Scientists make leap forward for genetic sequencing
Research to lead to improved personalized medicine and understanding of evolution

Date:
March 11, 2022
Source:
University of California - Irvine
Summary:
Researchers reveal new details about a key enzyme that makes
DNA sequencing possible. The finding is a leap forward into the
era of personalized medicine when doctors will be able to design
treatments based on the genomes of individual patients.



FULL STORY ==========================================================================
In a paper published today in Sciences Advances, researchers in the
Department of Chemistry and the Department of Physics & Astronomy at the University of California, Irvinerevealed new details about a key enzyme
that makes DNA sequencing possible. The finding is a leap forward into
the era of personalized medicine when doctors will be able to design
treatments based on the genomes of individual patients.


========================================================================== "Enzymes make life possible by catalyzing chemical transformations
that otherwise would just take too long for an organism," said Greg
Weiss, UCI professor of chemistry and a co-corresponding author of the
new study. "One of the transformations we're really interested in is
essential for all life on the planet -- it's the process by which DNA
is copied and repaired." The molecule the UCI-led team studied is an
enzyme called Taq, a name derived from the microorganism it was first discovered in, Thermos aquaticus. The molecule the UCI-led team studied
is an enzyme called Taq, a name derived from the microorganism it was
first discovered in, Thermos aquaticus. Taq replicates DNA. Polymerase
chain reaction, the technique with thousands of uses from forensics to
PCR tests to detect COVID-19, takes advantage of Taq.

The UCI-led team found that Taq, as it helps make new copies of DNA,
behaves completely unlike what scientists previously thought. Instead
of behaving like a well-oiled, efficient machine continuously churning
out DNA copies, the enzyme, Weiss explained, acts like an indiscriminate shopper who cruises the aisles of a store, throwing everything they see
into the shopping cart.

"Instead of carefully selecting each piece to add to the DNA chain, the
enzyme grabs dozens of misfits for each piece added successfully," said
Weiss. "Like a shopper checking items off a shopping list, the enzyme
tests each part against the DNA sequence it's trying to replicate."
It's well-known that Taq rejects any wrong items that land into its
proverbial shopping cart -- that rejection is the key, after all, to successfully duplicating a DNA sequence. What's surprising in the new work
is just how frequently Taq rejects correct bases. "It's the equivalent
of a shopper grabbing half a dozen identical cans of tomatoes, putting
them in the cart, and testing all of them when only one can is needed."
The take-home message: Taq is much, much less efficient at doing its
job than it could be.



==========================================================================
The find is a leap toward revolutionizing medical care, explained Philip Collins, a professor in the UCI Department of Physics & Astronomy who's a
co- corresponding author of the new research. That's because if scientists understand how Taq functions, then they can better understand just how
accurate a person's sequenced genome truly is.

"Every single person has a slightly different genome," said Collins,
"with different mutations in different places. Some of those are
responsible for diseases, and others are responsible for absolutely
nothing. To really get at whether these differences are important or
healthcare -- for properly prescribing medicines -- you need to know
the differences accurately." "Scientists don't know how these enzymes
achieve their accuracy," said Collins, whose lab created the nano-scale
devices for studying Taq's behavior. "How do you guarantee to a patient
that you've accurately sequenced their DNA when it's different from the accepted human genome? Does the patient really have a rare mutation,"
asks Collins, "or did the enzyme simply make a mistake?" "This work
could be used to develop improved versions of Taq that waste less time
while making copies of DNA," Weiss said.

The impacts of the work don't stop at medicine; every scientific field
that relies on accurate DNA sequencing stands to 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've entered the century of genomic data," said Collins. "At the
beginning of the century we unraveled the human genome for the very first
time, and we're starting to understand organisms and species and human
history with this newfound information from genomics, but that genomic information is only useful if it's accurate." Co-authors on this study
include Mackenzie Turvey, Ph.D., a former UCI graduate student in physics
& astronomy, and Kristin Gabriel, Ph.D., a former UCI graduate student
in molecular biology & biochemistry. This research was funded by the
National Human Genome Research Institute of the NIH.

Video: https://youtu.be/96VfOrbGkcw

========================================================================== Story Source: Materials provided by
University_of_California_-_Irvine. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Mackenzie W. Turvey, Kristin N. Gabriel, Wonbae Lee, Jeffrey
J. Taulbee,
Joshua K. Kim, Silu Chen, Calvin J. Lau, Rebecca E. Kattan,
Jenifer T.

Pham, Sudipta Majumdar, Davil Garcia, Gregory A. Weiss, Philip G.

Collins. Single-molecule Taq DNA polymerase dynamics. Science
Advances, 2022; 8 (10) DOI: 10.1126/sciadv.abl3522 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220311182514.htm

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