www.clinicalomics.com November/December 2017 Clinical OMICs 31
CombiMatrix Presents
Data from Genomic
Abnormalities Study
CombiMatrix has presented new data
from a first-of-its kind study showing
that genomic alterations decrease in
frequency and severity from conception
through development into childhood.
The study—which analyzed nearly 32,000
samples—was intended to provide a
comprehensive assessment of chromo-
somal imbalances and their adverse
impact upon human growth and devel-
opment from conception to childhood.
" These results support the impor-
tance of genomic testing for different
abnormalities that may occur at distinct
development stages," CombiMatrix Pres-
ident and CEO Mark McDonough said in
a statement. "We now have even more
compelling evidence of the importance
of the genetic information produced
from this testing from preconception
through early childhood."
Among key findings of the study:
• Embryo or early pregnancy loss sam-
ples showed the highest abnormality
rates and a predictable correlation
between the severity of chromosomal
abnormalities, primarily aneuploid-
ies, with unsuccessful implantation
or progression to viable pregnancy.
• Prenatal and neonatal samples
showed that the frequency of signif-
icant genomic alterations correlated
with the incidence of significant
physical and developmental abnor-
malities, but were not necessarily
incompatible with life.
• Pediatric samples were predomi-
nantly deletions and duplications
rather than aneuploidy and had less
drastic adverse effects.
ciated variants previously identified
by genome-wide association studies
(GWAS) overlapped with eQTLs.
According to Stephen Montgomery,
a Stanford University professor and
GTEx investigator, this suggests there
are expression mechanisms under-
lying those trait associations. "That
actually gives us quite a lot of infor-
mation to move forward with about
what molecular mechanisms underlie
complex diseases," he added.
In another analysis, researchers
examined how rare variants, which
may play an important role in deter-
mining individual disease risk,
impacted gene expression. By pin-
pointing outliers—genes that were
expressed at extremely high or low
levels—in the GTEx dataset, the team
discovered that these outliers were
more likely to have a rare variant
nearby than their counterparts.
A Global Resource
The consortium has made their data
publically available for research-
ers to access. This catalogue of raw
and unprocessed data is a "fantastic
resource for the research community,"
Ward said. The group is also maintain-
ing a biobank of the analysed tissue
samples.
However, the atlas does have its
limitations. For example, Brown
pointed out, the group analyzed het-
erogeneous tissues, rather than single
cells. "I think the next big leap will be
true cellular-level resolution," he said.
Another limitation, according to
Ward, is that "while this dataset pro-
vides insight into the associations
between genetic variants and gene
expression, I think more work is
needed to determine the causality."
One way scientists could do this, she
noted, is by using techniques like
CRISPR/Cas9 gene editing.
The release of the next version of the
GTEx atlas, which researchers expect
to publish sometime next year, will
more than double the sample size,
Brown said. This will allow research-
ers to address some questions that are
difficult to probe with the currently
available sample. Brown, for one, is
interested in examining more of the
trans-QTLs.
In addition to analyzing tissues
from more patients, some of the mem-
bers of the consortium are working
on characterizing additional factors,
such as DNA methylation, protein
abundance, alternative splicing, and
telomere length, by applying diverse
molecular assays to the available sam-
ples. This effort, dubbed "Enhancing
GTEx," will publish analyses associ-
ated with their data over the next two
years, according to Montgomery.
Ultimately, pooling all this infor-
mation could help benefit person-
alized medicine, "It could be in the
future that you go and you have your
genome taken, but you might get your
blood transcriptome, your metabo-
lome, your proteome—all these other
types of data," he added. "So if we build
the [analytical] infrastructure now, we
should get better predictions for indi-
viduals about genetic risk factors."
"All biomedical researchers should
welcome the wealth of data that con-
tinues to be released by the GTEx proj-
ect, and the insights it provides into
the regulatory code of our genomes,"
Nature's editors wrote in a recent edi-
torial. "It is an important step towards
the ultimate and ambitious goal of
being able to characterize genetic vari-
ation and gene regulation in all cells of
the human body."
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