New benchmark could improve detection of genetic variants linked to
spinal muscular atrophy, other diseases

Date:
February 7, 2022
Source:
National Institute of Standards and Technology (NIST)
Summary:
The stretches of DNA that differ from person to person, called
variants, are a major part of what makes us unique, but they can
also put us at greater risk of disease. Although we can currently
spell out between 80% and 90% of the millions that are in the
human genome, the remaining variants may hold clues for treating
an array of diseases. Today the list of variants yet to be decoded
has shrunk sizably. A team led by researchers at the National
Institute of Standards and Technology (NIST), Baylor College of
Medicine and DNAnexus has characterized over 20,000 variants in 273
genes of medical importance. In a study published in the journal
Nature Biotechnology, the researchers applied both cutting-edge
and long-standing DNA sequencing methods to decipher the genetic
codes of the variants with a high degree of certainty.



FULL STORY ==========================================================================
The stretches of DNA that differ from person to person, called variants,
are a major part of what makes us unique, but they can also put us at
greater risk of disease. Although we can currently spell out between 80%
and 90% of the millions that are in the human genome, the remaining
variants may hold clues for treating an array of diseases. Today the
list of variants yet to be decoded has shrunk sizably.


==========================================================================
A team led by researchers at the National Institute of Standards
and Technology (NIST), Baylor College of Medicine and DNAnexus has characterized over 20,000 variants in 273 genes of medical importance. In
a study published in the journal Nature Biotechnology, the researchers
applied both cutting-edge and long-standing DNA sequencing methods
to decipher the genetic codes of the variants with a high degree of
certainty. Using their results, they formulated benchmarks that will help
labs and clinics sequence the genes more accurately, which is critical
for gaining a better understanding of a host of diseases and eventually developing treatments.

"Some of these genes, which have previously been very difficult to
access, are suspected to have some connection to disease. Others
have very clear clinical importance," said NIST biomedical engineer
Justin Zook, a co-author of the study. "SMN1, for example, is a gene we characterized that is directly associated with spinal muscular atrophy,
a rare but severe condition." The new benchmark is the latest produced
by the Genome in a Bottle (GIAB) consortium, a NIST-hosted collaborative
effort aimed at improving DNA sequencing technologies and making them
practical for clinical application.

These benchmarks are highly accurate sequences of DNA that clinics and
research labs can use as a kind of answer key when testing their own
sequencing methods.

By sequencing the same genome used to develop a benchmark and then
comparing their result to the benchmark itself, they could learn how
well they can detect certain variants.

Over the years, producing benchmarks for some regions of the genome
has proved much more difficult than others. There are several reasons,
many of which are tied to the general approach people use to sequence DNA.



========================================================================== Rather than sequencing entire genomes in one go, DNA sequencing
technologies read out sequences of small fractions of DNA first, and
then attempt to place them together correctly, similar to a puzzle
set. Reference genomes, the first of which was completed by the Human
Genome Project, are nearly full genomes, stitched together from several people's DNA, that serve as guides for where to place the puzzle pieces.

Since we share close to 99.9% of our genetic makeup as a species, any
human genome will have mostly the same code as the reference genome. This
means putting together a genome is a matter of laying out the pieces
based on where they match up with the reference. Most variants fall in
line using this process. Certain types throw a wrench into it.

In particular, a type called a structural variant can create large
differences between a genome and a reference genome. They range from 50
up to thousands of letters, or bases, and take many forms, including
inserted, deleted or rearranged code. The more distinct a genome is
from the reference, the harder it is to use the reference as a guide,
Zook said.

Structural variants could cause labs to unintentionally misplace chunks
of DNA, and, in a clinical setting, that sort of error may cause a disease-linked variant to evade detection or a harmless variant to create alarm. On top of the human costs, treatments prescribed needlessly or
too late due to these mismeasurements could establish the need for more expensive or invasive treatments for patients down the road, driving up
health care costs drastically.

However, recent advances in sequencing technology have cleared some of
these obstacles. In the new study, the GIAB consortium applied the latest technology to decode some of the most elusive regions of the human genome
with either a known or suspected connection to diseases.



==========================================================================
A key player in the effort was high fidelity, or HiFi, sequencing, which
can sequence longer stretches of DNA. Common DNA sequencing methods can
read about a hundred bases, but with HiFi sequencing, you can accurately
read tens of thousands at a time, Zook said.

"Instead of having a thousand-piece puzzle, where you have these little,
tiny pieces that you have to put together, it's more like having a hundred-piece puzzle where you have bigger pieces that you can put
together," Zook said.

The team specifically employed HiFi with hifiasm, a state-of-the-art
software tool that simultaneously solves another issue that has hampered
DNA sequencing.

Rather than reading both copies of an individual's chromosomes (one from mother, the other from father), previous methods sequenced an amalgamation
of both, causing them to create errors and miss important details unique
to each copy.

With hifiasm, the researchers could independently spell out the separate
copies of a person's genome. In the case of this study, the genome was
from a single person, designated HG002, who had consented to publicizing
their genetic code through the Personal Genome Project.

The authors used these technologies in addition to previously established methods, leveraging the strengths of each at once. In the end, their
approach allowed them to unearth the sequences of more than 20,000
variants -- including dozens of the difficult-to-assess structural
variants -- across 273 genes, and did so with higher accuracy than could
be achieved just using a single method.

In addition to spinal muscular atrophy, the researchers characterized
variants in genes connected to heart disease, diabetes, celiac disease
and many other conditions.

The team also unexpectedly encountered errors in the two reference
genomes they were using. Some could cause sequencing methods to misread
genes that cause serious conditions, including homocystinuria, which is associated with skeletal, cardiovascular and nervous system disorders
and is usually detected through newborn screening, Zook said. With
their newly benchmarked variants, the authors proposed corrections to
the reference genomes they used.

The benchmarks themselves are now publicly available for labs to put
to good use. To do so, interested researchers or clinicians would first
need to sequence HG002 samples, which can be accessed through the NIST
Office of Reference Materials, and then check their results against
the benchmarks.

The study marks a significant step in the GIAB consortium's ongoing
journey to improve the accuracy of DNA sequencing. But with thousands
of important genes left to characterize containing variants that are
difficult to pin down, the researchers aim to trudge on, applying the
latest and greatest technologies as they become available.

========================================================================== Story Source: Materials provided by National_Institute_of_Standards_and_Technology_(NIST).

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Wagner, J., Olson, N.D., Harris, L. et al. Curated variation
benchmarks
for challenging medically relevant autosomal genes. Nat Biotechnol,
2022 DOI: 10.1038/s41587-021-01158-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220207112630.htm

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