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Oct 4, 2011

Clues to Genetic Basis of Autism Uncovered

  • Cold Spring Harbor Laboratory (CSHL) researchers have developed a mouse model of autism that exhibits many of the symptoms seen in humans with the disorder. The scientists believe the mice will prove critical in pinpointing the genetic basis of autism and for elucidating how these alterations affect the brain. The research might also lead to new ways to diagnose children with autism before they develop the full-blown syndrome as well as to design clinical interventions.

    The mice contain a chromosomal defect that corresponds to the 27-gene cluster deletion on human chromosome 16  that is found in some children with autism. CSHL investigator Michael Wigler, Ph.D., discovered the human gene cluster deletion, called 16p11.2, four years ago.

    The mouse model study was carried out by CSHL’s Alea Mills, Ph.D., and colleagues. Details appears in PNAS in a paper titled “Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism.”

    Dr. Mills said, “The idea that this deletion might be causing autism was exciting. So we asked whether clipping out the same set of genes in mice would have any effect.” Her group used a technique known as chromosome engineering to develop the new mouse model system.

    “The chromosome engineering strategy allows us to generate specific, that is, precise, chromosome rearrangements, such as those found in human diseases such as cancer and autism. This approach combines the power of gene targeting and Cre/loxP technology,” Dr. Mills told GEN.

    “We generate the desired rearrangement—in this case deletion and duplication of the region of the mouse genome corresponding to human 16p11.2 lesions found in autism—in mouse embryonic stem cells, and then use these cells to establish mice with the engineered rearrangement. In this way, we have created mouse models with gain (duplication) and loss (deletion) of the same group of genes affected in autism.”

    According to Guy Horev, Ph.D., a postdoctoral fellow in the Mills laboratory and first author of the PNAS paper, “mice with the deletion acted completely different from normal mice.” These mice had a number of behaviors characteristic of autism: hyperactivity, difficulty adapting to a new environment, sleeping deficits, and restricted, repetitive activities.

    Dr. Mills explained that her team is currently generating new mouse models that have “sub-deletions” of the 27-gene interval. “We will then analyze these mice for the same phenotypes we discovered in the full deletion,” she continued.

    Dr. Mills also noted that she and colleagues will be happy to collaborate with other investigators in future experiments. “There is still much work to be done,” she said.


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