16 THE SCIENTIST | the-scientist.com
Jumping
Disease
When Wellcome Sanger Institute genet-
icist Eugene Gardner set out to look for
a specific type of genetic mutation in a
massive database of human DNA, he fig-
ured it’d be a long shot. Transposons—
also known as jumping genes because
they can move around the genome—
create a new mutation in one of every
15 to 40 human births, but that’s across
the entire 3 billion base pairs of nuclear
DNA that each cell carries. The sequenc-
ing data that Gardner was working with
covered less than two percent of that,
with only the protein-coding regions, or
exons, included. Doing a quick calcula-
tion, he determined that, in the best-
case scenario, he could expect to find
up to 10 transposon-generated variants
linked to a developmental disease. And
“we really might get zero,” he says. “This
whole thing might be for naught.”
But Gardner had recently devel-
oped the perfect tool to find the sort
of de novo mobile element insertions
that come about as a result of trans-
poson movements and are often over-
looked in genetic screens and analyses.
As a graduate student in Scott Devine’s
lab at the University of Maryland, Bal-
timore’s Institute for Genome Sciences,
he had spent many hours making the
software for the mobile element loca-
tor tool he dubbed MELT. The pro-
gram was easy to use, so when Gardner
moved across the Atlantic for a postdoc
in Matthew Hurles’s lab at Sanger near
Cambridge and gained access to a data-
base of exomes from 13,000 patients
with developmental disorders, he fig-
ured running the tool was worth a t r y.
Of those 13,000, Gardner focused
on 9,738 people in the Deciphering
Developmental Disorders (DDD) study
whose parents’ exomes had also been
sequenced, making it easier to single
out variants present in the child but not
in mom and dad. And as it turned out,
he did get some hits. MELT picked up
40 potentially transposon-generatedvariants, which Gardner sat down at
his computer to review using the raw
sequencing data. Nine appeared to be
true de novo mobile element insertions.
“I remember being in my desk doing the
visualization of all the putative de novo
variants after I got the first results off the
pipeline,” he recalls. “I remember being
excited: I think I might have found a
diagnostic de novo!”
Discussing the literature on the genes
affected by such insertions with clinicians
and other colleagues, Gardner narrowed
the list down to four insertions found in
genes that may be causing or contribut-
ing to four different patients’ disorders
(Nat Commun, 10:4630, 2019). He sent
these results off to the physicians who
had referred each of the patients to the
database, and all the doctors confirmed
that the results made sense to them given
what had been published on those genes
and what they knew about other cases
involving patients with mutations in the
same sequences. In one case, the physi-cian had already linked the patient’s dis-
order to the gene Gardner had identified;
in the other three cases, the patients were
still undiagnosed.
“There is tremendous value for these
families that get a diagnosis,” says human
geneticist Dan Koboldt, who has collabo-
rated with Hurles in the past and has used
MELT in his studies of rare disease at the
Steve and Cindy Rasmussen Institute for
Genomic Medicine at Nationwide Chil-
dren’s Hospital in Columbus, Ohio, but
who was not involved in Gardner’s recent
study. A genetic answer not only can help
physicians connect patients to appropriate
medical and counseling resources; it puts
an end to the diagnostic odyssey that fami-
lies affected by rare disease often endure.
What’s more, the finding of four
potentially causative hits out of the
nearly 10,000 cases provides first esti-
mate of how commonly such mobile ele-
ment insertions underlie developmen-
tal disorders. “What’s interesting about
this study is that it’s taking a very broadNOTEBOOKANDRZEJ KRAUZE