It is a
major challenge for scientists to distinguish between harmless genetic variants
and those that are potentially hazardous to our health.
A new technique to cheaply and rapidly create myriad sets
of DNA fragments that detail all possible genetic variants in a
particular stretch of DNA has been developed by researchers at Washington University School of Medicine in St. Louis.
‘A new technique to cheaply and rapidly create myriad sets of DNA fragments that detail all possible genetic variants in a particular stretch of DNA has been developed by researchers’
By studying such DNA fragments, scientists
can more easily distinguish between genetic variants linked to disease
and those that are innocuous.
The findings, published in
, allow researchers to create sets of DNA variants in a
single day for a few hundred dollars. Current methods take up to a week
and cost tens of thousands of dollars.
"As a pediatric neurologist
who does a lot of genetic studies of kids with developmental
disabilities, I frequently will scan a patient's whole genome for
genetic variants," said Christina Gurnett, the study's senior
author and an associate professor of neurology and of pediatrics.
"Sometimes I'll find a known variant that causes a particular disease,
but more often than not I find genetic variants that no one's ever seen
before, and those results are very hard to interpret."
past, scientists tested the effect of genetic variants one by one, a
laborious process. At a single point in the DNA sequence, they replaced
the correct DNA letter - an A, T, C or G - with one of the other three
options. Then, they translated that DNA sequence into a protein and
evaluated whether the mutated protein behaved differently than the
More recently, researchers have begun creating sets
of hundreds of variants in which each letter in a particular DNA
sequence is changed, and then testing the set all at once. Such studies
have been limited, however, by the high cost of creating those sets.
Postdoctoral researcher Gabriel Haller, who was working in Gurnett's lab,
realized that he could harness common laboratory techniques and tools to
create sets of DNA variants without the expensive equipment and
reagents that drove up the price.
Haller copied a DNA sequence
using the four standard DNA letters and a nonstandard letter known as
inosine. Each copy of the sequence was identical except for one inosine,
which was located at a random spot and served as a placeholder. Then,
he replaced the inosine with one of the standard DNA letters, creating a
single mutation in each copy of the sequence.
colleagues are applying this technique to genes associated with aortic
aneurysms, a weakening and ballooning of the aortic wall that can be
fatal. Over the long term, Gurnett envisions the creation of a catalog
listing the effects of every possible variant. The speed and cheapness
of the new technique make such a catalog possible.
clinicians find a variant that's never been seen before in one of these
genes associated with aortic aneurysm, they can go through this catalog
and say, 'Yes, this mutation does have a negative effect on that
protein, so it's likely harmful'," Gurnett said. "It would help them
decide what to tell the patient. This would be one piece of the big
interpretation puzzle for genetic mutations."