Family studies suggest a strong genetic component to autism and
schizophrenia, but the disorders are thought to arise during early
development, making it difficult to study the underlying genetics.
Now researchers at Cold Spring Harbor Laboratory in New York have
created mice with chromosomal abnormalities that mirror those seen in
humans with these disorders, which should make it easier to study the
role of genetics in the development of the brain.
Mouse minds: This image, created from an MRI scan, shows areas of
a mouse's brain affected by chromosomal variations that are tied to
autism and schizophrenia in humans.
In 2008, several research groups identified a section of DNA on
chromosome 16 that appeared to be important for brain development in
humans. Deletions of this section were tied to autism and developmental
delays, while extra copies were linked to autism and schizophrenia.
The new mouse model should let scientists evaluate the effects of
genetic variants at different developmental stages, starting in the
womb. The hope is that these experiments will provide new clues about
the biology of autism and schizophrenia and possibly identify new tests
that could help clinicians diagnose these conditions. "We're especially
interested in finding early biomarkers for these disorders," says Alea Mills, the lead author of the new study, which appears today in the Proceedings of the National Academy of Sciences.
The researchers used a relatively new genetic technique called
chromosome engineering to target the mouse equivalent of the relevant
section of chromosome 16. They then used standard methods to generate
mice that either lacked the section or had extra copies of it.
The chromosomal deletion appeared to have more severe effects than
the duplication, which is consistent with what clinicians have observed
in humans. About half of the mice with the deletion died shortly after
birth, suggesting that this chromosomal section is essential for proper
development. Whether the deletion also contributes to infant mortality
in humans is unknown.
The mice with the deletion also exhibited behaviors associated with
autism, such as restricted, repetitive movements and sleep deficits.
When the researchers conducted MRI scans on the mice, they found the
deletion was associated with increased volume in several brain areas,
particularly in the hypothalamus, the brain region that regulates eating
and sleeping behaviors. The mice with the duplication tended to have
smaller brain areas compared to controls, but the effect was less
pronounced.
The next step for Mills and her colleagues is to figure out the
mechanisms behind the behavioral and anatomical differences they
observed. Most mouse models are created by manipulating a single gene,
but the human and mouse versions of the chromosome 16 section each
contain more than 20 genes, and it's unclear which are the most
important. "There's going to be a need to refine this area down to fewer
genes," says David Miller,
a genetics researcher at Children's Hospital Boston who has researched
the chromosome 16 deletion in humans but was not involved with this
study.
Toward this end, Mills and her team are working on dividing the
chromosomal section into smaller pieces and creating subgroups of their
deletion and duplication in mice. Studying the interactions of so many
genes will be challenging, but it may be necessary to understand
complex, heterogeneous disorders such as autism and schizophrenia. Many
clinics, including Children's Hospital Boston, already have a test that
can detect chromosome 16 deletions or duplications. "The trick is
knowing what it means when you find them," says Miller.
By Erica Westly
From Technology Review
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