the electrical signal as the DNA passes through the nanopore, like thread passing through the eye of a needle.
"It's not hard to detect damage. It's hard to detect where the damage occurs," White said. "We are reading the signal as a function of time. Image there is a kink in the thread. You see a signal for this kink. The time where the signal appears correlates with its position."
The team tested the technique on short strands of synthesized DNA, the longest of which was 100 bases, and has been able to identify one or two damaged sites. The team knew exactly where the damaged sites were and could locate them to within five to 10 bases.
"It's important to know how a damaged base leads to a mutation because that is the first step in a disease occurring. Right now, we can see the damaged site and tell approximately where it is within the piece of DNA we're analyzing," White said. "It's going to get better in a year. We'll get it to one base."
Better precision could be achieved by slowing the DNA's movement through the nanopore, White said, so researchers tried increasing the viscosity of the liquid. But that dampened the already faint electrical signal.
"We've still got to do a lot of research and come up with ways of improving this," White said. "It's a very promising and new way of doing it."
The U. is seeking a patent on the technique. Co-authors on the PNAS study are doctoral candidate Na An and Aaron Fleming, a postdoctoral research associate. The National Institutes of Health funded the study.