Research to improve personalized medicine and the understanding of evolution

In an article published today in Scientists progress, researchers from the Department of Chemistry and the Department of Physics and Astronomy at the University of California, Irvine have revealed new details about a key enzyme that makes DNA sequencing possible. The discovery is a leap forward into the era of personalized medicine where doctors will be able to design treatments based on the genomes of individual patients.

“Enzymes make life possible by catalyzing chemical transformations that would otherwise take an organism too long,” said Greg Weiss, UCI professor of chemistry and co-corresponding author of the new study. “One of the transformations that really interests us is essential for all life on the planet – it’s the process by which DNA is copied and repaired.”

The molecule studied by the UCI-led team is an enzyme called Taq, a name derived from the microorganism in which it was first discovered, Aquatic thermos. The molecule studied by the UCI-led team is an enzyme called Taq, a name derived from the microorganism in which it was first discovered, Thermos aquaticus. Taq replicates DNA. Polymerase chain reaction, the technique with thousands of uses ranging from forensics to PCR testing to detect COVID-19, takes advantage of Taq.

The UCI-led team found that Taq, because it helps create new copies of DNA, behaves completely contrary to what scientists previously thought. Instead of behaving like an efficient, well-oiled machine constantly producing copies of DNA, the enzyme, Weiss explained, acts like a blind shopper who roams the aisles of a store, throwing away everything it sees. in the basket.

“Instead of carefully selecting each piece to add to the DNA string, the enzyme catches dozens of misfits for each successfully added piece,” Weiss said. “Like a shopper checks the items on a shopping list, the enzyme tests each part against the DNA sequence it is trying to replicate.”

It’s well known that Taq rejects all the bad stuff that lands in its proverbial shopping cart – that rejection is the key, after all, to successfully duplicating a DNA sequence. What’s surprising about the new work is how often Taq rejects the correct foundation. “It’s the equivalent of a shopper grabbing half a dozen boxes of identical tomatoes, putting them in the cart and testing them all when only one box is needed.”

The take home message: Taq is much, much less efficient at doing its job than it could be.

The finding is a step towards revolutionizing medical care, explained Philip Collins, a professor in the UCI Department of Physics and Astronomy and co-corresponding author of the new research. Indeed, if scientists understand how Taq works, they can better understand just how accurate a person’s sequenced genome really is.

“Each person has a slightly different genome,” Collins said, “with different mutations in different places. Some of them are responsible for disease, and some are responsible for absolutely nothing. To really know if these differences are important or medical — to properly prescribe medications, you need to know the differences accurately.”

“Scientists don’t know how these enzymes achieve their precision,” said Collins, whose lab created the nanoscale devices to study Taq’s behavior. “How can you assure a patient that you have accurately sequenced their DNA when it is different from the accepted human genome? Does the patient really have a rare mutation,” Collins asks, “or the enzyme has Did she just make a mistake?”

“This work could be used to develop improved versions of Taq that waste less time making DNA copies,” Weiss said.

The impacts of work don’t stop at medicine; every field of science that relies on accurate DNA sequencing should benefit from a better understanding of how Taq works. In interpreting evolutionary histories using ancient DNA, for example, scientists rely on assumptions about how DNA changes over time, and those assumptions rely on accurate genetic sequencing.

“We have entered the century of genomic data,” Collins said. “At the turn of the century, we unveiled the human genome for the very first time, and we are beginning to understand organisms, species, and human history with this new information from genomics, but this genomic information is only useful if they are correct.”

Co-authors of this study include Mackenzie Turvey, Ph.D., a former UCI graduate student in physics and astronomy, and Kristin Gabriel, Ph.D., a former UCI graduate student in molecular biology and biochemistry. This research was funded by the National Human Genome Research Institute of the NIH.


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