Brain 311 T.
(photo credit: Thinkstock/Imagebank)
The neuro-cognitive, developmental disease of autism, whose symptoms appear
during the first three years of a child’s life, have for years been thought to
involve a number of genes, but there was no concrete proof.
Now a team at
Cold Spring Harbor Laboratory (CSHL) in New York, led by an Israeli doing
postdoctoral fellowship work on mice, has for the first time provided functional
evidence that inheriting fewer copies of genes on chromosome #16 leads to
Dr. Guy Horev, of the Weizmann Institute of Science
in Rehovot, worked at CSHL with Prof. Alea Mills and colleagues on mouse
models of autism that they created using chromosome engineering. The study, of
which Horev was the first author, has just appeared in Proceedings of the
National Academy of Sciences (PNAS).
Autism, or pervasive developmental
disorder, is a physical condition connected to abnormal chemistry and biology in
the brain and affects the brain’s normal development of social and communication
skills. Genes have for years been implicated, as identical twins have a much
higher risk than fraternal twins, or siblings, to both have autism.
with the deletion acted completely differently from normal mice,” said Horev,
who is working at Mills’s lab. These mice had a number of behaviors
characteristic of autism – hyperactivity, inadequate sleep, difficulty adapting
to a new environment and restricted, repetitive behaviors.
normally inherit one copy of a gene from each parent. We had the tools to see
whether copy number changes found in kids with autism were causing the
syndrome,” added Mills.
In 2007, CSHL Prof. Michael Wigler revealed that
some children with autism have a small deletion on chromosome 16, affecting 27
genes in a region of our genomes referred to as 16p11.2.
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The deletion –
which causes children to inherit only a single copy of the 27-gene cluster – is
one of the most common copy number variations (CNVs) associated with
“The idea that this deletion might be causing autism was
exciting,” recalled Mills. “So we asked whether clipping out the same set of
genes in mice would have any effect.”
After engineering mice that had a
chromosome defect corresponding to the human 16p11.2 deletion found in autism,
the researchers analyzed these models for a variety of behaviors, as the
clinical features of autism often vary widely from patient to patient, even
within the same family. Rodents that had been engineered to carry an extra copy,
or duplication, of the 16p11.2 region did not have these characteristics, but
instead, had the reciprocal behaviors.
For each behavior, the deletion
had a more dire consequence than the duplication, indicating that gene loss was
more severe. This might explain why 16p11.2 duplications are detected much more
frequently than deletions within the human population, and why patients with
16p11.2 deletions tend to be diagnosed earlier than those with duplications, the
The mouse models also revealed a potential link between
16p11.2 deletion and survival, as about half the mice died following
Whether these findings extend to the human population might be
answered by future studies that investigate the link between this deletion and
unexplained cases of infant death.
The researchers used MRI scans to
identify specific regions of the brain that were changed in the autism models,
revealing that eight different parts of the brain were affected. Horev and his
colleagues are now working to identify which gene or group of genes among the 27
that are located within the deleted region is responsible for the behaviors and
brain alterations observed.
They believe their findings on mice will be
invaluable for pinpointing the genetic basis of autism and for elucidating how
these alterations affect the brain.
Their research could also be used for
designing ways to diagnose children with autism before they develop the
full-blown syndrome, as well as for designing clinical interventions.
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